Clinical trial NCT03116841
Conditions: Reflux Esophagitis
Sponsor: Takeda
Start date: 2017-08-02; Completion date: 2017-12-20
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to exploratorily evaluate the effect of vonoprazan 20 mg on sleep disturbance of patients with reflux esophagitis, who have heartburn and/or regurgitation and ≥ 6.0 in the Pittsburgh Sleep Quality Index (PSQI) global score despite the maintenance treatment with PPI other than vonoprazan.

Detailed description:
The purpose of this study is to evaluate the effect of vonoprazan on sleep disturbance in the participants under maintenance treatment for reflux esophagitis with proton pump inhibitor (PPI) other than vonoprazan after initial treatment.

Participants who have been diagnosed as reflux esophagitis based on Los Angeles (LA) Classification Grades A to D, undergoing maintenance treatment with PPI other than vonoprazan after initial treatment, and with Pittsburgh Sleep Quality Index (PSQI) global score \>= 6.0 at enrolment (VISIT 1) will be eligible for study entry and will be administered vonoprazan 20 mg once daily for 8 weeks.

Planned number of participants is 25. The study period is 9 weeks. The number of visits is 6visits.

Arms: arm 1: Vonoprazan 20 mg orally administered once daily
Interventions: intervention 1: Vonoprazan
Intervention descriptions: intervention 1: Vonoprazan 20 mg

Protocol documents:
Prot_000.pdf: 
 
 
Title: Vonoprazan Study of Investigating the Effect on Sleep Disturbance Associated 
with Reflux Esophagitis - Exploratory Evaluation (VISTAEXE) 
 
NCT Number: NCT03116841 
Protocol Approve Date: 28-Mar-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. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


 
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PROTOCOL 
 
 
 
 
 
 
 
Vonoprazan study of investigating the effect on sleep disturbance associated with reflux 
esophagitis- exploratory evaluation 
(VISTAEXE) 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10, Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
Vonoprazan-4006 (MACS-2016-101812) 
Version Number 
1.0 
Study drug: 
Vonoprazan fumarate 
Creation date 
March 28, 2017 
 
 
 
 


 
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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 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES 
1.1 
Clinical Study Principles 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this protocol and also in accordance with the 
following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, 
Science and Technology and the Ministry of Health, Labour and Welfare, December 
22, 2014). 
 International Conference on Harmonisation E6 Good Clinical Practice: 
Consolidated Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws 
and conflict of interest guidelines. 
 
1.2 
Clinical Study Implementation 
This study will be conducted in accordance with the requirements of this protocol 
designed and prepared by the sponsor and also in accordance with the following. Other 
study administrative structures are shown in the annexes. 
 
Sponsor: 
Japan Medical Affairs,  
Japan Pharma Business Unit,  
Takeda Pharmaceutical Company Limited 
 
The sponsor shall be responsible for matters related to planning/preparation, 
implementation/operation, and results/reporting in this study. Methods of supervision of 
the contractor entrusted with the services related to this study will be described in the 
procedure to be prepared separately. 
Expenses* required for the operation of this study will be paid by the sponsor. 


 
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*:  Based on the “Consignment Service Contract,” expenses incurred for the services of 
Office of Clinical Study, monitoring, registration/allocation center, and statistical 
processing shall be paid to the contractor entrusted with services related to this study. 
Expenses agreed by the study site shall be paid to the site based on the “Research 
Expense Standard.” 
 
Chair of Steering Committee: 
 
1.3 
Contact Information on the Protocol 
Study office
 
 
 
PPD
PPD
PPD


 
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SIGNATURES 
The signature of MACS program head, Medical Director of Japan Medical Affairs and the 
responsible statistician can be found on the signature page. 
 
 
 
 
 
 
 
 
PPD
PPD


 
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TABLE OF CONTENTS 
 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES ........................................................................................................... 3 
1.1 
Clinical Study Principles ................................................................................... 3 
1.2 
Clinical Study Implementation .......................................................................... 3 
1.3 
Contact Information on the Protocol ................................................................. 4 
2.0 
STUDY SUMMARY ............................................................................................ 11 
3.0 
LIST OF ABBREVIATIONS ............................................................................... 15 
4.0 
INTRODUCTION ................................................................................................. 17 
4.1 
Background ...................................................................................................... 17 
4.2 
Rationale for the Proposed Study .................................................................... 18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 19 
5.1 
Objectives ........................................................................................................ 19 
5.2 
Endpoints ......................................................................................................... 19 
5.2.1 Primary Endpoint ....................................................................................... 19 
5.2.2 Secondary Endpoints ................................................................................. 19 
5.2.3 Additional Endpoint .................................................................................. 20 
6.0 
STUDY DESIGN AND DESCRIPTION ............................................................. 21 
6.1 
Study Design ................................................................................................... 21 
6.2 
Justification for Study Design ......................................................................... 22 
6.3 
Premature Termination of Study or Study Site ............................................... 23 
6.3.1 Criteria for Premature Termination of the Study....................................... 23 
6.3.2 Criteria for Premature Termination of Study Sites .................................... 23 
6.3.3 Procedures for Premature Termination or Suspension of the Study or 
the Participation of Study Sites ................................................................. 23 
6.4 
Procedures for Protocol Revision .................................................................... 23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS ............................................................................................................ 25 
7.1 
Inclusion Criteria ............................................................................................. 25 
7.2 
Exclusion Criteria ............................................................................................ 26 


 
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7.3 
Excluded Medications ..................................................................................... 27 
7.4 
Subject Management ....................................................................................... 27 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ................................ 28 
7.6 
Procedures for Discontinuation or Withdrawal of a Subjects ......................... 29 
8.0 
STUDY TREATMENT ......................................................................................... 30 
8.1 
Study Drug ....................................................................................................... 30 
8.1.1 Dose and Regimen ..................................................................................... 30 
8.1.2 Overdose .................................................................................................... 30 
8.2 
Prescription of the Study Drug ........................................................................ 30 
9.0 
STUDY PLAN ...................................................................................................... 31 
9.1 
Study Procedures ............................................................................................. 31 
9.1.1 Informed Consent Procedure ..................................................................... 31 
9.1.2 Demographics and Medication History ..................................................... 31 
9.1.3 Physical Examination Procedure ............................................................... 31 
9.1.4 Weight, Height and Body Mass Index ...................................................... 31 
9.1.5 Documentation of Concomitant Drugs ...................................................... 32 
9.1.6 Documentation of Concurrent Medical Conditions................................... 32 
9.1.7 Questionnaire About Sleep ........................................................................ 32 
9.1.8 Actigraph ................................................................................................... 32 
9.1.9 Heartburn and Regurgitation ..................................................................... 33 
9.1.10 Procedures for Clinical Laboratory Samples ............................................. 34 
9.1.11 Pregnancy .................................................................................................. 34 
9.1.12 Record of Subjects Who Are Withdrawn Before Start of 
Administration ........................................................................................... 35 
9.2 
Monitoring Subject Treatment Compliance .................................................... 35 
9.3 
Schedule of Observations and Procedures ...................................................... 36 
9.3.1 Screening [VISIT 1] .................................................................................. 36 
9.3.2 At the Baseline/Start of Administration [VISIT 2] ................................... 36 
9.3.3 At Week 2 [VISIT 3] ................................................................................. 37 
9.3.4 At Week 4 [VISIT 4] ................................................................................. 37 
9.3.5 At Week 6 [VISIT 5] ................................................................................. 37 


 
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9.3.6 At the End of Study [VISIT 6] or at the Early Termination ...................... 38 
10.0 
ADVERSE EVENTS ............................................................................................ 39 
10.1 
Definitions ....................................................................................................... 39 
10.1.1 AEs39 
10.1.2 Additional Points to Consider for AEs ...................................................... 39 
10.1.3 SAEs .......................................................................................................... 41 
10.1.4 Intensity of AEs ......................................................................................... 42 
10.1.5 Causality of AEs ........................................................................................ 42 
10.1.6 Relationship to Study Procedures .............................................................. 43 
10.1.7 Start Date ................................................................................................... 43 
10.1.8 Stop Date ................................................................................................... 43 
10.1.9 Action Concerning Study Drug ................................................................. 43 
10.1.10Outcome .................................................................................................... 44 
10.2 
Procedures ....................................................................................................... 45 
10.2.1 Collection and Reporting of AEs .............................................................. 45 
10.2.2 Collection and Reporting of SAEs ............................................................ 45 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................... 46 
10.2.4 Reporting of Additional Information Concerning AEs ............................. 46 
10.3 
Follow-up of SAEs .......................................................................................... 47 
10.3.1 Reporting of SAEs, etc., to IECs, etc., and Regulatory Authorities .......... 47 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................... 49 
11.1 
Steering Committee ......................................................................................... 49 
12.0 
DATA HANDLING AND RECORDKEEPING .................................................. 50 
12.1 
CRFs ................................................................................................................ 50 
12.2 
Timing of Data Entry into the EDC System .................................................... 51 
12.3 
Storage and Disposal of Specimens, Information, etc. .................................... 51 
13.0 
STATISTICAL METHODS ................................................................................. 52 
13.1 
Statistical and Analytical Plans ....................................................................... 52 
13.1.1 Analysis Sets ............................................................................................. 52 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ................ 52 
13.1.3 Efficacy Analysis ....................................................................................... 52 


 
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13.1.4 Safety Analysis .......................................................................................... 53 
13.1.5 Other Analysis ........................................................................................... 54 
13.2 
Interim Analysis and Criteria for Early Termination ...................................... 54 
13.3 
Determination of Sample Size ......................................................................... 54 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 56 
14.1 
Study-Site Monitoring Visits ........................................................................... 56 
14.2 
Deviation from the Ethical Guideline for Clinical Research and the 
Protocol ............................................................................................................ 56 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ...................... 56 
15.0 
ETHICAL ASPECT OF THE STUDY ................................................................. 58 
15.1 
IEC Approval ................................................................................................... 58 
15.2 
Conflict of Interests ......................................................................................... 59 
15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Subjects ............................................................................................................ 59 
15.4 
Personal Information of Subjects .................................................................... 60 
15.5 
Consultation for Subjects or Persons Related to the Study ............................. 61 
15.6 
Financial Burden or Reward to Subjects ......................................................... 61 
15.7 
Benefits and Inconveniences to Subjects......................................................... 61 
15.7.1 Benefits to Subjects ................................................................................... 61 
15.7.2 Inconveniences to Subjects ........................................................................ 61 
15.8 
Attribution of Study Results and Access Rights ............................................. 61 
15.8.1 Attribution of Study Results ...................................................................... 61 
15.8.2 Data Access Rights .................................................................................... 62 
15.9 
Reporting of Results, Publication, Disclosure, and Clinical Study 
Registration Policy .......................................................................................... 62 
15.9.1 Reporting of Results, Publication and Disclosure ..................................... 62 
15.9.2 Clinical Study Registration ........................................................................ 62 
15.9.3 Clinical Study Results Disclosure ............................................................. 63 
15.10 Insurance and Compensation for Injury .......................................................... 63 
16.0 
REFERENCES ...................................................................................................... 64 
 
 


 
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LIST OF IN-TEXT TABLES 
Table 9.a Question for Reflux Esophagitis Related Subjective Symptoms ...................... 33 
Table 9.b Severity Classifications of Reflux Esophagitis Related Symptoms .................. 34 
Table 9.c Clinical Laboratory Tests .................................................................................. 34 
Table 10.a Takeda Medically Significant Adverse Event List .......................................... 42 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a Schematic of Study Design .............................................................................. 22 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ................................................................... 66 
Appendix B 
Responsibilities of the principal investigator ............................................ 67 
Appendix C 
Questionnaire about sleep and symptoms ................................................. 69 
 


 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Study Drug: 
Vonoprazan fumarate 
Title of Protocol: 
Vonoprazan study of investigating the effect on sleep disturbance associated with reflux esophagitis- 
exploratory evaluation 
Study Number: Vonoprazan-4006 (MACS-2016-101812) 
Study Design: 
This is an interventional, exploratory, multicenter, open-label study to evaluate the effect of the 
potassium-competitive acid blocker (P-CAB) vonoprazan on sleep disturbance in subjects under 
maintenance treatment for reflux esophagitis with proton pump inhibitors (PPIs). 
Subjects who have been diagnosed as reflux esophagitis based on Los Angeles (LA) Classification1) 
Grades A to D, undergoing maintenance treatment with a PPI after initial treatment, and with Pittsburgh 
Sleep Quality Index (PSQI)2) 3) global score ≥ 6.0 at the baseline/start of administration (VISIT 2) will be 
eligible for study entry and will be administered vonoprazan 20 mg once daily for 8 weeks. 
Planned number of subjects is 25.  
The study period is 9 weeks. The number of visits is 6visits. 
Objectives: 
To evaluate the effect of vonoprazan 20 mg on sleep disturbance of patients with reflux esophagitis, who 
have heartburn and/or regurgitation and ≥ 6.0 in the PSQI global score despite maintenance treatment 
with PPIs. 
Subject Population: 
Patients with reflux esophagitis 
Number of Subjects: 
25 subjects 
Number of Sites: 
Approximately 5 sites 
Dose Level: 
Vonoprazan 20 mg orally administered once daily 
Route of Administration: 
Oral 
Duration of Treatment: 
8 weeks 
Period of Evaluation: 
9 weeks 
Criteria for Inclusion: 
Subjects fulfilling all of the following criteria shall be included in this study. 
1. 
Subjects who completed the initial treatment with PPIs (esomeprazole, omeprazole, rabeprazole or 
lansoprazole) and have received high dose PPIs (esomeprazole 20 mg, omeprazole 20 mg, 


 
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rabeprazole 10 mg or lansoprazole 30 mg) for more than 8 weeks at the time of informed consent as 
maintenance treatment for LA Classification Grades A to D reflux esophagitis.  
2. 
Subjects who have heartburn and/or regurgitation. 
3. 
Subjects with reflux esophagitis related sleep disturbance, fulfilling at least one of following in a 
week before the baseline/start of administration.  
 
