Conditions: Insomnia Major Depressive Disorder
Keywords: Drug Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate exploratorily the effect of ramelteon 8 mg once daily for 8 weeks in the treatment of insomnia patients with depression by using actigraphy.

Detailed description:
The drug being tested in this study is called ramelteon. Ramelteon is being tested to treat people who have insomnia with depression. This study will look at sleep activity of participants who take ramelteon.

The study will enroll approximately 30 patients. Participants will be administered:

• Ramelteon 8 mg

Participants will be asked to take 1 tablet orally at bedtime. This multi-center study will be conducted in Japan. The overall period to participate in this study is 9 weeks (Run-in period for 1 week and treatment period for 8 weeks). Participants will make multiple visits to clinic including the final visit 8 weeks after the start of treatment.

Arms:
arm 1: Ramelteon 8 mg, tablet, orally, once daily at bedtime for 8 weeks.

Interventions: intervention 1: Ramelteon
Intervention descriptions: intervention 1: Ramelteon tablets

Protocol document:
Prot_001.pdf: 
 
 
Title: The exploratory study to investigate the effect of Ramelteon for insomnia patients 
with major depressive disorder by using actigraphy 
 
NCT Number: NCT02669082 
Protocol Approve Date: 31-Jul-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 
 
 
 
 
The exploratory study to investigate the effect of Ramelteon  
for insomnia patients with major depressive disorder by using actigraphy 
 
 
 
 
 
 
 
 
 
 
Sponsor  
Takeda Pharmaceutical Company Limited  
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668 
Study Number 
Ramelteon-4002 
Version Number 
Amendment No. 1 
Study Drug  
Ramelteon 
Date 
July 31, 2017 
 
 
 


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Amendment History:  
Date 
Amendment Number 
Applicable Sites 
March 29, 2016 
Initial version 
All study sites  
July 31, 2017 
Amendment No.1 
All study sites 
 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered 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 research subjects to whom the drug may be administered. 
Furthermore, the information is only intended for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
STUDY ADMINISTRATIVE INFORMATION AND STUDY 
PRINCIPLES 
1.1 
Contact Information and Responsibilities for Study-Related Activities 
See the attachment. 
1.2 
Clinical Study Principals 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
•The ethical principles that have their origin in the Declaration of Helsinki. 
•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. 


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TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND STUDY 
PRINCIPLES ...................................................................................................... 3 
1.1 
Contact Information and Responsibilities for Study-Related Activities .......... 3 
1.2 
Clinical Study Principals................................................................................ 3 
2.0 
STUDY SUMMARY .......................................................................................... 9 
3.0 
ABBREVIATIONS ........................................................................................... 13 
4.0 
INTRODUCTION ............................................................................................. 14 
4.1 
Background ................................................................................................. 14 
4.2 
Rationale for the Proposed Study ................................................................. 14 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 15 
5.1 
Objectives.................................................................................................... 15 
5.1.1 Primary objective ................................................................................... 15 
5.1.2 Secondary objective ............................................................................... 15 
5.2 
Endpoints .................................................................................................... 15 
5.2.1 Primary endpoint ................................................................................... 15 
5.2.2 Secondary endpoints .............................................................................. 15 
5.2.3 Other endpoints...................................................................................... 16 
6.0 
STUDY DESIGN .............................................................................................. 17 
6.1 
Study Design ............................................................................................... 17 
6.2 
Rationale for the Study Design .................................................................... 18 
6.3 
Premature Termination of Entire Clinical Research or Premature 
Termination of Clinical Research at a Study Site ......................................... 19 
6.3.1 Premature termination criteria of entire clinical research ........................ 19 
6.3.2 Criteria for premature termination of study sites..................................... 19 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site ............................................ 19 
6.4 
Procedures for Protocol Revision ................................................................. 19 
7.0 
SELECTION AND WITHDRAWAL CRITERIA ............................................. 21 
7.1 
Inclusion Criteria ......................................................................................... 21 
7.2 
Exclusion Criteria ........................................................................................ 22 
7.3 
Prohibited Medications and Therapies ......................................................... 23 


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7.4 
Management of Study Participants ............................................................... 23 
7.5 
Criteria for Discontinuation or Withdrawal of a Research Subject ................ 24 
7.6 
Procedures for Discontinuation of Individual Research Subjects .................. 25 
8.0 
TREATMENT .................................................................................................. 27 
8.1 
Study Drug .................................................................................................. 27 
8.1.1 Study drug ............................................................................................. 27 
8.1.2 Overdose ............................................................................................... 27 
8.2 
Prescription of the Study Drug ..................................................................... 27 
8.3 
Prescription of Antidepressant Medication ................................................... 28 
8.4 
Non-pharmacological Insomnia Treatment .................................................. 28 
9.0 
STUDY PLAN .................................................................................................. 29 
9.1 
Study Procedures ......................................................................................... 29 
9.1.1 Informed consent ................................................................................... 29 
9.1.2 Demographic data, medical history and prior medication ....................... 29 
9.1.3 History of insomnia ............................................................................... 29 
9.1.4 History of Depression ............................................................................ 29 
9.1.5 Physical examination ............................................................................. 30 
9.1.6 Body weight, height and Body Mass Index (BMI).................................. 30 
9.1.7 Actigraphy ............................................................................................. 30 
9.1.8 Sleep diary ............................................................................................. 30 
9.1.9 17-item Hamilton Rating Scale for Depression (HAM-D17) .................. 31 
9.1.10 Patient Global Impression (PGI) ............................................................ 31 
9.1.11 3 Dimensional Sleep Scale (3DSS) ........................................................ 31 
9.1.12 Columbia Suicide Severity Rating Scale (C-SSRS) ................................ 31 
9.1.13 Concomitant medications ....................................................................... 32 
9.1.14 Concurrent conditions ............................................................................ 32 
9.1.15 Pregnancy .............................................................................................. 32 
9.1.16 Documentation of withdrawals before study treatment ........................... 32 
9.2 
Monitoring of Treatment Compliance in Participants ................................... 33 
9.3 
Schedule of Examinations and Observations ................................................ 33 
9.3.1 Start of the run-in period (VISIT 1) ........................................................ 33 