Difficulty in falling asleep for ≥ 3 nights  
 
Nocturnal awaking or early morning awaking for ≥ 3 nights 
4. 
Subjects whose heartburn and/or regurgitation at the time of informed consent were alleviated from 
initial treatment. 
5. 
Subjects with PSQI global score ≥ 6.0  
6. 
Subjects who, in the opinion of the investigator, are capable of understanding the content of the 
study and complying with the protocol requirements. 
7. 
Subjects who can sign and date an informed consent form and information sheet prior to the 
initiation of the study procedures.  
8. 
Male or female subjects aged 20 years or older at the time of informed consent 
9. 
Therapeutic category: Ambulatory 
Criteria for Exclusion: 
Subjects fulfilling any of the following criteria will be excluded from this study. 
1. 
Subjects with Zollinger-Ellison syndrome. 
2. 
Subjects with diseases that affect sleep (chronic obstructive pulmonary disease, bronchitis asthma, 
sleep apnea syndrome, mental disorder, etc.) 
3. 
Nightshift workers. 
4. 
Subjects who have a plan to travel beyond three time zones during the study. 
5. 
Subjects with a history of concurrent or suspicious functional dyspepsia or functional heartburn, 
based on Rome IV criteria. 
6. 
Subjects with history of surgery or treatment affecting gastroesophageal reflux (fundoplication or 
dilation for esophageal stenosis [except for Schatzki's ring], etc.). 
7. 
Subjects with an esophagus-related complication (eosinophilic esophagitis, esophageal varices, 
scleroderma, viral or fungal infection, esophageal stenosis, etc.), a history of radiotherapy or 
cryotherapy of the esophagus, a caustic or physiochemical trauma (esophageal sclerotherapy, etc.). 
However, participants with Schatzki's ring (mucosal tissue ring around inferior esophageal 
sphincter) or Barrett's esophagus are allowed to be included.  
8. 
Subjects with a history of gastrectomy, gastrointestinal resection or vagotomy. 
9. 
Subjects who took antidepressant agents or anti-anxiety agents within 8 weeks before the time of 
informed consent. 
10. Subjects who took H2 receptor antagonist within 8 weeks before the time of informed consent. 


 
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11. Subjects planning to take prohibited concomitant medications during the study period. 
12. Subjects who have any of the following abnormal clinical laboratory test values at the screening 
(VISIT 1): 
ALT or AST > ULN 
Bilirubin (Total bilirubin) > ULN 
13. Subjects with a malignant tumor. 
14. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant. 
15. Subjects who have serious renal diseases. 
16. Subjects with the conditions listed under administration contraindication in the vonoprazan package 
insert. 
17. Subjects participating in other clinical studies. 
18. Subjects who have been determined as inappropriate subjects by the investigator. 
Criteria for Evaluation and Analyses: 
< Primary endpoint > 
 
Changes in PSQI global score 
[End of study (VISIT 6) – Baseline/Start of Administration (VISIT 2) ] 
< Secondary endpoints > 
Efficacy endpoints: 
 
Changes in PSQI global score 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
 
Percentage of subjects with PSQI global score <6.0 at Week 4 (VISIT 4) and the end of 
study (VISIT 6) 
 
Changes in 6 component scores of PSQI (Sleep quality, Sleep latency, Sleep duration, 
Habitual sleep efficiency, Sleep disturbances, Daytime dysfunction) 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[End of study (VISIT 6) – Baseline/Start of Administration (VISIT 2)]  
 
Changes in number of nocturnal awakenings (assessed by questionnaire) 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[End of study (VISIT 6) – Baseline/Start of Administration (VISIT 2)]  
 
Changes in actigraph-measured sleep efficiency, sleep latency, and number of nocturnal 
awakenings 
[Week 4 (mean value during 7 days before VISIT 4) – Baseline/Start of Administration 
(mean value during 7 days before VISIT 2)] 
[End of study (mean value during 7 days before VISIT 6) – Baseline/Start of 


 
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Administration (mean value during 7 days before VISIT 2)] 
Safety endpoints: 
 
Adverse events 
< Additional endpoint > 
 
Changes in nighttime heartburn and regurgitation (nighttime and daytime) 
Statistical Considerations: 
Descriptive statistics of primary endpoint and 95% confidence interval of the mean are calculated. 
Statistically significance of the change is assessed using paired t-test. 
Sample Size Justification : 
In the clinical study assessed effect of esomeprazole on sleep disturbance caused by gastroesophageal 
reflux disease, mean (SD) changes in PSQI global score from baseline at 4 weeks of treatment with 
esomeprazole 40 mg, 20 mg, and placebo were -3.5 (3.6), -3.8 (3.8), and -2.0 (3.7), respectively4). In the 
similar clinical study with dexlansoprazole, changes in PSQI global score from baseline at 4 weeks of 
treatment with dexlansoprazole 30 mg, and placebo were -2.70 (3.08), and -1.35 (3.23), respectively5). 
These results suggest that effect sizes during treatment with PPI and placebo are 0.87-1.00 and 0.42-0.54, 
respectively. 
Although subjects for the present study are different from these studies which excluded subjects who 
received treatment with PPI in a certain period before randomization, we can assume that effect size of 
the present study will be less than PPI and greater than placebo. So we assumed effect size of changes in 
PSQI global score from baseline at 8 weeks of treatment will be 0.75. 
21 subjects are required as number of subjects for evaluation of primary endpoint to obtain 90% of power 
using estimated effect size. Considering drop out of certain subject, 25 subjects are required as enrolled 
subject. 
 


 
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3.0 
LIST OF ABBREVIATIONS  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
COI 
conflict of interest 
CRO 
contract study organization 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
LA Classification 
Los Angeles Classification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAB 
nocturnal acid breakthrough 
pH4 HTR 
pH4 Holding Time Ratio 
PPI 
proton pump inhibitor  
PSQI 
Pittsburgh Sleep Quality Index 
TEAE 
treatment emergent adverse event 
 
The terms used in this protocol are defined as follows: 
Study site: 
A corporation, governmental agency and sole proprietor conducting the study, excluding cases 
where only a part of the services related to storage of samples/information, statistical processing and 
other studies are entrusted. 
Investigators: 
Principal investigators and other parties involved in conduct of the study (including operations at 
institutions involved in collection/distribution of samples/information). Those involved only in 
providing existing samples/information outside the study sites and those engaged in part of the 
entrusted operations related to the study are excluded. 
Principal Investigator: 
An investigator who is engaged in implementation of the study and integrates the operations 
involved in this study at an affiliated study site. 


 
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Chief executive of the study site: 
A representative of a corporation, head of a governmental agency, or a sole proprietor 
Subject: 
A subject who meets any of the following:  
1. 
Subjects being studied (including those who have been asked to be studied)  
2. 
Subjects from whom existing samples/information to be used in the study have been obtained. 
 


 
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4.0 
INTRODUCTION 
4.1 
Background 
 
Reflux esophagitis is caused by reflux of gastric acid due to relaxation of the inferior 
esophageal sphincter, reduced esophageal clearance function, impaired esophageal 
mucosal defense mechanisms and results in the symptoms such as heartburn or 
regurgitation. Severity of the symptoms caused by reflux esophagitis is correlated with 
the duration of esophageal exposure to acid and pH of refluxed gastric contents. In the 
initial treatment of reflux esophagitis, therefore, PPI, which can more strongly suppress 
gastric acid secretion, is recommended as the first choice6). 
PPI well suppresses gastric acid secretion during daytime, however, it is known that 
some patients experience nocturnal acid breakthrough (NAB) under the treatment with 
PPI7). 
 
It is considered that NAB is related to sleep disturbance and the higher prevalence of 
sleep disturbance among the patients with reflux esophagitis was also reported 8). Sleep 
disturbance can cause decreased activity or productivity and affect patients' quality of 
life. Thus, the efficacy of PPI on sleep disturbance caused by reflux esophagitis has 
been recently investigated in various ways. 
 
In the study conducted in the US among the patients with moderate-to-severe nighttime 
heartburn and GERD-related sleep disturbances, 34.3% of the patients treated with 
esomeprazole 20 mg achieved nighttime heart burn relief and 10.4% of the patients 
treated with placebo and the difference was statistically significant (p<0.0001). 
Furthermore, the percentage of the patients achieved relief of GERD-related sleep 
disturbance was 71.5% in esomeprazole group and 55.2% in placebo group (p=0.006). 
In addition, change in PSQI global score from baseline at 4 weeks of treatment was 
-2.93 in esomeprazole group and -1.80 in placebo group (p=0.0034)9). 
In Japan, it has been reported that the sleep disturbance in the patients with reflux 
esophagitis was improved by PPI administration in some studies10)-12) and there was a 
study which showed significant improvement when stratified by the existence of acid 
reflux symptoms13). 
 
On the other hand, it has been also reported that more than 80% of patients taking PPI 
to treat GERD experience some kind of nocturnal symptoms14). For the treatment of 
sleep disturbance related to reflux esophagitis, several therapeutic options such as PPI 


 
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administration before dinner, double-dose PPI twice daily, and administration of an 
additional H2-receptor antagonist have been investigated. This indicates that the 
treatment to more strongly suppress gastric acid and alleviate NAB is required in 
clinical practice8). 
 
Vonoprazan is an acid suppressant in a new category that suppresses gastric acid 
secretion more strongly and more continuously than conventional PPIs by reversibly 
inhibiting H+, K+ -ATPase in the final stage of acid secretion in a K + -competitive 
manner. In Japanese clinical pharmacology study in healthy adult, investigating with 
crossover design between esomeprazole and vonoprazan, and rabeprazole and 
vonoprazan, daytime pH4 Holding Time Ratio (pH4 HTR) on 7 days after 
administration was 77.6% in esomeprazole group and 96.5% in vonoprazan group and 
night-time pH4 HTR was 44.8% in esomeprazole group and 75.2% in vonoprazan 
group. In cross-over comparison with rabeprazole, daytime pH4 HTR on Day 7 was 
76.1% in rabeprazole group and 98.8% in vonoprazan group and night-time pH4 HTR 
was 54.1% in rabeprazole group and 88.8% in vonoprazan group15).  
4.2 
Rationale for the Proposed Study 
It is expected that vonoprazan can improve sleep disturbance caused by NAB better 
than PPIs due to its strong acid-inhibitory effect, however this has not been investigated 
so far. 
Accordingly, in the present study, the effect of vonoprazan will be evaluated in patients 
who have sleep disturbance despite the treatment with PPIs for reflux esophagitis. 
 