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9.3.2 Start of the study treatment period (VISIT 2) ......................................... 34 
9.3.3 Treatment period (VISIT 3) ................................................................... 34 
9.3.4 At completion (VISIT 4) or withdrawal ................................................. 35 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENT .................................... 36 
10.1 
Definitions ................................................................................................... 36 
10.1.1 Adverse events ....................................................................................... 36 
10.1.2 Considerations for Adverse Events......................................................... 36 
10.1.3 Serious adverse events ........................................................................... 38 
10.1.4 Severity of adverse events ...................................................................... 39 
10.1.5 Causality of adverse events .................................................................... 39 
10.1.6 Date of onset .......................................................................................... 39 
10.1.7 Date of resolution .................................................................................. 40 
10.1.8 Actions taken for the study drug............................................................. 40 
10.1.9 Outcome ................................................................................................ 41 
10.2 
Procedures ................................................................................................... 41 
10.2.1 Collection and reporting of adverse events ............................................. 41 
10.2.2 Collection and reporting of serious adverse events ................................. 42 
10.2.3 Reporting of additional information concerning adverse events .............. 43 
10.3 
Follow-up of Serious Adverse Events .......................................................... 43 
10.3.1 Reporting of serious adverse events to Ethics Review Committee and 
regulatory authorities ............................................................................. 43 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ...................................... 45 
11.1.1 Steering Committee ............................................................................... 45 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS .............................. 46 
12.1 
Case Report Form ........................................................................................ 46 
12.2 
Storage of Records....................................................................................... 47 
13.0 
STATISTICAL METHODS .............................................................................. 48 
13.1 
Statistical and Analytical Plans .................................................................... 48 
13.1.1 Analysis sets .......................................................................................... 48 
13.1.2 Analysis of demographic and other baseline characteristics .................... 48 
13.1.3 Efficacy analysis .................................................................................... 48 


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13.1.4 Methods of data conversion and handling of missing data ...................... 49 
13.1.5 Significance level and confidence coefficient ......................................... 49 
13.1.6 Safety analysis ....................................................................................... 50 
13.2 
Interim Analysis and Criteria for Early Termination .................................... 50 
13.3 
Determination of Sample Size...................................................................... 50 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 51 
14.1 
Monitoring of the Study Site ........................................................................ 51 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the Research Protocol.................................. 51 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections .................... 51 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH ........................................ 53 
15.1 
Approval of the Ethical Review Board, etc. ................................................. 53 
15.2 
Conflict of Interests ..................................................................................... 53 
15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Research Subjects ........................................................................................ 54 
15.4 
Personal Information of the Research Subjects............................................. 55 
15.5 
Consultation Windows for the Research Subjects or Persons Related to 
the Research Concerned ............................................................................... 56 
15.6 
Financial Burden or Reward to the Research Subjects .................................. 56 
15.7 
Benefits and Inconveniences to the Research Subjects ................................. 56 
15.7.1 Benefits to research subjects .................................................................. 56 
15.7.2 Inconveniences to research subjects ....................................................... 56 
15.8 
Attribution of Research Results and Access Rights ...................................... 56 
15.8.1 Attribution of research results ................................................................ 56 
15.8.2 Data access rights .................................................................................. 56 
15.9 
Reporting of Results, Publication, Disclosure, and Clinical Research 
Registration Policy ...................................................................................... 57 
15.9.1 Reporting of results, publication and disclosure ..................................... 57 
15.9.2 Clinical research registration .................................................................. 57 
15.9.3 Clinical trial results disclosure ............................................................... 57 
15.10 Insurance and compensation for injury ......................................................... 58 
16.0 
REFERENCES .................................................................................................. 59 


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LIST OF TABLES 
Table 10.a 
Takeda Medically Significant AE List ................................................... 38 
LIST OF FIGURES 
Figure 6.a 
Schematic of Study Design .................................................................... 17 
LIST OF APPENDICES 
TABLE 10.A 
TAKEDA MEDICALLY SIGNIFICANT AE LIST ......................... 38 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: Ramelteon 
Study title: The exploratory study to investigate the effect of Ramelteon for insomnia patients 
with major depressive disorder by using actigraphy 
Protocol number: Ramelteon-4002 (293/NRP-003)  
Clinical study design: Multicenter, open-label study  
Objective: To investigate explanatorily the effect of ramelteon 8 mg once daily for 8 weeks in treatment 
for insomnia patients with depression by using actigraphy. 
Study Population: Insomnia patients with major depressive disorder 
Planned number of research subjects: 30 
Number of study sites: Approximately 5 
medical institutions 
Dose and method of administration: 
Ramelteon 8 mg once daily orally at bedtime  
Route of administration: Oral 
Duration of treatment: 8 weeks 
Duration of evaluation: 9 weeks 
(Run-in period for 1 weeks and treatment 
period for 8 weeks)  
Main criteria for inclusion: 
1. Patients with sleep-onset insomnia on ≥3 days per week for ≥4 consecutive weeks at the time of 
informed consent  
2. Patients with a diagnosis of depression according to the DSM-5 
3. Men or women aged ≥20 and <65 years at the time of informed consent  
4. Outpatients  
5. Patients with the 17-item Hamilton Rating Scale for Depression (HAM-D17) score(s) meeting either 
of the following at the start of the run-in period and the start of the study treatment period:  
- a score of 2 for the “6: Insomnia Early” item  
- a score of 1 for the “6: Insomnia Early” item with a subtotal score of ≥3 for the “7: Insomnia 
Middle” and “8: Insomnia Late” items  
6. Patients with a total HAM-D17 score of ≤16 at the start of the run-in period and the start of the study 
treatment period 
7. Patients on stable antidepressant medication, defined as no change of antidepressant medication (s) 
and no change in the dosage for at least 4 weeks before the run-in period 
8. Patients who maintain a routine sleep schedule in daily life, defined as going to bed between 21:00 
and 1:00 on ≥4 days a week  
9. Patients in whom the run-in period actigraphy shows sleep latency ≥30 minutes and total nocturnal 


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sleep time ≤6.5 hours on ≥3 days 
10. Patients who, in the opinion of the principal investigator or investigator, are capable of understanding 
the contents of the study and complying with study requirements 
11. Patients capable of signing and dating the informed consent form in person before any study 
procedures 
Main criteria for exclusion: 
1. Patients with a history of hypersensitivity to ramelteon or melatonin  
2. Patients with severe liver disorder 
3. Patients who took oral ramelteon within 4 weeks before informed consent  
4. Patients who took any oral insomnia medications (including investigational drugs and unapproved 
drugs) within 2 weeks before the study treatment period  
5. Shift workers or night workers  
6. Patients with concurrent psychiatric or neurological diseases other than depression which may affect 
sleep status 
7. Patients with a score of ≥1 for the HAM-D17 “11: Suicide” item at the start of the run-in period or 
the start of the study treatment period, or with any suicide attempts within 24 weeks before or during 
the run-in period  
8. Pregnant women, nursing mothers, or women who plan to become pregnant or donate eggs before the 
informed consent, during the study period or within 4 weeks after the end of the study  
9. Patients participating in another investigational or post-marketing clinical trial/study  
10. Other patients judged by the principal investigator or investigator to be inappropriate for participation 
in this study 
Endpoints: 
<Primary endpoint> 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study treatment 
period) to the end of the treatment period 
*: Mean value from the past 7 days 
<Secondary endpoints> 
• Change in diary-measured sleep latency* from baseline to the end of the treatment period  
• Change in actigraphy-measured total nocturnal sleep time* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured nocturnal wake time* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured number of nocturnal awakenings* from baseline to the end of 
the treatment period 
• Change in actigraphy-measured sleep efficiency* from baseline to the end of the treatment 