 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
To evaluate the effect of vonoprazan 20 mg on sleep disturbance of patients with reflux 
esophagitis, who have heartburn and/or regurgitation and ≥ 6.0 in the PSQI global score 
despite maintenance treatment with PPIs. 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
 
Changes in PSQI global score 
[End of Study (VISIT 6) – Baseline/Start of Administration (VISIT 2)] 
5.2.2 Secondary Endpoints 
Efficacy endpoints: 
 
Changes in PSQI global score 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
 
Percentage of subjects with PSQI global score <6.0 at Week 4(VISIT 4) and 
the End of Study (VISIT 6) 
 
Changes in 6 component scores of PSQI (Sleep quality, Sleep latency, Sleep 
duration, Habitual sleep efficiency, Sleep disturbances, Daytime 
dysfunction) 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[End of Study (VISIT 6) – Baseline/Start of Administration (VISIT 2)]  
 
Changes in number of nocturnal awakenings (assessed by questionnaire) 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[End of Study (VISIT 6) – Baseline/Start of Administration  (VISIT 2)]  
 
Changes in actigraph-measured sleep efficiency, sleep latency, and number 
of nocturnal awakenings 
[Week 4 (mean value during 7 days before VISIT 4) – Baseline/Start of 
Administration (mean value during 7days before VISIT 2)] 
 
[End of Study (mean value during 7 days before VISIT 6) – Baseline/Start 
of Administration (mean value during 7 days before VISIT 2)] 
 


 
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Safety endpoints: 
 
Adverse events 
5.2.3 Additional Endpoint 
 
Changes in nighttime heartburn and regurgitation (daytime and nighttime) 


 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
<Study design> 
This is an interventional, exploratory, multicenter, open-label study to evaluate the 
effect of the P-CAB vonoprazan on sleep disturbance in subjects under maintenance 
treatment for reflux esophagitis with PPIs. 
Subjects who have been diagnosed as reflux esophagitis based on LA Classification 
1) Grades A to D, undergoing maintenance treatment with a PPI after initial 
treatment, and with PSQI 2) 3) global score ≥ 6.0 at the baseline/start of 
administration (VISIT 2) will be eligible for study entry and will be administered 
vonoprazan 20 mg once daily for 8 weeks. 
Planned number of subjects is 25 subjects.  
The study period is 9 weeks. The number of visits is 6visits. 
<Treatment> 
1. Drugs to be administered 
Vonoprazan 20 mg will be administered.  
2. Start of study drug administration and dose 
After acquisition of informed consent, subjects determined eligible for the study in 
accordance with the inclusion and exclusion criteria will receive vonoprazan 20 mg 
orally (once daily). Study drug will be administered at the same time as it was for 
the previous PPI. 
3. Duration of treatment 
Vonoprazan 20 mg: 8 weeks 
<Planned duration of participation and number of visits for subjects> 
The study period is 9 weeks from the screening to the end of study.  
The number of visits is 6. Subjects will visit study sites at the time of screening 
(Week -1), baseline/start of administration (Week 0), Week 2, 4, 6 and the end of study 
(Week 8). 
<Planned number of subjects> 
25 subjects 


 
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<Number of study sites> 
Approximately 5 sites 
 
A schematic of the study design is included as Figure 6 (a). A schedule of assessments 
is listed in Appendix A. 
 
<Outline of the study design> 
Study period: 9 weeks 
Number of visits: 6 
 
Informed 
Consent 
Screening 
Baseline/Start of 
Administration 
 
 
 
End of 
Study 
 
 
Week -1 
Week 0 
Week 2 
Week 4 
Week 6 
Week 8 
 
 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
 
 
 
PSQI 
 
 
 
 
PSQI 
 
 
PSQI 
ACT(b)
ACT(b)
ACT(b) 
 
Initial 
Treatment(a) 
Maintenance Treatment(a) 
Vonoprazan 20 mg 
 
(a) 
Treatment of PPIs (in a routine medical practice). 
Subjects who have been under maintenance treatment for more than 8 weeks at the time of screening will be included.  
(b) 
ACT: Evaluation of Actigraph 
Figure 6.a Schematic of Study Design 
6.2 
Justification for Study Design 
(1) Justification for study design 
Since the objective of this study is to evaluate the effect of vonoprazan 20 mg on sleep 
disturbance of subjects with reflux esophagitis, it is designed as a multicenter, 
open-label study. 
(2) Justification for dose and administration method 
Vonoprazan 20 mg will be orally administered once daily to subjects with reflux 
esophagitis in accordance with the package insert. 
(3) Justification for the planned number of subjects 


 
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Refer to Section 13.3. 
 
6.3 
Premature Termination of Study or Study Site 
6.3.1 Criteria for Premature Termination of the Study 
The sponsor should immediately discontinue the study when at least one of the 
following criteria is applicable: 
 
New information or other evaluation regarding the safety or efficacy of the study 
drug that indicates a change in the known risk/benefit profile for the product, such 
that the risk/benefit is no longer acceptable for subjects participating in the study. 
 
Significant violation of Good Clinical Practice (GCP) that compromises subject 
safety. 
6.3.2 Criteria for Premature Termination of Study Sites 
A study site may be terminated prematurely if the site (including the principal 
investigator) is found in significant violation of the Ethical Guideline for Clinical 
Research, protocol, or contractual agreement, is unable to ensure adequate performance 
of the study or as otherwise permitted by the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor or a study site committee such an independent ethics 
committee (IEC) elects to terminate or suspend the study or the participation of a study 
site, a study-specific procedure for early termination or suspension will be provided by 
the sponsor; the procedure will be followed by applicable study sites during the course 
of termination or study suspension. 
6.4 
Procedures for Protocol Revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to 
revise the protocol. 
The principal investigator of each study site shall be informed of the details of each 
protocol revision. Investigators shall confirm the content of the revision of the protocol 
and submit an agreement form to the sponsor as evidence of agreement with the 
protocol revision. 


 
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[Protocol revision is required in the following cases:] 
1. Change or addition of objectives 
2. Change in or addition of efficacy or safety evaluation methods 
3. More frequent or additional laboratory tests for which subjects incur additional 
expenses or changes in laboratory test methods 
4. Change in dose 
5. Significant change in or addition of inclusion and/or exclusion criteria 
6. Change in the planned number of subjects 
7. Change in plans or in description of the protocol due to serious adverse events or 
other reasons 
8. Change which is considered as a significant change, as a result of discussion 
between the sponsor and the chair of the Steering Committee 
 
Upon notification, the principal investigator at each study site shall submit the revised 
contents to the relevant committees (such as an institutional ethics review committee), 
for review and approval as necessary according to institutional regulations. 


 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
The investigators shall confirm all the inclusion/exclusion criteria prior to enrollment. 
7.1 
Inclusion Criteria 
Subjects fulfilling all of the following criteria shall be included in this study. 
1. Subjects who completed the initial treatment with PPIs (esomeprazole, omeprazole, 
rabeprazole or lansoprazole) and have received high dose PPI (esomeprazole 20 mg, 
omeprazole 20 mg, rabeprazole 10 mg, or lansoprazole 30 mg) for more than 8 
weeks at the time of informed consent as maintenance treatment for LA 
Classification Grades A to D reflux esophagitis.  
2. Subjects who have heartburn and/or regurgitation. 
3. Subjects with reflux esophagitis related sleep disturbance, fulfilling at least one of 
following in a week before the baseline/start of administration.  
 
Difficulty in falling asleep for ≥ 3 nights 
 
Nocturnal awaking or early morning awaking for ≥ 3 nights 
4. Subjects whose heartburn and/or regurgitation at the time of informed consent were 
alleviated from initial treatment. 
5. Subjects with PSQI global score ≥ 6.0  
6. Subjects who, in the opinion of the investigators, are capable of understanding the 
content of the study and complying with the protocol requirements. 
7. Subjects who can sign and date an informed consent form and information sheet 
prior to the initiation of the study procedures. 
8. Male or female subjects aged 20 years or older at the time of informed consent 
9. Therapeutic category: Ambulatory 
[Justification of inclusion criteria] 
1-3, 5 
These were set to include the subjects with sleep disturbance caused by 
heartburn and/or regurgitation even under the maintenance treatment, 
despite his or her healed mucosal injury by the initial treatment. 
4 
This criterion was set to include the subjects who respond to PPI.  
6, 7, 9 
These were set as fundamental items for the study. 


 
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8. 
This was set to evaluate in both genders. The lower age limit was set to 
20 years to allow subjects to make a voluntary decision regarding their 
participation in this study. 
7.2 
Exclusion Criteria 
Subjects fulfilling any of the following criteria will be excluded from this study. 
1. Subjects with Zollinger-Ellison syndrome. 
2. Subjects with diseases that affect sleep (chronic obstructive pulmonary disease, 
bronchitis asthma, sleep apnea syndrome, mental disorder, etc.) 
3. Nightshift workers. 
4. Subjects who have a plan to travel beyond three time zones during the study. 
5. Subjects with a history of concurrent or suspicious functional dyspepsia or 
functional heartburn based on Rome IV criteria. 
6. Subjects with history of surgery or treatment affecting gastroesophageal reflux 
(fundoplication or dilation for esophageal stenosis [except for Schatzki's ring], etc.). 
7. Subjects with an esophagus-related complication (eosinophilic esophagitis, 
esophageal varices, scleroderma, viral or fungal infection, esophageal stenosis, etc.), 
a history of radiotherapy or cryotherapy of the esophagus, a caustic or 
physiochemical trauma (esophageal sclerotherapy, etc.). However, participants with 
Schatzki's ring (mucosal tissue ring around inferior esophageal sphincter) or 
Barrett's esophagus are allowed to be included.  
8. Subjects with a history of gastrectomy, gastrointestinal resection, or vagotomy. 
9. Subjects who took antidepressant agents or anti-anxiety agents within 8 weeks 
before the time of informed consent. 
10. Subjects who took H2 receptor antagonist within 8 weeks before the time of 
informed consent. 
11. Subjects planning to take prohibited concomitant medications during the study 
period. 
12. Subjects who have any of the following abnormal clinical laboratory test values at 
the screening (VISIT 1): 
ALT or AST > ULN. 
Bilirubin (Total bilirubin) > ULN 


 
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13. Subjects with a malignant tumor. 
14. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to 
become pregnant. 
15. Subjects who have serious renal diseases. 
16. Subjects with the conditions listed under administration contraindication in the 
vonoprazan package insert. 
17. Subjects participating in other clinical studies. 
18. Subjects who have been determined as inappropriate subjects by the investigator. 
[Justification for exclusion criteria] 
1-11 
These were set because they would affect efficacy evaluation. 
12-16 
These were set in consideration of safety of the subjects. 
17-18 
These were set as fundamental items for the study. 
7.3 
Excluded Medications 
The following drugs should not be used concomitantly with the study drug during the 
study: 
1. Drugs with which vonoprazan should not be used concomitantly according to the 
package insert. 
2. PPIs 
3. H2 receptor antagonist 
4. Antidepressant agents and anti-anxiety agents 
[Justification for excluded medications] 
1 
These were set in consideration of safety of the subjects.  
2-4 These were set because they would affect efficacy evaluation.  
7.4 
Subject Management 
The principal investigator and investigators shall instruct subjects to adhere to the 
following throughout the study period:  
1. Adhere to the instructions or restrictions prescribed in the study period 
(compliance with study treatment, prohibited concomitant drugs, wearing 
actigraph).  


 
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2. Inform the investigator of any planned treatment by another physician. Promptly 
report any treatment done by another physician.  
3. Visit the study site as scheduled to undergo physical examination or other 
specified tests. Cancel an appointment for study visit in a timely manner if 
applicable.  
4. Avoid excessive eating or drinking, excessive diet change (e.g., change to 
extremely high-fat diet), and excessive exercise throughout the study period.  
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 case report form (CRF) using the following 
categories. For subjects who withdraw from the study before administration, refer to 
Section 9.1.12. 
1. Adverse event 
The subject has experienced an adverse event (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 AE. 
 
Liver Function Test (LFT) Abnormalities. 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status), if the following circumstances occur at any time during 
study drug treatment: 
ALT or AST or bilirubin (total bilirubin) > 2×ULN. 
2. Significant protocol deviation 
The discovery after the first dose of study drug that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented in the subject’s 
source 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 CRF. 