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period 
• Change in diary-measured total nocturnal sleep time* from baseline to the end of the treatment 
period 
• Change in diary-measured number of nocturnal awakenings* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured daytime activity level* from baseline to the end of the 
treatment period 
 
 *: Mean value from the past 7 days 
<Additional endpoints> 
Efficacy endpoints 
• Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, number 
of nocturnal awakenings, sleep efficiency, and daytime activity level 
• Diary-measured sleep latency, total nocturnal sleep time, and number of nocturnal awakenings 
• PGI 
• HAM-D17 
• 3DSS 
Safety endpoints 
• Adverse events 
• Body weight 
Statistical method: 
1. Analysis Sets 
The analysis set for this study will be the "Full Analysis Set," which is defined as "all 
participants given at least one dose of the study drug." 
2. Efficacy Analysis 
 
[Primary endpoint] 
In the Full Analysis Set, the change in actigraphy-measured sleep latency from baseline to the 
end of the treatment period will be summarized by calculation of summary statistics (i.e., 
number of participants, mean, standard deviation, maximum, minimum, and quartiles; 
hereinafter the same) and a two-sided 95% confidence interval for the mean, and assessed using 
the one-sample t-test. 
[Secondary endpoints] 
In the Full Analysis Set, the individual secondary endpoints will be summarized by calculation 
of summary statistics and two-sided 95% confidence intervals for the means, and assessed using 
the one-sample t-test.  
Sample Size Justification: 
The sample size is set to 30 in light of feasibility of this study to investigate the effect of 
ramelteon in insomnia patients with depression. This planned sample size is not based on 


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statistical power calculation. 


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3.0 
ABBREVIATIONS 
 
BZD 
Benzodiazepine 
COI 
Conflict of Interest 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
HAM-D 
Hamilton Rating Scale for Depression 
PGI 
Patient Global Impression  
3DSS 
3 Dimensional Sleep Scale 


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4.0 
INTRODUCTION 
4.1 
Background 
Insomnia is commonly encountered in today's medical practice in Japan, and has been 
raised as a clinical and social issue.1) Depression also shows a dramatically increasing 
trend recently2)3), partly because of changes in the working environment, and its social 
impact is becoming a growing concern. Insomnia and depression are known to be often 
comorbid4), and improvement of insomnia symptoms has been described as a key to 
successful resolution of depression.5) Insomnia is known to be associated with not only 
aging and lifestyle-related diseases, but also hypervigilance due to tension from 
excessive expectation about sleep, as well as disturbance of the bodily circadian rhythm 
due to irregular living schedule with a delayed sleep-wake cycle. Depression, on the 
other hand, is typically associated with anxiety, but is now known to be linked with 
negative influence of irregular living schedule as well. Thus, insomnia and depression 
share some same risk factors, and this can explain the high co-existence rate of these 
two disorders.6)7)  
The mainstays in the treatment of insomnia have long been benzodiazepine (BZD)-class 
hypnotics and nonbenzodiazepine-class hypnotics, both classes of which exert sedative 
and anxiolytic effects. A novel melatonin receptor agonist, ramelteon (trade name, 
Rozerem), has been available in Japan since 2010. Ramelteon can improve sleep-onset 
insomnia by working on the bodily clock mechanism and adjusting the circadian rhythm. 
Ramelteon's mechanism of action without sedative or anxiolytic properties appears to be 
of high clinical significance particularly in the treatment of insomnia patients with 
concurrent depression. 
4.2 
Rationale for the Proposed Study  
Reports have been limited on the efficacy and safety of ramelteon in insomnia patients 
with depression or other psychiatric diseases8)9), and none used objective measures. The 
present study is thus designed to use actigraphy to objectively explore the efficacy of 
ramelteon on insomnia in insomnia patients with depression. 
 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary objective 
To investigate exploratorily the effect of ramelteon 8 mg once daily for 8 weeks in 
treatment for insomnia patients with depression by using actigraphy. 
5.1.2 Secondary objective 
To investigate exploratorily the safety of ramelteon 8 mg once daily for 8 weeks in 
insomnia patients with depression. 
5.2 
 Endpoints 
5.2.1 Primary endpoint 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study 
treatment period) to the end of the treatment period 
*: Mean value from the past 7 days 
5.2.2 Secondary endpoints 
• 
Change in diary-measured sleep latency* from baseline to the end of the treatment 
period 
• 
Change in actigraphy-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 
• 
Change in actigraphy-measured nocturnal wake time* from baseline to the end of 
the treatment period 
• 
Change in actigraphy-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured sleep efficiency* from baseline to the end of the 
treatment period 
• 
Change in diary-measured total nocturnal sleep time* from baseline to the end of 
the treatment period 
• 
Change in diary-measured number of nocturnal awakenings* from baseline to the 
end of the treatment period  
• 
Change in actigraphy-measured daytime activity level* from baseline to the end of 
the treatment period 
*: Mean value from the past 7 days 


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5.2.3 Other endpoints  
(1) Efficacy 
• 
Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, 
number of nocturnal awakenings, sleep efficiency, and daytime activity level 
• 
Sleep diary-measured sleep latency, total nocturnal sleep time, and number of 
nocturnal awakenings 
• 
PGI 
• 
HAM-D17 
• 
3DSS 
(2) Safety 
• 
Adverse events 
• 
Body weight 




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6.2 
Rationale for the Study Design 
<Rationale for the study population> 
For ramelteon, a drug approved for "improvement of sleep onset difficulty in 
insomnia", data have been limited on its efficacy and safety in insomnia patients with 
psychiatric disease, and construction of the clinical evidence is desired. Among 
psychiatric diseases, depression is common and often coexists with insomnia 
symptoms. Thus, the study population is set to insomnia patients with depression. 
 
<Rationale for the study design> 
An uncontrolled, open-label design is employed in light of feasibility of this 
post-marketing clinical research, although the primary objective is to explore the 
effect of ramelteon in treating insomnia patients with a history of co-morbid 
depression. 
<Rationale for the dosage> 
The approved dosage and method of administration for ramelteon are employed. 
<Rationale for the endpoints> 
The "Guideline for Clinical Evaluation of Hypnotic Agents" (Notification No. 1213-1 
of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, 
dated December 13, 2011) recommends the use of polysomnography for objective 
efficacy evaluation in addition to the use of patient-recorded sleep logs for subjective 
efficacy evaluation. While polysomnography is a complex examination and repeated 
polysomnography can impose heavy burden on participants, actigraphy has been 
recognized to provide sleep data highly correlated with those provided by 
polysomnography and is a simple tool posing less burden to participants. Thus, 
actigraphy is selected as an objective assessment tool in this study10). For subjective 
measures, this study uses a sleep diary, as well as the Patient Global Impression 
(PGI) as an index of global improvement, and the 3 Dimensional Sleep Scale (3DSS) 
as a new tool to assess sleep dimensions including sleep phases. The HAM-D17 is 
selected for evaluation of depressive symptoms, in line with preceding studies. 
The safety will be evaluated based on adverse events, body weight. 
<Rationale for the treatment duration> 
The treatment duration is set to 8 weeks on the basis of the Japanese long-term 
clinical trial of ramelteon (24-week treatment), which demonstrated gradual 


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manifestation of the efficacy of ramelteon on sleep latency under repeated dosing 
over a certain period, and the efficacy peaked around Week 8. 
<Rationale for the sample size> 
See Section 13.3 
6.3 
Premature Termination of Entire Clinical Research or Premature 
Termination of Clinical Research at a Study Site 
6.3.1 Premature termination criteria of entire clinical research 
The sponsor should immediately discontinue the study when at least one of the 
following criteria is applicable: 
• 
When new information or other evaluation on the safety or efficacy of the study 
drug becomes available that shows a change in the known risk/benefit profile of the 
concerned compound, and risks/benefits are no longer tolerable for research subject 
participation in the study. 
• 
When there is serious deviation from ethical guidelines that may threaten safety of 
the research subjects. 
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at 
the discretion of the sponsor if the entity (e.g., principal investigator) is found in 
significant violation of the ethical guidelines, protocol, or contractual agreement, or is 
unable to ensure proper conduct of the research. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site 
In the event that the sponsor or a study site committee such as an ethics review 
committee decides to prematurely suspend or terminate the entire clinical study or 
clinical study at a study site, a study-specific procedure shall be provided by the sponsor. 
The procedure shall be followed by applicable study sites during the course of clinical 
study suspension or premature termination. 
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. 


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Upon notification, the principal investigator at each study site shall submit the revised 
contents to committees such as the IEC, as necessary according to institutional 
regulations for review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA 
7.1 
Inclusion Criteria  
Participants must fulfill all of the following criteria to be included in this study: 
1. Patients with sleep-onset insomnia on ≥3 days per week for ≥4 consecutive weeks 
at the time of informed consent 
2. Patients with a diagnosis of depression according to the DSM-5 
3. Men or women aged ≥20 and <65 years at the time of informed consent  
4. Outpatients  
5. Patients with the 17-item Hamilton Rating Scale for Depression (HAM-D17) 
score(s) meeting either of the following at the start of the run-in period and the start 
of the study treatment period:  
- a score of 2 for the “6: Insomnia Early” item  
- a score of 1 for the “6: Insomnia Early” item with a subtotal score of ≥3 for the 
“7: Insomnia Middle” and “8: Insomnia Late” items  
6. Patients with a total HAM-D17 score of ≤16 at the start of the run-in period and the 
start of the study treatment period 
7. Patients on stable antidepressant medication, defined as no change of antidepressant 
medication (s) and no change in the dosage for at least 4 weeks before the run-in 
period 
8. Patients who maintain a routine sleep schedule in daily life, defined as going to bed 
between 21:00 and 1:00 on ≥4 days a week  
9. Patients in whom the run-in period actigraphy shows sleep latency ≥30 minutes and 
total nocturnal sleep time ≤6.5 hours on ≥3 days 
10. Patients who, in the opinion of the principal investigator or investigator, are capable 
of understanding the contents of the study and complying with study requirements 
11. Patients capable of signing and dating the informed consent form in person before 
any study procedures 
[Rationale for the inclusion criteria] 
1: This criterion is set to exclude patients with transient insomnia.  
2: This criterion is set to specify the target study population and applicable diagnostic 
criteria.  
3: This criterion is set because both men and women need to be included for evaluation. 
The lower age limit of 20 years is set because personal voluntary consent is valid at and 
above this age. The upper age limit is set for this study to enroll participants who are 
active during daytime and thus appropriate for evaluation using actigraphy.  


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4, 6, 7: These criteria are set to determine patients whose depression symptoms have 
been mild or less and stable.   
5, 9: These criteria are set to determine patients with symptoms of sleep-onset insomnia 
during the run-in period.  
8: This criterion was set to ensure appropriate evaluation of the efficacy and safety of 
the study drug.  
10, 11: These criteria are set as essential elements for the study implementation.  
7.2 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from this study: 
1. Patients with a history of hypersensitivity to ramelteon or melatonin  
2. Patients with severe liver disorder 
3. Patients who took oral ramelteon within 4 weeks before informed consent  
4. Patients who took any oral insomnia medications (including investigational drugs 
and unapproved drugs) within 2 weeks before the study treatment period  
5. Shift workers or night workers  
6. Patients with concurrent psychiatric or neurological diseases other than depression 
which may affect sleep status 
7. Patients with a score of ≥1 for the HAM-D17 “11: Suicide” item at the start of the 
run-in period or the start of the study treatment period, or with any suicide attempts 
within 24 weeks before or during the run-in period  
8. Pregnant women, nursing mothers, or women who plan to become pregnant or 
donate eggs before the informed consent, during the study period or within 4 weeks 
after the end of the study  
9. Patients participating in another investigational or post-marketing clinical trial/study  
10. Other patients judged by the principal investigator or investigator to be 
inappropriate for participation in this study 
[Rationale for the exclusion criteria] 
1, 2: These criteria are set in consideration of the safety of the participants. 
3 to 6: These criteria are set to ensure appropriate evaluation of the efficacy and safety 
of the study drug. 
7, 8: These criteria are set in consideration of the safety of the participants. 
9, 10: These criteria are set as essential elements for the study implementation. 