 
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Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(ie, withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
5. Study termination 
The sponsor, IEC or regulatory authority terminates the study. Refer to Section 6.3.1 
for details. 
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 9.1.11. 
7. Lack of efficacy  
The investigator has determined that the subject is not benefiting from study 
treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Others 
The investigator determined to terminate the study for other reasons. 
Note: The specific reasons should be recorded on the CRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subjects 
The investigator may discontinue a subject’s study participation at any time during the 
study when the subject meets the study termination criteria described in Section 7.5. In 
addition, a subject may discontinue his or her participation without giving a reason at 
any time during the study. Should a subject’s participation be discontinued, the primary 
criterion for termination must be recorded by the investigator. In addition, efforts should 
be made to perform all procedures scheduled for the Early Termination Visit. 


 
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8.0 
STUDY TREATMENT 
This section indicates the treatment regimen of this study. See the latest package insert 
for details and handling of the drug. 
8.1 
Study Drug 
Generic name: vonoprazan fumarate 
Chemical name: 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]- 
N-methylmethanamine monofumarate 
8.1.1 Dose and Regimen 
Vonoprazan 20 mg is to be orally taken once daily for 8 weeks. 
Study drug will be administered at the same time as it was for the previous PPI. 
8.1.2 Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the protocol. 
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the CRF, in order to capture this important safety information 
consistently in the database. Cases of overdose without manifested signs or symptoms 
are not considered AEs. AEs associated with an overdose will be documented on AE 
CRF according to Section 10.0. 
Serious AEs (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2. 
In the event of overdose, the subject should be treated symptomatically. 
8.2 
Prescription of the Study Drug 
The investigator will prescribe the study drug to the subject fulfilling all inclusion 
criteria and not fulfilling any of exclusion criteria in accordance with the study 
procedure. 
 


 
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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 15.3. 
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 and Medication History 
Demographic information to be obtained will include date of birth (or age at the time of 
informed consent), sex, smoking status, drinking history, and consumption of 
caffeine-containing beverage. 
Medication history information will be obtained regarding the drug name (trade name or 
generic name) of following relevant to eligibility criteria and efficacy/safety evaluation 
stopped at or within 12 weeks prior to the administration of study drug. 
 PPIs 
 Hypnotics 
 Antianxiety agents 
9.1.3 Physical Examination Procedure 
All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first dose examination. 
9.1.4 Weight, Height and Body Mass Index 
Weight and height will be measured. Body Mass Index (BMI) will be calculated from 
the following formula by the sponsor. 
Metric:  BMI = weight (kg) / height (m)2 


 
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Height is recorded in centimeters without decimal places. Weight is collected in 
kilograms with 1 decimal place. BMI should be report to 1 decimal place by rounding. 
9.1.5 Documentation of Concomitant Drugs 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. At each study 
visit, subjects will be asked the status of use (drug name, route of administration, 
treatment period) of any medication other than the study drug (including vitamin 
compound, over-the-counter medication, and Chinese medicine) used from the time of 
start of administration of study drug to the end of the study. 
9.1.6 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 or physical examination abnormalities noted at baseline examination, 
according the judgment of the investigator. The condition (ie, diagnosis) should be 
described. 
9.1.7 Questionnaire About Sleep 
The subjects will answer a questionnaire (Appendix C) which consists of PSQI and 
questions about nocturnal awakenings according to the schedule of study procedures 
(Appendix A). The investigator will record the answers of subjects in the CRF.  
PSQI is a self-rated questionnaire for sleep quality which consists of 18 items and was 
developed and standardized in the Department of Psychiatry, the University of 
Pittsburg. 
9.1.8 Actigraph 
After full instructions are provided an actigraph will be provided to the subject at the 
time of screening (VISIT 1), and actigraph recording will be started. The subjects will 
be instructed to wear it until the end of study (VISIT 6).  
The subjects will be instructed to bring the actigraph at VISIT 2, 4 and 6. The 
investigator will collect the actigraph and will provide a new actigraph for the recording 
during the next 4 weeks.  


 
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The value of actigraph parameters will be analyzed by the central analysis organization. 
The results of analysis will be returned to the investigator, who is responsible for 
reviewing and filing these results. 
The detailed procedures between sending actigraph to the organization and reporting the 
results of analysis to investigators will be defined in “Procedures for central evaluation 
for data of actigraph” prepared separately.  
The parameters to be observed and evaluated are as follows. 
［Parameters］ 
1) Changes in sleep efficiency, sleep latency, and number of nocturnal awakenings 
 Baseline/Start of Administration (mean value during 7 days* before VISIT 2) 
 Week 4 (mean value during 7 days* before VISIT 4)  
 End of Study (mean value during 7 days* before VISIT 6) 
 
*The value of parameters for each sleep during 7 days before each visit will be 
analyzed and mean values will be calculated. 
9.1.9 Heartburn and Regurgitation 
Daytime and nighttime heartburn and regurgitation will be recorded respectively as 
reflux esophagitis related subjective symptoms. Questions for each subjective symptom 
are shown in Table 9.a. 
According to the schedule of study procedures (Appendix A), subjects will answer a 
questions along with the questionnaire about sleep (Appendix C) during 7 days before 
each visit based on Table 9.b. 
 
Table 9.a Question for Reflux Esophagitis Related Subjective Symptoms 
Reflux esophagitis related 
subjective symptoms 
Question 
Heartburn 
Did the subject have heartburn caused by reflux esophagitis? 
If yes, how bad was it? 
Regurgitation 
Did the subject have acid reflux caused by reflux esophagitis?  
If yes, how bad it was it? 
 


 
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Table 9.b Severity Classifications of Reflux Esophagitis Related Symptoms 
Reflux Esophagitis related 
subjective symptoms 
Severity 
Heartburn 
Acid reflux 
No symptom 
Mild 
Moderate 
Severe 
 
9.1.10 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. 
Clinical laboratory tests are listed in Table 9.c. 
 Table 9.c Clinical Laboratory Tests 
Chemistry 
AST 
ALT 
Bilirubin (total bilirubin) 
Creatinine 
The central laboratory will perform laboratory tests. The results of laboratory tests will 
be returned to the investigator, who is responsible for reviewing and filing these results. 
If subjects experience ALT or AST > 2×ULN or bilirubin (total bilirubin) level > 
2×ULN, follow-up laboratory tests (at a minimum, serum ALP, ALT, AST, bilirubin 
(total bilirubin), GGT, and international normalized ratio [INR]) should be performed 
within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was noted.  
Refer to Section 7.5 if ALT or AST or bilirubin (total bilirubin) > 2×ULN. 
In addition, refer to Section 10.2.3 in relation to ALT or AST > 3×ULN in conjunction 
with bilirubin (total bilirubin) > 2×ULN when a decision is made that these 
abnormalities in the liver function test cannot reasonably be explained by other factors. 
9.1.11 Pregnancy 
When a subject or a partner of subject was found to be pregnant during the study period, 
the investigator should notify the monitoring staff of the sponsor. The investigator 


 
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should provide detailed information using the Follow-up Form for Pregnancy separately 
wherever possible. 
9.1.12 Record of Subjects Who Are Withdrawn Before Start of Administration 
A CRF shall be created for all subjects who sign the consent form and are then 
withdrawn before start of administration.  
The following items are to be recorded on the CRF: 
 Date of consent obtainment 
 Date of birth (or the age at the time of informed consent) 
 Sex 
 Eligibility 
 
Reason for withdrawal 
The primary reason for withdrawal before start of administration shall be recorded on 
the CRF according to the following classification:  
 Did not meet inclusion criteria or did meet exclusion criteria 
 Significant protocol deviation 
 Lost to follow-up 
 Voluntary withdrawal <specify reason> 
 Study termination 
 Pregnancy 
 Others <specify the reason> 
Subject identification numbers assigned to subjects withdrawn from the study before 
start of administration should not be reused.  
9.2 
Monitoring Subject Treatment Compliance 
The investigator will confirm treatment compliance of study drug at every visit. 
Treatment compliance will be classified into 4 categories, as follows: “took the drug 
properly (≥ 90%),” “usually took the drug (≥ 70%),” “took the drug more than half of 
the time (≥ 50%),” and “took the drug less than half of the time (< 50%).” 


 
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9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix 
A 
Schedule of Study Procedures. Assessments should be completed at the 
designated visit/time points. 
9.3.1 Screening [VISIT 1] 
After acquisition of informed consent, a physical examination and tests for screening 
will be performed. Eligibility of subjects will be determined in accordance with the 
inclusion and exclusion criteria as described in Section 7.0. 
Tests and observations to be performed and endpoints to be assessed at the screening 
(VISIT 1) are shown below. 
 Informed consent 
 Demographics  
 Physical examination 
 Weight, height and BMI 
 Concurrent medical conditions 
 Actigraph (Provide device and instruction how to use） 
 Clinical laboratory test 
9.3.2 At the Baseline/Start of Administration [VISIT 2] 
Tests and observations to be performed and endpoints to be assessed at the baseline/start 
of administration (VISIT 2) are shown below.  
The investigator will explain the administration of study drug according to Section 6.1 
toward the subjects fulfilling all inclusion criteria and not fulfilling any of exclusion 
criteria in Section 7.0 
Refer to Section 9.1.12 for the recording of subjects who are withdrawn before the start 
of administration. 
 Medication history 
 Physical examination 
 Concomitant medications 
 Concurrent medical conditions 


 
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 Questionnaire about sleep 
 Actigraph (mean during 7 days before VISIT 2) 
 Heartburn and regurgitation 
9.3.3 At Week 2 [VISIT 3] 
Tests and observations to be performed and endpoints to be assessed at Week 2 
(VISIT 3) are shown below.  
 Physical examination 
 Concomitant medications 
 Clinical laboratory test 
 Treatment compliance 
 AEs 
9.3.4 At Week 4 [VISIT 4] 
Tests and observations to be performed and endpoints to be assessed at Week 4 
(VISIT 4) are shown below.  
 Physical examination 
 Concomitant medications 
 Questionnaire about sleep  
 Actigraph (mean value during 7days before VISIT 4) 
 Heartburn and regurgitation 
 Clinical laboratory test 
 Treatment compliance 
 AEs 
9.3.5 At Week 6 [VISIT 5] 
Tests and observations to be performed and endpoints to be assessed at Week 6 
(VISIT 5) are shown below.  
 Physical examination 
 Concomitant medications 


 
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 Clinical laboratory test 
 Treatment compliance 
 AEs 
9.3.6 At the End of Study [VISIT 6] or at the Early Termination 
A visit in 8 weeks after start of administration is defined as the last VISIT (VISIT 6). 
Tests and observations to be performed and endpoints to be assessed at the End of Study 
(VISIT 6) are shown below. At the Early Termination, following procedures will be 
performed as well. 
 
Physical examination 
 Concomitant medications 
 Questionnaire about sleep  
 Actigraph (mean value during 7 days before VISIT 6) and receive of device 
 Heartburn and regurgitation 
 Clinical laboratory test 
 Treatment compliance 
 AEs 
At the end of the study, the status all subjects administered the study drug will be 
recorded on the CRF.  
 


 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 AEs 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product (including the study drug). It does not necessarily have to have 
a causal relationship with this pharmaceutical product (including the study drug).  
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically 
significant abnormal laboratory value), symptom, or disease temporally associated with 
the use of a pharmaceutical product (including the study drug) whether or not it is 
considered related to the pharmaceutical product (including the study drug). 
10.1.2 Additional Points to Consider for AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions or underlying disease should not 
be considered AEs.). 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in the dose of the study drug, or 
concomitant medication. 
 Be considered unfavorable by the investigator for any reason. 
Diagnosis 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 an AE(s). 
Laboratory values and ECG findings: 
Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required 
or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory or ECG re-test and/or continued monitoring of an abnormal 


 
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value or findings are not considered an intervention. In addition, repeated or additional 
noninvasive testing for verification, evaluation or monitoring of an abnormality is not 
considered an intervention. 
If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as an AE. 
Pre-existing conditions (a disease or symptom that is present at the start of study drug 
administration): 
Pre-existing conditions are considered concurrent medical conditions and should NOT 
be recorded as AEs. However, if the subject experiences a worsening or complication of 
such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after start of study drug). 
Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”). 
If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, 
epilepsy) any occurrence of an episode should only be captured as an AE if the 
condition becomes more frequent, serious or severe in nature. Investigators should 
ensure that the AE term recorded captures the change in the condition from baseline (eg 
“worsening of…”). 
Worsening of AEs: 
If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, "worsening of…”). 
Changes in intensity of AEs: 
If the subject experiences changes in intensity of an AE, the event should be captured 
once with the maximum intensity recorded. 
Preplanned procedures (surgery or interventions): 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be recorded as an AE. Complications resulting 
from any planned surgery should be reported as AEs. 


 
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Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as AEs, but should be documented in the subject’s 
source documents. Complications resulting from an elective surgery should be reported 
as AEs. 
Insufficient clinical response (lack of efficacy):  
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be 
recorded as an AE. The investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy. 
Overdose: 
Cases of overdose with any medication without manifested side effects are NOT 
considered AEs, but instead will be documented on an Overdose page of the CRF. Any 
manifested side effects will be considered AEs and will be recorded on the AE page of 
the CRF. 
10.1.3 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death, 
2. Is life threatening*, 
3. Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. Results in persistent or significant disability/incapacity, 
5. Leads to a congenital anomaly/birth defect, 
6. Is an important medical event that may expose the subject to danger even though 
the event is not immediately life-threatening or fatal does not result in 
hospitalization, or requires intervention to prevent items 1 through 5 above. In 
addition, event or synonym described in the Takeda Medically Significant 
Adverse Event List (Table 10.a) is included in this section. 
* 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. 


 
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Table 10.a Takeda Medically Significant Adverse Event List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of 
infection by a medicinal product 
Confirmed or suspected endotoxin shock 
10.1.4 Intensity of 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 interrupts the subject’s usual 
activities. 
Severe 
The event causes considerable interference 
with the subject’s usual activities. 
10.1.5 Causality of AEs 
The relationship of each AE to the study drug will be assessed using the following 
categories. 
Related 
An AE that follows a temporal sequence (including clinical course after discontinuation), 
or an AE in which there is at least a reasonable probability that a causal relationship to 
the study drug cannot be ruled out, although other factors such as underlying disease, 
complications, or concomitant drugs/treatment are also suspected. 
Not 
related 
An AE that does not follow a temporal sequence from administration of the study drug 
or comparative drug. Very likely due to other factors such as underlying disease, 
complications, or concomitant drugs/treatment. 


 
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10.1.6 Relationship to Study Procedures 
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. 
10.1.7 Start Date 
The start date of AEs will be determined using the following criteria. 
AE 
Start date 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
subject and/or the investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the test 
results indicate an old sign(s) of the disease or an approximate time 
of its onset. 
Exacerbation of comorbidities 
The date on which the first worsening of diseases/symptoms was 
noted by the subject and/or the investigator. 
Onset of a test abnormality after 
the start of study drug 
administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after the start of 
study drug administration 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.8 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved 
but with sequelae or the subject died. The AE will be recorded as “ongoing” if the 
subject has not yet recovered by the end of the study. 
10.1.9 Action Concerning Study Drug 
Action concerning study drug will be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an AE (including withdrawal by the 
subject at his/her discretion). 
If the study drug is continued after the study termination, the action should be 
“Dose not changed”. 
Dose not changed 
The dose was not changed after the onset of the AE. 
The study drug was discontinued, reduced, or increased because of another AE. 
The study drug was discontinued or reduced for a reason other than the AE, e.g., 
inadvertence of the subject. 


 
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Unknown 
It has not been possible to determine what action has been taken because the 
subject is lost to follow-up. 
Not Applicable 
The administration of the study drug had already been completed or discontinued 
before the onset of the AE. 
Dose reduced 
The dose of the study drug was reduced because of the AE (including dose 
reduction by the subject at his/her discretion). 
Washout 
The study drug was suspended (i.e., interrupted) because of the AE (including 
suspension/interruption by the subject at his/her discretion), but resumed later. 
10.1.10 Outcome 
Outcome of AEs is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 
Laboratory values returned to normal or baseline 
Improved 
The intensity is lowered by one or more stages 
Symptoms or findings mostly disappeared 
Laboratory values improved, but have not returned to normal or baseline 
The subject died from a cause other than the concerned AE while the condition was 
resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The subject died from another cause before resolution of the concerned AE 
(recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 
Death 
Direct relationship between death and the concerned AE 
“Direct relationship” means that the concerned AE was the cause of death, or the 
concerned AE was clearly responsible for death. 
Outcome of an AE which was not determined (judged, presumed) a direct cause of 
death observed in the same subject is not considered as death. 
The date of death shall be recorded. 
Unknown 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 


 
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10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 AE Collection Period 
Collection of AEs will commence from the time that the subject is first administered 
study drug (VISIT 2). Routine collection of AEs will continue until VISIT 6. 
10.2.1.2 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?”.  
Subjects may report AEs occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study 
drug or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory 
explanation for the changes observed. All AEs will be documented in the AE page of 
the CRF, whether or not the investigator concludes that the event is related to the drug 
treatment. The following information will be documented for each event:  
1. Event term. 
2. Start and stop date. 
3. Intensity. 
4. Investigator's opinion of the causal relationship between the event and 
administration of the study drug (related or not related),  
5. Investigator's opinion of the causal relationship to study procedures, including the 
detail of the suspected procedure. 
6. Action concerning study drug. 
7. Outcome of event. 
8. Seriousness.  
10.2.2 Collection and Reporting of SAEs 
When a SAE occurs through the AE collection period it should be reported according to 
the following procedure: 


 
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At the time of onset of a SAE or notification of the onset by the subject, the principal 
investigator shall report the SAE to the chief executive of the study site immediately, 
and the sponsor or the contract study organization (CRO) to whom the sponsor has 
entrusted responsibility shall notify the principal investigator of the study site. 
A SAE should be report by the investigator to the sponsor within 1 business day of the 
SAE occurrence. The investigator should submit the detailed SAE Form to the sponsor 
(for contact information, refer 1.3) within 10 calendar days. .  
Furthermore, it shall be mandatory to include the contents below in the report to be 
submitted to the sponsor within 1 working day, and other items shall be reported as far 
as possible. 
 A short description of the event and the reason for why the event is categorized 
as serious. 
 Study title. 
 Subject identification number. 
 Study site's name. 
 Investigator's name. 
 Name of the study drug. 
 Causality assessment.. 
The investigator shall report spontaneously reported SAEs that are collected even after 
the AE collection period to the sponsor. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST > 3×ULN and bilirubin (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 principal investigator or the 
investigator must contact the monitoring staff for discussion of the relevant subject 
details and possible alternative etiologies, such as acute viral hepatitis A or B or other 
acute liver disease or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.1.10 must also be performed. 
10.2.4 Reporting of Additional Information Concerning AEs 
If the sponsor requests provision of additional information concerning AEs for reporting 
to regulatory authorities, the principal investigator or the investigator shall confirm the 


 
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necessary additional information and enter in the electronic data capture (EDC) system 
or submit a report within the period specified by the sponsor. 
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 (copy) or provide other 
written documentation and submit it to the sponsor (for contact information, refer 1.3) 
within 1 working day. Relevant data collected at the study site (e.g., ECG charts, 
laboratory test values, discharge summary, postmortem results) shall be sent to the 
sponsor or the committee such as the ethics review committee upon request. 
All SAEs should be followed up until resolution or permanent outcome of the event.  
10.3.1 Reporting of SAEs, etc., to IECs, etc., and Regulatory Authorities 
When the chief executive of study site receives a report of a SAE from the principal 
investigator, the chief executive of study site shall consult the Ethical Review Board, 
etc., and notify the study sites that are conducting the study through the sponsor or the 
CRO consigned by the sponsor. 
When the principal investigator reported a SAE for which a causal relationship to the 
study (study drug or comparative drug) cannot be ruled out and is unexpected, the chief 
executive of the study site shall prepare a written report of the unexpected SAE 
containing the information reported by the principal investigator plus the information 
below, and submit the report to the Minister of Health, Labour and Welfare, and notify 
other study sites conducting the study. (The chief executive of the study site may report 
it to the Minister of Health, Labour and Welfare via the sponsor, and notify it to other 
study sites via the sponsor.) 
 Actions taken for SAEs 
(discontinuation of new enrollment, revision of informed consent form, 
re-consents from other subjects, etc.) 
 Date of review, summery of review, result, necessary action, etc., related to 
Ethics Review Committee, etc. 
 Notification to other study sites 
The sponsor shall report, in accordance with regulations, unexpected serious adverse 
drug reactions and other SAEs that are subject to emergency reporting to regulatory 
authorities, the investigators, and chief executive s of study sites. 


 
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From the time point of first acknowledging the event or receiving additional 
information, the sponsor or the CRO consigned by the sponsor shall comply with 
regulatory required time frames for reporting, and make emergency reports concerning 
unexpected serious adverse drug reactions and expected serious adverse drug reactions 
to regulatory authorities. Also, the sponsor shall, in the same way, make an emergency 
report of other critical safety information that may have a major effect on the 
risks/benefits of the study drug, continuation of study drug administration, or 
continuation of study. The study site shall submit copies of emergency report 
documents to the Ethics Review Committee, etc. 


 
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11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Steering Committee 
The Steering Committee will comprise of the chair and the sponsor. The Steering 
Committee will supervise implementation and reporting of the study, secure medical 
guidance of a high degree of professionalism and a high-level scientific quality, and 
revise the protocol appropriately. The responsibilities of the committee will be 
prescribed in the procedures of the Steering Committee. 


 
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12.0 
DATA HANDLING AND RECORDKEEPING 
Data Management department of the sponsor shall be in charge of implementing data 
management operation according to the standard operating procedures, independently 
from Medical Affairs department. AEs, medical history, and concurrent conditions shall 
be coded using MedDRA. Drugs shall be translated using the World Health 
Organization (WHO) Drug Dictionary.  
12.1 
CRFs 
Completed CRFs are required for each subject who signs informed consent.  
The sponsor or its designee will provide study sites with access authorization to the 
EDC system. Before use of the EDC system, the sponsor shall provide training to the 
principal investigator, investigators, and study collaborators. The CRF shall be used to 
report the information collected during the study period to the sponsor. The CRF shall 
be prepared in Japanese. Data shall be directly entered in preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the 
information before and after the change or correction, the person who made the change 
or correction, date of change or correction, and its reason. 
The principal investigator or its designee shall ensure the accuracy and completeness of 
the CRF, and provide an electronic signature on the relevant page of the CRF. The 
principal investigator bear full responsibility for the accuracy and reliability of all the 
data entered on the CRF. 
The following data shall be recorded on the CRF directly, except for those recorded in 
the source documents: 
 Severity, degree, the causal relationship with the study drug, or the study 
procedures, outcome 
The following data shall not be recorded on the CRF directly: 
 Actigraph 
 clinical laboratory test 
When the principal investigator or the investigator makes a change or correction in the 
data entered on the CRF after fixation of clinical data base, a record (Data Clarification 
Form) of change or correction on the CRF provided by the sponsor shall be used. The 
principal investigator shall confirm that the record of change or correction on the CRF 
is accurate and complete, and sign or write name/ affix a seal, and date it. 


 
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The sponsor or the designee shall confirm that the CRF has been made appropriately in 
conformity with the procedure defined for each study. The sponsor or its designee shall 
have access to the medical records of the subjects and in-house records to ensure the 
accuracy of the CRF as necessary. The completed CRF shall be the property of the 
sponsor, and the investigator shall not disclose the information to a third party without 
written permission from the sponsor. 
12.2 
Timing of Data Entry into the EDC System 
The sponsor or its designee shall request the principal investigator and investigator to 
promptly enter data into the EDC system following enrollment of the subject, each visit 
during study treatment, and completion/discontinuation of the study. 
12.3 
Storage and Disposal of Specimens, Information, etc. 
The principal investigator or the chief executive of the study site shall store 
human-derived specimens and the following materials (information, etc.), including 
those specified in Section 12.1 and study-specific documents to be used by the 
regulatory authority and the sponsor or its designee for investigation and audit. The 
documents shall include, but shall not be limited to the materials related to the 
information used in the study such as the subject ID number list, subjects’ medical 
records, study work sheet, original signed and dated informed consent forms, an 
electronic copy of the EDC system with audit trails, and the drug management records. 
The principal investigator and the chief executive of the study site shall appropriately 
retain the specimens/information related to this study for at least 5 years from the date 
of reporting the end of the study by the principal investigator, or for 3 years from the 
date of reporting final publication of the study result, whichever date is later. However, 
when the sponsor requires a longer storage period, the chief executive of the study site 
shall discuss the period and methods of storage with the sponsor. When disposing the 
specimens, information, etc., the chief executive of the study site shall dispose them 
anonymously. 