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7.3 
Prohibited Medications and Therapies  
During the study period, the principal investigator or investigator will instruct the 
participants not to take any other medications than those instructed to be taken, 
including over-the-counter drugs, without first consulting with the principal investigator 
or investigator. 
[Prohibited medications] 
Fluvoxamine maleate will be prohibited from the start of the run-in period. Insomnia 
medications other than ramelteon (including investigational drug and unapproved drugs) 
will be prohibited from at least 2 weeks before treatment period to the end of the study 
period. 
1. Fluvoxamine maleate 
2. Insomnia medications other than ramelteon (including investigational drug and 
unapproved drugs) 
3. Antidepressant medications other than those used at the time of 4 weeks prior to start 
of the run-in period 
[Rationale for prohibited medications] 
1. Fluvoxamine maleate is contraindicated for use with the study drug, ramelteon. 
2, 3. Medications may prevent appropriate evaluation of the efficacy and safety of the 
study drug. 
7.4 
Management of Study Participants 
The following should be observed or instructed to the participants by the principal 
investigator and investigator. 
1. Participants should make scheduled visits and undergo physical examination by 
physician and other specified examinations (Actigraphy, Sleep Diary) . When a 
scheduled visit cannot be made, the participant should promptly contact the principal 
investigator or investigator. 
2. In the event of any symptomatic worsening or other abnormalities except scheduled 
visits, the participant should promptly contact the principal investigator or 
investigator for instructions. 


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3. Participants should take the study drug as instructed by the principal investigator or 
investigator. If not, this must be reported to the principal investigator or investigator 
at the next visit. 
4. Participants should not take any other medications than those instructed to be taken, 
including over-the-counter drugs, without first consulting with the principal 
investigator or investigator (except for emergency situations). 
5. Whenever participants visit another hospital between the informed consent and the 
end of the study, the participant should tell the physician of the other hospital that 
he/she is participating in this study. 
6. Whenever participants visit another hospital between the informed consent and the 
end of the study, the participant should report to the principal investigator or 
investigator about background for the visit and treatment details. 
7. Women of childbearing potential whose male partners are not surgically sterile must 
use appropriate contraception from the time of informed consent to the end of the 
study.  
7.5 
Criteria for Discontinuation or Withdrawal of a Research Subject 
The principal investigator or investigator shall record the main reason for 
discontinuation of protocol treatment on the case report form according to the 
classification described below. Refer to Section 9.1.12 for research subjects who 
withdraw from the research before 
1. Adverse event 
This is selected when an adverse event occurred in a study participant that requires 
premature termination to avoid an unacceptable risk to the participant’s health 
imposed by continued participation in the study; or the study participant is unwilling 
to remain in the study because of the adverse event.  
2. Major protocol deviation  
This is selected when the study participant is found not to fulfill the 
protocol-specified eligibility criteria after the start of the study treatment, or has 
failed to adhere to protocol requirements, and thus the participant’s continued 
participation in the study would pose an acceptable risk to his/her health.  
3. Lost to follow-up  
This is selected when the study participant has not returned to the study site and lost 
contact. In such instances, all attempts to contact the participant must be recorded in 
the source document.  


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4. Voluntary withdrawal  
This is selected when the study participant has requested to withdraw his/her 
participation in the study. The reason for withdrawal, if provided by the participant, 
will be recorded in the case report form.  
5. Discontinuation of the entire study  
This is selected when discontinuation of the entire study is decided by the sponsor, 
institutional review board, regulatory authority, etc. See Section 6.3.1 for details.   
6. Pregnancy 
This is selected when a female study participant is found to be pregnant.  
Note: A participant found to be pregnant must be immediately withdrawn from the 
study. For the withdrawal procedure, see Section 9.1.11.  
7. Lack of efficacy 
This is selected when the investigator or subinvestigator has judged that, because of 
lack of efficacy of study treatment, the participant’s continued participation in the 
study would pose an unacceptable risk to the participant. 
8. Sign of suicide  
This is selected when the HAM-D17 “11: Suicide” item score became ≥1; or the 
principal investigator or investigator judged that the C-SSRS results or other findings 
indicate a sign of suicide. 
9. Remission of depression 
This is selected when the participant’s depression remitted to no longer require 
antidepressant medication etc.  
10. Other  
This is selected when the principal investigator or investigator has decided 
withdrawal of the participant for any other reason. The reason must be detailed in the 
case report from. 
 
7.6 
Procedures for Discontinuation of Individual Research Subjects 
The principal investigator or investigator shall terminate a research subject's research 
participation when the research subject meets the criteria described in Section 7.5. 
Individual research subjects may discontinue their research participation without giving 
a reason at any time during the research. Should a research subject's participation be 
discontinued, the primary reason for termination shall be recorded on the CRF by the 


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principal investigator or investigator. In addition, efforts shall be made to perform all 
tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
TREATMENT 
8.1 
Study Drug  
8.1.1 Study drug  
Nonproprietary name: Ramelteon [JAN] 
Chemical name: N-{2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl} 
propanamide 
Dosage: 8 mg once daily 
Method of administration: Orally at bedtime 
Duration of treatment: 8 weeks  
8.1.2 Overdose 
Overdose is defined as intentional or accidental administration of the study drug at a 
higher dose than that specified in the protocol, either by a health professional or by the 
research subject.  
To consistently collect important safety information about overdose, the principal 
investigator or investigator(s) shall record all cases of overdose on the "Overdose" page 
of the CRF, irrespective of the presence or absence of accompanying adverse event. 
Adverse events associated with overdose shall be recorded on the "Adverse events" 
page of the CRF, in accordance with the procedures described in Section 10.0, 
"ADVERSE EVENTS." 
In addition, serious adverse events associated with overdose shall be recorded in 
accordance with the procedures described in Section 10.2.2, "Collection and reporting 
of SAEs." 
In the event of overdose, the principal investigator or investigator shall treat the subject 
as required based on symptoms 
8.2 
Prescription of the Study Drug  
The principal investigator or investigator will prescribe the study drug according to the 
protocol, to participants who fulfill all of the inclusion criteria and do not meet any of 
the exclusion criteria. 


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8.3 
Prescription of Antidepressant Medication  
The oral antidepressant medication being used in each participant at the time of 4 weeks 
prior to start of the run-in period will be continued without any change to the dosage 
regimen during participation in the study. Addition of antidepressant will not allowed 
after the time of 4 weeks prior to start of the run-in period. 
8.4 
Non-pharmacological Insomnia Treatment  
During the study period, non-pharmacological insomnia treatment should be added or 
changed.  