 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
The person in charge of analysis shall prepare a statistical analysis plan (SAP) before 
the acquisition of the informed consent of the earliest subject, and issue the first edition. 
Detailed definition of endpoints and analysis methods should be specified in the SAP to 
deal with all the purposes of the study. 
13.1.1 Analysis Sets 
In this study, “Full Analysis Set” shall be established. The “Full Analysis Set” is 
defined as “subjects who are given at least one dose of the study drug”. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Using “Full Analysis Set”, major demographic and other baseline characteristics shall 
be aggregated.  
13.1.3 Efficacy Analysis 
Using “Full Analysis Set”, efficacy analysis will be performed.  
[Primary endpoints] 
 
Changes in PSQI global score 
[End of study(VISIT 6) – Baseline/Start of Administration (VISIT 2)] 
 
[Analytical methods] 
For primary endpoints, descriptive statistics, such as summary statistics [sample size, 
mean, standard deviation (SD), maximum, minimum and quantile] and 95% confidence 
interval of the mean are calculated. Statistically significance of the changes is assessed 
using paired t-test. 
 
[Secondary endpoints] 
 
Changes in PSQI global score 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[Analytical methods] 


 
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Descriptive statistics and 95% confidence interval of the mean are 
calculated.  
 
Percentage of subjects with PSQI global score <6.0 at Week 4 (VISIT 4) 
and the end of study (VISIT 6) 
[Analytical methods] 
Percentage of subjects with PSQI global score <6.0 at Week 4 and the end 
of study are calculated. 
 
 
Changes in 6 component scores of PSQI (Sleep quality, Sleep latency, Sleep 
duration, Habitual sleep efficiency, Sleep disturbances, Daytime 
dysfunction) and number of nocturnal awakenings (assessed by 
questionnaire) 
[Week 4 (VISIT 4) – Baseline/Start of Administration (VISIT 2)] 
[End of Study(VISIT 6) – Baseline/Start of Administration (VISIT 2)]  
[Analytical methods] 
Descriptive statistics and 95% confidence interval of the mean are 
calculated.  
 
 
Changes in actigraph-measured sleep efficiency, sleep latency, and number 
of nocturnal awakenings 
[Week 4 (mean value during 7days before VISIT 4) – Baseline/Start of 
Administration (mean value during 7days before VISIT 2)] 
[End of Study (mean value during 7days before VISIT 6) – Baseline/Start of 
Administration (mean value during 7days before VISIT 2)] 
[Analytical methods] 
Descriptive statistics and 95% confidence interval of the mean are 
calculated.  
13.1.4 Safety Analysis 
[Secondary endpoint] 
 
Incidence of AEs (TEAEs) 
[Analytical methods] 


 
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A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of 
study or control treatment for the healing phase. For TEAEs in the maintenance phase, 
the analyses listed below shall be performed for each treatment group. TEAEs shall be 
reported using MedDRA terminology and summarized using the Preferred Term (PT) 
and System Organ Class (SOC) of the MedDRA.  
 
 Aggregation of frequencies of all TEAEs in the maintenance phase 
 Aggregation of frequencies of TEAEs related to the study drug 
 Aggregation of frequencies of all TEAEs by severity 
 Aggregation of frequencies of TEAEs related to the study drug  
 Aggregation of frequencies of TEAEs leading to discontinuation of study treatment  
 Aggregation of frequencies of serious TEAEs 
13.1.5 Other Analysis 
 
Changes in heartburn and regurgitation (daytime and nighttime) 
[Analytical methods] 
Using “Full Analysis Set”, percentage of subjects without each symptom at 
Week 4 and the end of study among subjects who had symptoms are 
calculated. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
25 subjects 
 
<Rationale for the number of planned subjects> 
In the clinical study assessed effect of esomeprazole on sleep disturbance caused by 
gastroesophageal reflux disease, mean (SD) changes in PSQI global score from baseline 
at 4 weeks of treatment with esomeprazole 40 mg, 20 mg, and placebo were -3.5 (3.6), 
-3.8 (3.8), and -2.0 (3.7), respectively4). In the similar clinical study with 
dexlansoprazole, changes in PSQI global score from baseline at 4 weeks of treatment 
with dexlansoprazole 30 mg, and placebo were -2.70 (3.08), and -1.35 (3.23), 
respectively5). These results suggest that effect sizes during treatment with PPI and 


 
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placebo are 0.87-1.00 and 0.42-0.54, respectively. 
Although subjects for the present study is different from these studies which excluded 
subjects who received treatment with PPI in a certain period before randomization, we 
can assume that effect size of the present study will be less than PPI and greater than 
placebo. So we assumed effect size of changes in PSQI global score from baseline at 8 
weeks of treatment will be 0.75. 
21 subjects are required as number of subjects for evaluation of primary endpoint to 
obtain 90% of power using estimated effect size. Considering drop out of certain subject, 
25 subjects are required as enrolled subject. 


 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
The sponsor or its designee shall perform periodic monitoring of study sites during the 
study to confirm that the study is conducted in accordance with all specifications in the 
protocol. In the monitoring, the data recorded on the CRF will be checked by comparing 
them with those in the source documents. Source documents are the original documents, 
data and records. The principal investigator and the chief executive of the study site 
shall ensure that the sponsor or its designee and the Ethics Review Committee, etc., 
have access to the source documents. 
The sponsor or its designee shall access the records, including the list of subject ID 
codes, medical records of the subjects, and signed and dated original consent forms, to 
confirm that the study is appropriately conducted in compliance with the protocol. Also, 
confirm the consistency between CRF and the related source documents. The 
investigator, and other personnel involved in the study shall spare sufficient time to 
facilitate monitoring procedures during visits to the study site. 
Detailed procedures for monitoring shall be described in a procedure manual prepared 
separately.  
14.2 
Deviation from the Ethical Guideline for Clinical Research and the Protocol 
The investigator shall record all deviations from the Ethical Guideline for Clinical 
Research and the protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief 
executive of the study site and the sponsor. As necessary, the principal investigator will 
discuss protocol revisions with the sponsor to reach agreement. For protocol revisions, 
draft revisions should be submitted as early as possible to the study site for approval of 
the committee such as ethics review committee. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The sponsor or the designee shall perform audit at the study site as necessary. In such a 
case, the auditor designated by the sponsor shall contact the study site in advance to 
determine the date of audit. The auditor may ask to visit the facilities where laboratory 
specimens are collected and any other facilities used during the study. In addition, this 
study may be inspected by regulatory agencies, including those of foreign governments 
(e.g., the Food and Drug Administration [FDA], the United Kingdom Medicines and 
Healthcare products Regulatory Agency [MHRA]). If the study site is contacted for an 


 
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inspection by a regulatory body, the sponsor should be notified promptly. The principal 
investigator and the chief executive of the study site shall ensure that the auditor has 
access to all the study-related source documents. 


 
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15.0 
ETHICAL ASPECT OF THE STUDY 
This study shall be conducted with the highest respect for the individual participants 
(i.e., subjects) according to the protocol, the ethical principles that have their origin in 
the Declaration of Helsinki, and the Ethical Guideline for Clinical Research. Each 
investigator will conduct the study according to regulatory requirements and in 
accordance with “Responsibilities of the Investigator” that are listed in Appendix B. 
15.1 
IEC Approval 
The IEC, etc., shall be constituted in accordance with the regulations. 
The sponsor or its designee should obtain the document listing the name and title of 
each committee member. When a committee member directly participates in this study, 
the document describing that he/she is not participating in deliberation or voting for the 
study will be obtained. 
The sponsor or the designee shall provide related documents for review and approval of 
the protocol to the Ethical Review Board, etc. In addition to the protocol, a copy of the 
informed consent form and information sheet, written materials related to subject 
recruitment, advertisement, and other documents required by regulations, when 
necessary, shall be submitted to the central committee or a study site committee such as 
the Ethics Review Committee to obtain approval. The sponsor or the designee shall 
obtain records of approval by the Ethical Review Board, etc., for the protocol and the 
informed consent form and information sheet before the start of the protocol therapy. 
The records of approval by the Ethical Review Board, etc., shall include the study title, 
protocol number, preparation / revision date of the protocol, and version number and 
approval date of other reviewed documents (Example: informed consent and 
information sheet). The sponsor shall notify the study site and the investigator after 
confirming the validity of the regulatory documents of the study site. Protocol 
procedures such as obtainment of consent shall not be started until the study site and 
investigator receive notification.  
The study site shall observe all requirements that the Ethical Review Board prescribes. 
The requirements may include notifications to committees such as ethics review 
committee, for example, revision of the protocol, revision of the informed consent form 
and information sheet, revision of materials related to subject recruitment, reports on 
safety in accordance with the regulatory requirements, reports on status of 
implementation of the study at intervals determined by a study site committee such as 
the Ethics Review Committee, and submission of the study completion report. The 


 
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sponsor or its designee shall obtain written approval from a study site committee such 
as the Ethics Review Committee related to the above mentioned items and all related 
materials. 
15.2 
Conflict of Interests 
This study shall be conducted with the support of the sponsor. 
Prior to the conduction of this study, the investigators involved in this study shall ensure 
appropriate management of any conflicts of interest (COI) in the conduct of the study in 
accordance with the rules of the study site.16)-20) 
The study site shall comply with all requirements specified by a committee such as an 
ethics review committee, including the COI self-statement form, the protocol, and the 
informed consent form and information sheet. 
15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Subjects 
The informed consent and information sheet form shall contain specific requirements of 
the Declaration of Helsinki, Ethical Guideline for Clinical Research and all applicable 
laws and regulations. The informed consent form and information sheet shall specify the 
use of personal information and medical information of subjects in this study (both in 
and outside Japan: supply to a third party), and disclosure. The informed consent form 
and the information sheet will explain in detail the nature of the study, its objectives, 
and potential risks and benefits. The informed consent form will detail the requirements 
of the participant and the fact that subject is free to withdraw at any time without giving 
a reason and without any negative effect on the further medical care. 
The principal investigator is responsible for the preparation, contents, and approval of 
the informed consent form and subject information sheet by the committee such as 
ethics review committee. The informed consent form and information sheet must be 
approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can 
be easily understood by the potential subjects. The investigator shall be responsible for 
providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form 
whenever possible and in manner deemed appropriate by the committee such as ethics 
review committee. 


 
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The investigator shall ensure that the potential subjects have (1) an opportunity to 
inquire about the study and (2) sufficient time to decide on their participation. If a 
potential subject decides to participate in the study, then the informed consent form 
must be signed and dated by the potential subject prior to entering into the study as a 
subject. The investigator shall instruct the potential subject to sign using their legal 
names, not nicknames, using a blue or black ball point ink pen. Also the investigator 
shall sign and date the informed consent form prior to entering into the study. 
Once signed, the original informed consent form shall be retained by the investigator. 
The investigator shall record the date that the potential subject signed the informed 
consent form in the subject’s medical record. A copy of the signed informed consent 
form shall be given to the subject. 
The investigator shall follow the same procedure as for obtaining the initial consent 
when newly obtaining re-consent from the concerned subject when the informed 
consent form is revised. The date of obtaining new consent shall be recorded in the 
subject’s medical record, and a copy of the revised consent form shall be provided to the 
subject. 
15.4 
Personal Information of Subjects 
The sponsor or the designee shall affirm the principle of the protection of subjects’ 
private/personal information. Throughout this study, subject ID codes shall be used to 
link the subject’s source data to the sponsor’s study database and study-related 
documents. Limited information on subjects such as gender, age, and date of birth may 
be used within the scope of all applicable laws and regulations for identification of 
subjects and confirmation of accuracy of subject ID code. 
For verification of the conduct of the study in compliance with this protocol and the 
Ethical Guideline for Clinical Research, the sponsor shall require the principal 
investigator to provide the study sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board 
direct access to subjects’ original medical records (source data or documents), including 
laboratory test results, ECG results, admission and discharge records during a subject’s 
study participation, and autopsy reports. The investigator shall obtain specific 
authorization of the subject as part of the informed consent process for access to 
subject’s original medical records by study sponsor’s designee and representatives of 
regulatory authorities (see Section 15.3). 