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The principal investigator or investigator will collect data according to the following 
procedures. In principle, the same principal investigator or investigator should perform 
the examinations, observations, and evaluations in the same participant. The study 
schedule is provided in Appendix A. 
9.1.1 Informed consent 
Informed consent procedures are described in Section 15.3. 
Study procedures may be started only after informed consent is obtained from the 
participant. 
Participants who provided informed consent will be assigned participant identification 
codes for de-identification. The assigned participant identification codes will be used 
throughout the study period without changes. 
9.1.2 Demographic data, medical history and prior medication 
Demographic data will be obtained in terms of date of birth, sex, and history of alcohol 
consumption, and history of smoking. 
Medical history will be obtained in terms of any clinically relevant diseases or 
symptoms that had disappeared or resolved within 1 year before the informed consent. 
Ongoing symptoms or diseases should be regarded as concurrent conditions (see 
Section 9.1.11). 
9.1.3 History of insomnia 
Regarding current insomnia, the following data will be obtained:  
  - Date of onset 
  - Initial/Recurrence 
  - Any non-pharmacological therapy 
9.1.4 History of Depression 
Regarding the current depressive episode, the following data will be obtained: 
  - Date of onset 
  - Initial/Recurrence 
  - Any use of psychotherapy 


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9.1.5 Physical examination 
Physical examination will be performed. Findings of physical examination after the start 
of the treatment period will be compared with those before the treatment period, and 
assessed for any abnormalities that can be clinically relevant. 
9.1.6 Body weight, height and Body Mass Index (BMI) 
Body weight and height will be measured. BMI will be calculated by the sponsor, using 
the following equation: 
Body Mass Index (BMI) = Body Weight (kg) / (Height (m))2 
Height will be measured to the nearest whole number in centimeters. Body weight will 
be measured to the first decimal place in kilograms. The calculated BMI value will be 
expressed to the first decimal place. 
9.1.7 Actigraphy 
At the end of the informed consent, an actigraph will be lent to each participant. After 
full instructions on actigraphy are provided to the participants, actigraphy recording will 
be started. Patients meeting the inclusion criteria on the basis of the data in the run-in 
period will keep the actigraph, and be instructed to wear it until the end of the treatment 
period.  
Participants will be instructed to bring the actigraph at each study visit. For analysis of 
the data recorded in the actigraph, the actigraph will be connected to a computer with an 
actigraphy data analysis software installed, and the following data will be transferred to 
the analysis software: sleep latency, total nocturnal sleep time, nocturnal wake time, the 
number of nocturnal awakenings, sleep efficiency and daytime activity level (step 
counts). For each of these parameters, the validity of the measured data will be checked 
according to the “Procedures for actigraphic sleep assessment” prepared separately, and 
the data during the run-in period (Weeks -1 to 0) and the treatment period (Weeks 3 to 4 
and 7 to 8) will be recorded in the case report form. The actigraph device will be 
retrieved after completion of the actigraphy recording on the 3 occasions, or when the 
participant is withdrawn from the study.  
9.1.8 Sleep diary 
At the end of the informed consent, a sleep diary will be provided to each participant, 
with instruction on how to keep the diary during the study period. The following diary 
data during the run-in period (Weeks -1 to 0) and the treatment period (Weeks 3 to 4 
and 7 to 8) will be recorded in the case report form: sleep latency, bedtime hour, 


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awakening hour and number of nocturnal awakenings. Any missing entries, 
discrepancies, or other potentially dubious entries in the sleep diary will be checked 
with the participant, and explained in the sleep diary by the participant. Accordingly, 
necessary additions and corrections will be made to the sleep diary, and recorded in the 
case report form.  
9.1.9 17-item Hamilton Rating Scale for Depression (HAM-D17) 
The Hamilton Rating Scale for Depression (HAM-D) is a questionnaire used to rate the 
severity of depression based on general symptoms of depression, including physical 
symptoms. The rater will assess individual items on a scale from 0 to 2, 3, or 4 
depending on the items, based on an interview with the participant.6) The time frame 
assessed by the HAM-D is one week before each visit. This study will use the 17-item 
version (HAM-D17), and the scores of individual items and the total score will be 
assessed and recorded in the case report form. 
9.1.10 Patient Global Impression (PGI) 
The Patient Global Impression (PGI) is a patient-rated scale to measure the degree of 
any improvement (or worsening). Participants will rate their own condition compared 
with the run-in period (before the start of study treatment), and enter the score in the 
PGI form. The principal investigator or investigator will record the score in the case 
report form. 
9.1.11 3 Dimensional Sleep Scale (3DSS) 
The 3 Dimensional Sleep Scale (3DSS) is a patient-administered questionnaire 
developed in Japan, and used to assess sleep dimensions including sleep phases.7) At 
each visit, participants will assess their own condition within the past month and 
complete the 3DSS form. The principal investigator or investigator will record the 
results of 3DSS in the case report form. 
9.1.12 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire developed by researchers at Columbia University as a 
tool to help systematically assess suicidal ideation and behavior in the individuals 
during participation in a clinical research.13)14) The C-SSRS consists of 3 questions 
addressing suicidal behavior and 5 questions addressing suicidal ideation, with 
subquestions assessing the severity. The principal investigator or investigator will 
perform the C-SSRS assessment based on an interview with the participant. Since this is 
performed to detect any signs of suicide during the study period, the C-SSRS 
assessment results will not be recorded in the case report form.  


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9.1.13 Concomitant medications 
Concomitant medications are any psychotherapeutic drugs (Drugs for Insomnia, 
Antidepressant) that are used in addition to the study drug, and include drugs prescribed 
by doctors or over-the-counter drugs purchased by the participants. At each visit, 
participants will be interviewed about any psychotherapeutic drugs used other than the 
study drug from the time of informed consent to the end of the study and specific usage 
(drug name). 
9.1.14 Concurrent conditions 
Concurrent conditions are defined as symptoms or diseases that are present at the time 
of the informed consent. Abnormal findings from physical examination at the start of 
the run-in period will be regarded as concurrent conditions at the discretion of the 
principal investigator or investigator. 
9.1.15 Pregnancy 
If pregnancy of a participant is found during the study, with agreement of the female 
participant, the principal investigator or investigator will inform her 
obstetrics/gynecology doctor about the fact of her participation in the clinical study at 
the onset of the pregnancy, as well as details of the study drug. 
All pregnancies reported during the study will be followed up to their outcomes by the 
principal investigator or investigator, with agreement of the participants with pregnancy. 
The outcome of pregnancy, including any premature labor, will be reported to the 
sponsor, using a designated report form. Assessment after childbirth will also be 
performed. 
9.1.16 Documentation of withdrawals before study treatment 
For all participants withdrawn before the start of study treatment after signing the 
consent form, the case report form will be completed. 
The following data will be recorded in the case report form: 
• 
Date of informed consent 
• 
Date of birth 
• 
Sex 
• 
Eligibility 
• 
Reason for withdrawal 
The main reason for the withdrawal before the start of study treatment will be recorded, 
using the following classification: 