 
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When providing a copy of source documents to the sponsor, the investigator shall delete 
information that may lead to identification of an individual (name and address of subject, 
other personal information not recorded on the CRF of the subject). 
15.5 
Consultation for Subjects or Persons Related to the Study 
The principal investigator shall establish a contact service to respond to inquiries 
concerning this study from subjects or concerned people. Details of the contacts for 
inquiries will be described in the informed consent form. 
15.6 
Financial Burden or Reward to Subjects 
Of the expenses for this study, the sponsor shall pay for medical treatment not covered 
by health insurance and examinations necessary for the study as study expenses. The 
subjects shall pay expenses for medical treatment covered by ordinary health insurance. 
In addition, the principal investigator shall pay expenses such as transportation expenses 
for participation in this study to the subjects at each visit from the study funds. Details 
of the financial burden on the subjects and rewards shall be described in the informed 
consent form and information sheet. 
15.7 
Benefits and Inconveniences to Subjects 
15.7.1 Benefits to Subjects 
The subjects will obtain detailed information on the status of his or her EE through 
participation in this study.  
15.7.2 Inconveniences to Subjects 
Participation in this study may increase burden on the subjects due to increased 
frequencies of visits and examinations, as compared with routine medical practice.  
15.8 
Attribution of Study Results and Access Rights 
15.8.1 Attribution of Study Results 
The study results and data obtained from this study shall belong to the sponsor. In 
addition, secondary use (meta-analysis, etc.) of the data obtained in this study may be 
possible if used in such a way that the data shall not be linked to personal identification 
information. 


 
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15.8.2 Data Access Rights 
Access rights for all data and information generated from this study will be given to 
personnel approved by the sponsor. 
15.9 
Reporting of Results, Publication, Disclosure, and Clinical Study 
Registration Policy 
15.9.1 Reporting of Results, Publication and Disclosure 
The principal investigator shall report a written summary of results of the study to the 
chief executive of the study site and provide the sponsor with all the results and data 
obtained from the study. Only the sponsor may disclose the study information to other 
principal investigators, investigators or regulatory authorities during the study period, 
except when required by laws and regulations. The sponsor shall be responsible for 
publication of the protocol and study-related results (including the public web site) 
except for other cases permitted in the study contract. 
During and after the study, the sponsor or its designee should promptly summarize the 
results and present them to medical journals and academic conferences, etc. The sponsor 
may publish any data or information obtained from the study (including data and 
information provided by the principal investigator) without obtaining agreement of the 
principal investigator. 
The principal investigator or the investigator should obtain the prior written approval 
from the sponsor when publishing the information obtained in this study at an academic 
conference, etc. 
The sponsor shall report to the chief executive of the study site when final publication 
of the study results has been made. 
15.9.2 Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely 
manner and to comply with applicable laws, regulations and guidance, Takeda will, at a 
minimum register all interventional clinical trials it sponsors anywhere in the world on 
ClinicalTrials.gov and Japan Pharmaceutical Information Center Clinical Trials 
Information (JAPIC) before start of study. Takeda contact information, along with 
investigator’s city, country, and recruiting status will be registered and available for 
public viewing. 


 
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15.9.3 Clinical Study Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and JAPIC, as 
required by applicable laws and/or regulations. 
15.10 Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable 
to the site where the subject is participating. If a local underwriter is required, then the 
sponsor or sponsor’s designee will obtain clinical study insurance against the risk of 
injury to study subjects. Refer to the study site agreement regarding the sponsor’s policy 
on subject compensation and treatment for injury. If the investigator has questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee. 
 


 
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16.0 
REFERENCES 
1. 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;45:172-180. 
2. Doi Y, Minowa M, Uchiyama M, et al. Development of the Japanese version of 
the Pittsburgh Sleep Quality Index. Japanese Journal of Psychiatry Treatment. 
1998;13:755-763. 
3. Doi Y, Minowa M, Uchiyama M, et al. Psychometric assessment of subjective 
sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index 
(PSQI-J) in psychiatric disordered and control subjects. Psychiatry Study 2000; 
97: 165-172. 
4. Johnson DA1, Orr WC, Crawley JA, et al. Effect of esomeprazole on nighttime 
heartburn and sleep quality in patients with GERD: a randomized, 
placebo-controlled trial. Am J Gastroenterol. 2005;100:1914-1922. 
5. Fass R1, Johnson DA, Orr WC, et al. The effect of dexlansoprazole MR on 
nocturnal heartburn and GERD-related sleep disturbances in patients with 
symptomatic GERD. Am J Gastroenterol. 2011;106:421-431. 
6. Edited by the Japanese Society of Gastroenterology. Guidelines for Management 
of Gastroesophageal Reflux Disease (GERD). Tokyo. Nankodo. 2015. 
7. Fass R, Shapiro M, Dekel R, et al. Systematic review: proton-pump inhibitor 
failure in gastro-oesophageal reflux disease – where next? Aliment Pharmacol 
Ther 2005; 22: 79-94. 
8. Fujiwara Y, Arakawa T, Fass R, et al. Gastroesophageal reflux disease and sleep 
disturbance. J Gastroenterol.2012; 47: 760-769. 
9. Johnson D, Crawley A, Hwang C, et al. Clinical trial: esomeprazole for 
moderate-to severe nighttime heartburn and gastro-oesophageal reflux disease 
-related sleep disturbances. Aliment Pharmacol Ther. 2010; 32: 182-190. 
10. Hongo M, Kinoshita Y, Miwa H, et al. The demographic characteristics and 
health-related quality of life in a large cohort of reflux esophagitis patients in 
Japan with reference to the effect of lansoprazole: the REQUEST study. J 
Gastroenterol 2008; 43: 920-927. 
11. Fujiwara Y, Kohata Y, Kaji M, et al. Sleep Dysfunction in Japanese patients with 
gastroesophageal reflux disease: Prevalence, risk factors, and efficacy of 
rabeprazole. Digestion 2010; 81: 135-141. 
12. Hiramoto K, Fujiwara Y, Okuyama M, et al. Effects of esomeprazole on sleep in 
patients with gastroesopphageal reflux disease as assessed on actigraphy. Intern 
Med 2015; 54: 559-565 


 
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13. Aimi M, Komazawa Y, Hamamoto N, et al. Effects of omeprazole on sleep 
disturbance: randomized multicenter double-blind placebo-controlled trial. 
Clinical and Translational Gastroenterology. 2014; 5: e57. 
14. Chey WD, Mody RR, Wu EQ et al. Treatment patterns and symptom control in 
patients with GERD: US community-based survey. Curr Med Res Opin. 
2009;25(8):1869 
15. Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 
mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult 
male subjects - a randomized open-label cross-over study. Aliment Pharmacol 
Ther. 2015; 42:719-73. 
16. Report of the Working Group on Conflict of Interest (Ministry of Education, 
Culture, Sports, Science and Technology dated November 1, 2002). 
17. Guidelines for determining the conflict of interest polity for clinical study 
(Review group for ethical aspects of clinical study and conflict of interest, March 
2006). 
18. Guidelines on the Management of Conflict of Interest (COI) in Health and 
Labour Sciences Study (March 31, 2008). 
19. Guidelines for management of COI in medical study (COI Committee of Japan 
Association of Medical Sciences, February 2011). 
20. Common guidelines for conflict of interest (COI) in clinical study (Japanese 
Society of Internal Medicine, Japan Society of Hematology, Japanese Circulation 
Society, Japan Endocrine Society, Japan Diabetes Society, Japanese Respiratory 
Society, Japanese Society of Hematology, Japanese Society of Allergology, 
Japanese Association for Infectious Diseases, Aug 2011). 


 
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Appendix A 
Schedule of Study Procedures 
 
Screening 
Baseline/Start 
of 
Administration
Week 2 
Week 4 
Week 6 
End of Study
Visit timing 
-1W 
0W 
2W 
4W 
6W 
8W/ 
Withdrawal(d)
Allowable range (Day) (a) 
-14~-7 
1 
11~17 
25~31 
39~45 
53~59 
VISIT Number 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
Informed consent procedure (b) 
× 
 
 
 
 
 
Inclusion/Exclusion criteria 
× 
× 
 
 
 
 
Demographics 
× 
 
 
 
 
 
Medication history 
 
× 
 
 
 
 
Physical examination 
× 
× 
× 
× 
× 
× 
Weight, height and BMI 
× 
 
 
 
 
 
Concomitant drugs 
 
× 
× 
× 
× 
× 
Concurrent medical conditions 
× 
× 
 
 
 
 
Questionnaire about sleep 
 
× 
 
× 
 
× 
Actigraph 
 
×(c) 
 
× 
 
× 
Heartburn/ regurgitation 
 
× 
 
× 
 
× 
Clinical laboratory test 
× 
 
× 
× 
× 
× 
Prescription of study drug 
 
× 
× 
× 
× 
 
Treatment compliance 
 
 
× 
× 
× 
× 
AE monitoring 
 
 
× 
× 
× 
× 
(a) 
The starting day of study treatment (day of the first dose) will be designated as Day 1.  
(b) 
Informed consent will be obtained, prior to all study procedures. 
(c) 
An actigraph will be lent to the subject and the subject will be instructed on how to wear and evaluate an actigraph on at the 
screening (VISIT 1). 
(d) 
At 8 weeks after the start of treatment with study drug, which is the final visit, tests/observations/evaluations, will be 
performed. When subjects are withdrawn from the clinical study, all tests/observations/evaluations will be performed within 7 
days after the day of the last administration of study drug as possible (the next day after last administration will be designated 
as first day). 


 
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Appendix B 
Responsibilities of the principal investigator 
1. To appropriately conduct the study in compliance with this protocol and the Ethical 
Guideline for Clinical Research and with the highest respect for human rights, 
safety, and welfare of subjects. 
2. To prepare a list of any other investigators and/or study collaborators when certain 
important study-related activities are divided by investigators and/or study 
collaborators, and submit the list to the sponsor as required. 
3. To prepare the informed consent form and revise it as necessary. 
4. To check the contents of the study contract. 
5. To provide sufficient information on the protocol, drug and duties of each 
personnel to investigators and study collaborators, and give guidance and 
supervision. 
6. To select subjects who satisfy the inclusion criteria, give explanation using written 
information, and obtain consent in writing. 
7. To be responsible for all medical judgments related to the study. 
8. Corresponding to request from the chief executive of the study site, to report the 
latest progress status at least once a year to the chief executive of the study site.  
9. To ensure that the most updated status is confirmed and comprehended regarding 
the COI of the investigators participating in the study according to the procedure 
defined by the study site. 
10. To ensure, together with the chief executive of the study site, that sufficient medical 
care is provided to subjects for all study-related clinically problematic AEs 
throughout the period of subjects’ study participation and thereafter. 
11. When a subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the subject’s 
study participation and study completion/discontinuation after obtaining the 
subject’s consent, and prepare a record. 
12. When emergency reporting of SAEs, etc., is required, to immediately report it in 
writing to the chief executive of the study site and the sponsor. 
13. To ensure that the CRFs are accurate and complete, electronically sign, and submit 
them to the sponsor.  
14. To verify any entries on the CRFs made by the investigator or transcribed by the 
collaborator from source documents, electronically sign, and submit them to the 
sponsor.  


 
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15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the study completion in writing to the chief executive of the study site. 
17. To receive continuing education and training for conducting the study properly 
including Ethical Guideline for Clinical Research and GCP during the study period 
(at least once a year is recommended). 