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• 
Not fulfilling all of the inclusion criteria, or meeting any of the exclusion criteria 
• 
Major protocol deviation 
• 
Lost to follow-up 
• 
Voluntary withdrawal (The reason should be specified) 
• 
Discontinuation of the entire study 
• 
Pregnancy 
• 
Other (The reason should be specified) 
Participant identification codes assigned to the participants withdrawn before the start of 
study treatment must not be reused. 
9.2 
Monitoring of Treatment Compliance in Participants 
At each visit, the principal investigator or investigator will assess the participant's 
compliance with the study drug and antidepressant medication. The compliance status 
will be classified into 4 categories: nearly all of the prescribed doses were taken (≥90%), 
most of the prescribed doses were taken (≥70%), about half of the prescribed doses 
were taken (≥50%), or less than half of the prescribed doses were taken (<50%). 
Throughout the study period, participants will be reinstructed about medication. If poor 
compliance with the study drug after the previous visit, such as <50% of prescribed 
doses, is found and does not improve, the participant may be withdrawn as appropriate. 
9.3 
Schedule of Examinations and Observations 
The schedule for all examinations, observations, and evaluations is shown in Appendix 
A. The principal investigator or investigator will perform the following examinations, 
observations, and evaluations as scheduled. 
9.3.1 Start of the run-in period (VISIT 1) 
After informed consent, the following data will be obtained by physical examination 
and other examinations. In addition, participants will be instructed to keep a sleep diary 
and to perform actigraphy recording for 1 week before VISIT 2 (i.e., Week -1 to Week 
0). Eligibility of participants will be confirmed against the inclusion and exclusion 
criteria given in Section 7.0. For documentation of participants withdrawn during the 
run-in period, the procedures in Section 9.1.13 should be followed. 
During the run-in period, the following examinations, observations, and evaluations will 
be performed: 
• 
Informed consent 


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• 
Demographic data, medical history, prior medication, history of insomnia, 
depressive episodes  
• 
Physical examination 
• 
Height, body weight and BMI 
• 
Concurrent medications 
• 
Concurrent conditions 
• 
HAM-D17 
• 
C-SSRS (baseline) 
9.3.2 Start of the study treatment period (VISIT 2) 
At the start of administration of the study drug, the following examinations, 
observations, and evaluations will be performed. 
For participants fulfilling all of the inclusion criteria and not meeting any of the 
exclusion criteria given in Section 7.0, the principal investigator or investigator will 
instruct to start taking the study drug according to Section 6.1. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
Concurrent conditions 
• 
HAM-D17 
• 
Assessment of the actigraphy data from Week -1 to Week 0 
• 
Sleep diary 
• 
3DSS 
• 
C-SSRS (after last assessment) 
9.3.3 Treatment period (VISIT 3) 
During the treatment period (VISIT 3), the following examinations, observations, and 
evaluations will be performed.  
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
HAM-D17 
• 
Assessment of actigraphy data from Week 3 to Week 4 
• 
Sleep diary 


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• 
Adverse events 
• 
3DSS 
• 
Treatment compliance 
• 
C-SSRS (after last assessment) 
9.3.4 At completion (VISIT 4) or withdrawal 
Final visit will be made at 8 weeks after the start of study treatment, when the following 
examinations, observations, and evaluations will be performed. In withdrawn 
participants, the same examinations, observations, and evaluations will be performed at 
withdrawal from the study. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
HAM-D17 
• 
Assessment of actigraphy data from Week 7 to Week 8* 
• 
Sleep diary 
• 
Adverse events 
• 
3DSS 
• 
Treatment compliance 
• 
C-SSRS(after last assessment) 
• 
PGI 
For all participants given the study drug, the study completion/withdrawal status will be 
recorded in the case report form. 
 


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10.0 
Pretreatment Event and Adverse Event 
10.1 
Definitions 
10.1.1 Adverse events 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product (including a study drug) 
and which does not necessarily have to have a clear causal relationship with this 
treatment. 
An adverse event can therefore be any unfavorable or unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
10.1.2 Considerations for Adverse Events 
Generally unfavorable findings are described below: 
• Newly diagnosed disease or unexpected aggravation of existing symptom 
(intermittent event of an existing symptom is not considered an adverse event) 
• Requiring action or medical practice 
• Requiring invasive diagnostic treatment 
• Requiring discontinuation or a change in the dose of the study drug 
• Considered unfavorable by the investigator or the subinvestigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including 
abnormal laboratory values, abnormal ECG findings) and symptoms shall not be 
recorded as adverse events. If an adverse event could not be expressed by a diagnosis 
name, the signs or symptoms shall be recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when 
the principal investigator or investigator judges the results are clinically problematic (in 
other words, when certain action or medical practice is required, or when the principal 
investigator or the investigator judges the change has exceeded the normal physiological 
variation range of the research subject). Retest and/or continued monitoring of an 
abnormality are not considered medical practice. Also, repeated or additional 


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conduction of non-invasive tests for verification, evaluation, and monitoring of an 
abnormality are not considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying 
symptoms of a disease diagnosed as an adverse event (e.g., increased creatinine due to 
renal dysfunction, etc.), the adverse event shall be handled by its diagnosis name. 
Pre-existing conditions (at start of treatment period):  
A disease or symptoms that had been present since before the start of observation period 
shall be regarded as a concurrent disease and not an adverse event. When a concurrent 
medical condition is aggravated, the aggravation shall be determined as an adverse 
event and the investigator or the subinvestigator shall record on the CRF that the 
adverse event is an aggravation of the concurrent disease (e.g., "aggravation of 
hypertension," etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each 
episode shall be recorded as an adverse event if the episodes become more frequent, 
serious, or severe in nature. If a research subject has a chronic concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition shall be recorded as adverse 
event if the degree of the worsening exceeds that which would be expected. The 
principal investigator or investigator shall ensure that the adverse event term to be 
recorded represents the change in the condition from baseline (e.g. "worsening of…"). 
Worsening of adverse events: 
If a research subject experiences a worsening of the adverse event after a change to the 
study drug, or secondary signs and symptoms are caused by the adverse event, the 
worsening or the secondary signs and symptoms shall be recorded as a new adverse 
event on the CRF. The principal investigator or investigator shall use an adverse event 
term that explicitly means a change of the condition (e.g., "worsening of…"). 
Change of severity of adverse events: 
If the research subject experiences changes in the severity of an adverse event, the event 
shall be recorded once, at its peak severity. 
Previously planned surgery or treatment: 
Preplanned surgeries or interventions that were scheduled before study treatment shall 
not be considered adverse events. However, when the existing symptom is aggravated 
to a degree requiring emergency surgery or treatment, the condition or the event shall be 
considered an adverse event. A concurrent disease that resulted from previously planned 
surgery shall be reported as an adverse event. 