 
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Appendix C 
Questionnaire about sleep and symptoms 
 
Instructions: 
The following questions relate to your usual sleep habits during the past month only. Your answers 
should indicate the most accurate reply for the majority of days and nights in the past month.  
Please answer all questions. 
1. 
During the past month, what time have you usually gone to bed at night? 
USUAL BED TIME 
 
2. 
During the past month, how long (in minutes) has it usually take you to fall asleep each night? 
NUMBER OF MINUTES 
 
3. 
During the past month, what time have you usually gotten up in the morning?  
USUAL GETTING UP TIME 
 
4. 
During the past month, how many hours of actual sleep did you get at night?(This may be different 
thant the number of hours you spend in bed.)  
HOURS OF SLEEP PER NIGHT 
 
For each of the remaining questions, check the one best response. Please answer all questions. 
5. 
During the past month, how often have you had trouble sleeping because you...  
(a) 
Cannot get to sleep within 30 minutes 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(b) Wake up in the middle of the night or early morning 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(c) 
Have to get up to use the bathroom 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(d) Cannot breathe comfortably 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 


 
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(e) 
Cough or snore loudly 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(f) 
Feel too cold 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(g) Feel too hot 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(h) Had bad dreams 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(i) 
Have pain 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
(j) 
Other reason(s), please describe 
 
 
How often during the past month have you had trouble sleeping because of this? 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
6. 
During the past month, how would you rate your sleep quality overall? 
Very good 
 
Fairly good 
 
Fairly bad 
 
Very bad 
 


 
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7. 
During the past month, how often have you taken medicine (prescribed, or "over the counter") to 
help you sleep? 
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
8. 
During the past month, how often have you had trouble staying awake while driving, eating meals or 
enagaging in social activity?  
Not during the 
past month 
 
Less than once 
a week 
 
Once or twice 
a week 
 
Three or more 
times a week 
 
9. 
During the past month, how much of a problem has it been for you to keep up enough enthusiasm to 
get things done?  
No problem at all 
 
Only a very slight problem 
 
Somewhat of a problem 
 
A very big problem 
 
 
Instructions: 
The following questions ask you condition of your sleep during the past week.  
 
10. During the past week, did you wake up in the middle of the night?  
No 
(this is end of 
this question)
 
Yes 
(please answer 
next question)
 
 
11. During the past week, how many times did you wake up in the middle of the night in the most 
frequent night? 
 
times 
 
 
 


 
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Instructions: 
The following questions ask you condition of symptoms during the past week.  
 
12. During the past week, did you have heartburn caused by reflux esophagitis during daytime? If yes, 
how bad was it?  
No 
  
Yes: Mild 
 
    Moderate 
 
    Severe 
 
 
13. During the past week, did you have regurgitation caused by reflux esophagitis during daytime? If 
yes, how bad was it?  
No 
  
Yes: Mild 
 
    Moderate 
 
    Severe 
 
 
14. During the past week, did you have heartburn caused by reflux esophagitis during nighttime? If yes, 
how bad was it?  
No 
  
Yes: Mild 
 
    Moderate 
 
    Severe 
 
 
15. During the past week, did you have regurgitation caused by reflux esophagitis during nighttime? If 
yes, how bad was it?  
No 
  
Yes: Mild 
 
    Moderate 
 
    Severe 
 
 
 

SAP_001.pdf: 
 
 
Title: Vonoprazan Study of Investigating the Effect on Sleep Disturbance Associated 
with Reflux Esophagitis - Exploratory Evaluation (VISTAEXE) 
 
NCT Number: NCT03116841 
Statistical analysis plan Approve Date: 15-Feb-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. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


 
 
 
 
 
 
 
Vonoprazan study of investigating the effect on sleep disturbance 
associated with reflux esophagitis- exploratory evaluation 
(Protocol number: Vonoprazan-4006) 
 
Statistical Analysis Plan 
(Ver.2.0: 15 Feb 2018) 
 
 
Sponsor: Takeda Pharmaceutical Company Limited 
 
 
 
 
 
 
Authorizer:  
Takeda Pharmaceutical Company Limited 
 
Biostatistics Manager: 
PPD
PPD
PPD


 
 
Contents 
1. 
DEFINITIONS of TERMS ........................................................................................... 1 
2. 
TIME WINDOW ........................................................................................................... 1 
3. 
ANALYSIS SET ............................................................................................................ 2 
4. 
CONSIDERATIONS for ANALYSIS ........................................................................... 2 
5. 
OTHER DATA HANDLING ......................................................................................... 2 
6. 
SUBJECTS ................................................................................................................... 3 
6.1. Subject Disposition ........................................................................................................ 3 
7. 
GRAPH ......................................................................................................................... 4 
7.1. Laboratory Test ............................................................................................................. 4 
7.2. 7 Components of PSQI................................................................................................... 5 
7.3. Actigraph ...................................................................................................................... 5 
7.4. Heartburn and Regurgitation ........................................................................................... 5 
8. 
LISTING ....................................................................................................................... 6 
9. 
CONSIDERATIONS on STATISTICAL ANALYSIS ................................................... 6 
9.1. Adjustments for Covariates ............................................................................................. 6 
9.2. Handling of Dropouts or Missing Data............................................................................. 6 
9.3. Criteria for Interim Analysis and Early Discontinuation ..................................................... 6 
9.4. Multicenter Studies ........................................................................................................ 6 
9.5. Multiple Comparisons/Multiplicity .................................................................................. 6 
9.6. Examination of Subgroups ............................................................................................. 6 
10. REFERENCES ............................................................................................................. 7 
11. REVISION HISTORY .................................................................................................. 7 
 


 
1 
 
1. 
DEFINITIONS of TERMS 
・ MedDRA: Medical Dictionary for Regulatory Activities 
・ PSQI: Pittsburgh Sleep Quality Index 
・ TEAE: Treatment-emergent adverse event (Adverse event or complication which occurs 
after the first administration) 
 
2. 
TIME WINDOW 
For each assessment, evaluable data will be selected according to the following table. When 
there are two or more evaluable data in the same time window, the one with the nearest date to 
the reference date will be selected, and if the differences from the reference date are the same, 
the later one will be adopted. For discontinued subjects, data will be evaluated based on days 
after the first administration and days after the end of treatment. 
(1) PSQI, Actigraph, Heartburn and Regurgitation 
Assessment time point 
Reference Date 
Time window 
Days after the first 
administration 
Days after the end 
of treatment 
At the start of the treatment 
Day 1 
Day-14 - Day1 
 
Week 4  
Day 28 
Day2 - Day35 
<= Day7 
At the end of the study 
Day 56 
Day2 - Day63 
<= Day7 
 
(2) Laboratory Test 
Assessment time point 
Reference Date 
Time window 
Days after the first 
administration 
Days after the 
end of treatment
At the screening 
Day -7 
Day-14 - Day -1 
 
Week 2  
Day 14 
Day 1 - Day 21 
<= Day 7 
Week 4  
Day 28 
Day 22 - Day 35 
<= Day 7 
Week 6  
Day 42 
Day 36 - Day 49 
<= Day 7 
At the end of the study 
Day 56 
Day 2 - Day 63 
<= Day 7 
For reference date and days after the first administration, the first day of administration will be 
referred to as Day 1, and the day before the first day of the administration as Day -1. 
For days after the end of treatment, the day after the last administration will be referred to as Day 
1. 
 
 


 
2 
 
3. 
ANALYSIS SET 
・ Full Analysis Set 
Full Analysis set consists of the subjects who are given at least one dose of the study drug. 
 
4. 
CONSIDERATIONS for ANALYSIS 
・ Confidence coefficient  
95% (two-sided) 
・ Display digit 
 [Mean, Confidence Intervals (CIs), Quartiles] 
Round down to the one digit lower than significant digits of the data. 
 [Standard Deviation] 
Round down to the two digits lower than significant digits of the data. 
 [Minimum and Maximum Values] 
Display the data at the significant digits.  
 [Proportion, Percentage] 
Round to one decimal place. 
 
5. 
OTHER DATA HANDLING 
[Study Drug] 
・ Study drug exposure in days will be calculated as follows: 
Date of last dose – date of first dose +1 
 
 [PSQI] 
・ Global PSQI Score, 7 component scores of PSQI 
Scores will be derived from PSQI according to the rule described in the reference 1). 
 
 [Change in endpoints] 
Changes in endpoints are the differences from the start of the treatment or screening to each 
time point. 
 
 


 
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6. 
SUBJECTS 
6.1. Subject Disposition 
6.1.1. Study Information 
Analysis set: All subjects who are obtained informed consent 
Analysis Items: The earliest date of informed consent 
The latest date of the last date of administration 
Version of MedDRA 
Version of SAS 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The above items will be listed. 
If the last date of administration is missing, the last visit date will be 
substituted. 
 
6.1.2. Eligibility of Subjects 
Analysis set: All subjects who are obtained informed consent 
Analysis Items: Eligibility to enter the treatment period in the study 
 
[Yes, No (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The number of subjects and the percentage will be calculated.  
 
6.1.3. Subject Disposition 
Analysis set: Full Analysis Set 
Analysis Items: Status at the end of study 
 
[Complete, Incomplete (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The number of subjects and the percentage will be calculated.  
 
 


 
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6.1.4. Protocol Deviations and Analysis Datasets 
6.1.4.1. Protocol Deviations 
Analysis set: All subjects who enter the treatment period 
Analysis Items: Protocol Deviations 
[Major GCP violations, Deviations of protocol entry criteria, 
Deviations of discontinuation criteria, Deviations related to 
treatment procedure or dose, Deviations concerning excluded 
medication or therapy, Deviations to avoid emergency risk, 
Other deviations] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
The number of subjects with any protocol deviations will be 
calculated, and classified into the above categories. Subjects 
with two or more deviations will be counted for each 
deviation. 
(1) The number of subjects and the percentage will be calculated. 
 
6.1.4.2. Datasets Analyzed 
Analysis set: All subjects who enter the treatment period 
Analysis Items: Full Analysis Set [Inclusion, Exclusion (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The number of subjects and the percentage will be calculated. Subjects 
with two or more reasons of exclusion will be counted for each reason. 
7. 
GRAPH 
7.1. Laboratory Test 
Analysis set: Full Analysis Set 
Analysis items: Blood serum chemistry (AST, ALT, Total Bilirubin, Creatinine) 
Time point: Screening, Week 2, Week 4, Week 6, End of study 
Analysis methods: Case plots will be made for observed value and change from 
screening. 
 
 


 
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7.2. 7 Components of PSQI  
Analysis set: Full Analysis Set 
Analysis items: 7 component scores of PSQI 
Subjective sleep quality 
 Sleep latency 
Sleep duration 
Sleep efficiency 
Sleep disturbance 
Use of sleep medication 
Daytime dysfunction 
Time Point: Start of the treatment period, Week 4, End of study 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) For each component score, case plots will be made for observed value 
and change from the start of the treatment.  
(2) For global PSQI score, case plots will be made for observed value and 
change from the start of the treatment. 
 
7.3. Actigraph 
Analysis set: Full Analysis Set 
Analysis items: Sleep efficiency, Sleep latency, Number of Nocturnal Awakenings 
(Actigraph) 
Time Point: Start of the treatment period, Week 4, End of study 
Analysis Methods: Case plots will be made for observed value and change from the 
start of the treatment period. 
7.4. Heartburn and Regurgitation 
Analysis set: Full Analysis Set 
Analysis items: Heartburn(daytime), Heartburn(nighttime), Regurgitation(daytime), 
Regurgitation(nighttime) 
Time Point: Start of the treatment period, Week 4, End of study 
Analysis Methods: For intensity of the above endpoints, case plots will be made for 
observed value. 
 
 


 
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8. 
LISTING 
The following data will be listed for the subjects in Full Analysis Set. 
・ Demographic data 
・ Concurrent medical conditions 
・ Medication history 
・ Concomitant medications 
・ Drug compliance 
・ Discontinued subjects 
・ PSQI 
・ Intensity of heartburn and regurgitation 
・ Actigraph 
・ Laboratory test 
・ TEAE 
 
 
9. 
CONSIDERATIONS on STATISTICAL ANALYSIS 
9.1. Adjustments for Covariates 
Adjustments for covariates will not be performed. 
 
9.2. Handling of Dropouts or Missing Data 
Any imputation for missing data will not be performed. 
 
9.3. Criteria for Interim Analysis and Early Discontinuation 
No interim analyses will be performed. 
 
9.4. Multicenter Studies 
No statistical adjustments will be made to compensate for multi-center study. 
 
9.5. Multiple Comparisons/Multiplicity 
No statistical adjustments will be made for multiple comparisons. 
 
 
9.6. Examination of Subgroups 
No subgroup analyses will be performed.  
 
 


 
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10. REFERENCES 
Treatment and Practice Guideline for Sleep Disorder. 2nd ed., Edited by Makoto Uchiyama. JIHO. 
2012; 246-247 
 
11. REVISION HISTORY 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision
1.0 
12 APR 2017
- 
 
2.0 
15 FEB 2018 
Remove the analysis plans to 
calculate descriptive statistics 
such as summary statistics, 
tabulation by category, 95% CI 
and statistical test, and add the 
plans to make graphs and listings.
To amend whole 
analysis plan 
because of a deficit 
of sample size 
(Although 25 
subjects were 
planned, only 4 
subjects were 
enrolled into the 
study.)  
 
PPD