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Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a 
research subject (cosmetic surgery, etc.) shall not be considered an adverse event; 
however, it shall be recorded in the source documents. Concurrent diseases due to a 
non-urgent surgery shall be reported as an adverse event. 
The Insufficient clinical response (lack of efficacy) 
Insufficient clinical response, efficacy, or pharmacological action shall not be recorded 
as an adverse event. The principal investigator or investigator shall make the distinction 
between worsening of a pre-existing condition and lack of therapeutic efficacy. 
Overdose of the study drug 
Overdose of any medication without manifested symptoms shall not be recorded as an 
adverse event, but the overdose shall be recorded on the "Overdose" page of the CRF. 
Any manifested symptoms shall also be recorded as adverse events on the "Adverse 
events" of the CRF. 
10.1.3 Serious adverse events 
Of all the unfavorable medical events that develop with administration of drugs 
(irrespective of dose), a serious adverse event is an event that: 
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, or 
6. other medically significant condition: a medically important event that causes a 
risk to a research subject even if it is not immediately life-threatening and does 
not result in death or hospitalization, or requires an action or treatment to 
prevent the results described in 1 to 5 above. Points described in the Takeda 
Medically Significant Adverse Event List (Table 10 (a)) are included in this 
section. 
* The term "life threatening" refers to an event in which the research 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. 
Table 10.a 
Takeda Medically Significant AE List 
 


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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 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
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 adverse events 
The causal relationship of each adverse event to the study drug and control drug shall be 
classified and defined as shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). Possibly due to the study drug or control drug, although other 
factors such as underlying disease, concurrent diseases, or concomitant drugs/treatment 
are also suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug and control drug. Very likely due to other factors such 
as underlying disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.6 Date of onset 
The date of onset of adverse events shall be determined according to the following 
rules: 
Adverse event, etc. 
Date of onset 


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Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the principal investigator or 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 concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of the study 
drug administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.7 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject 
recovered (including resolution with sequelae). If a research subject died due to the 
adverse event concerned, it shall be the date of death. The adverse event shall be 
recorded as "ongoing" if the research subject has not yet recovered by the end of the 
study. 
10.1.8 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including withdrawal 
by the research subject at his/her own discretion). 
When the treatment with the study drug is continued after withdrawal from the 
study, it is defined as "Dose not changed." 
 
Dose not changed 
The dose was not changed after the onset of the adverse event. 
The study drug or control drug was discontinued, reduced, or increased because of 
another adverse event. 
The study drug was discontinued or reduced for a reason other than the adverse 
event, e.g., inadvertence of the research subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
research 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 adverse event. 


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Dose reduced  
The dose or control drug was reduced because of the adverse event (including 
dose reduction by the research subject at his/her own discretion). 
Washout  
The study drug or control drug was suspended (i.e., interrupted) by the research 
subject at his/her discretion) because of the adverse event (including 
suspension/interruption, but resumed thereafter. 
10.1.9 Outcome 
Outcome of adverse events 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 research subject died from a cause other than the concerned adverse event 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 research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 
Death 
Direct relationship between death and the concerned adverse event 
"Direct relationship" means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research 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. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Adverse events will be collected for the following periods:  
• 
Any adverse events occurring between the start of study drug administration 
and completion (or discontinuation) of the treatment period 


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10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence 
of any onset of subjective symptoms. A neutral question, such as "How have you been 
feeling since your last visit?" may be asked to collect any adverse events that occurred 
between the previous and present visits. 
The principal investigator or investigator shall follow up all research subjects 
experiencing an adverse event irrespective of the causal relationship with the study drug, 
until the symptom resolve, or any clinically significant abnormal laboratory values have 
returned to baseline or there is a satisfactory explanation for the change (permanent and 
irreversible adverse events, etc.). All adverse events shall be entered on the CRF, with 
the event term, onset date, resolution date, severity, causal relationship with the study 
drug (i.e. "Unrelated" or "Related"), action taken for the study drug, outcome, causal 
relationship with any study procedure (with specific procedure if assessed to be causally 
related), and seriousness. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the 
time when the principal investigator or investigator judges that further follow-up would 
be unnecessary. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it 
shall be reported according to the following procedures.  
At the time of onset of a serious adverse event or notification of the onset by the 
research subject, the principal investigator shall report the serious adverse event to the 
chief executive of the study site immediately, and the sponsor or CRO to whom the 
sponsor has entrusted responsibility shall notify the principal investigator of the study 
site. 
The principal investigator shall then report the serious adverse event to the sponsor (for 
the contact information, refer to the attachment) within 1 day of becoming aware of the 
event onset. Further, the investigator shall submit a formal report within 10 calendar 
days to the sponsor. 
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. 
・ Brief description of adverse event and the reason for why it was determined as 
serious 


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・ Research subject ID number 
・ Name of investigator or the subinvestigator 
・ Name of the study drug 
・ Determined causal relationship 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events 
for reporting to regulatory authorities, the investigator or the subinvestigator shall 
confirm the necessary additional information and enter in the EDC system or submit a 
report within the period specified by the sponsor. 
10.3 
Follow-up of Serious Adverse Events 
When information that was not included in the detailed report was obtained later, the 
principal investigator or investigator shall state it in the copy of the report on serious 
adverse events, or create another document and submit it to the contact address shown 
on the attached sheet. 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 IEC upon request. 
The investigator or the subinvestigator shall follow-up all serious adverse events, until 
recovery is confirmed, or the final outcome is determined.  
10.3.1 Reporting of serious adverse events to Ethics Review Committee and 
regulatory authorities 
When the chief executive of the study site receives a report of a serious adverse event 
from the investigator, the chief shall consult the Ethics Review Committee, etc., and 
notify the study sites that are conducting the clinical research through the sponsor or the 
CRO consigned by the sponsor. 
Serious adverse event reported by the principal investigator is unexpected, the chief 
executive of the study site shall prepare a written report of the unexpected serious 
adverse event containing the information reported by the principal investigator plus the 
information below, and submit the report to the Minister of Health, Labor and Welfare, 
and notify other clinical study sites. (The chief executive of the study site may report it 
to the Minister of Health, Labor and Welfare via the sponsor, and notify it to other 
clinical study sites via the sponsor.)  


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• 
Actions taken for serious adverse events 
(discontinuation of new enrollment, revision of informed consent form, 
re-consents to other research 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 serious adverse events that are subject to emergency reporting 
to regulatory authorities, the investigators, and directors of study sites. 
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 study drug 
risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The study site shall submit copies of emergency report documents to the 
Ethics Review Committee, etc. 
 
 
 
 
 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
The Steering Committee will be established for this study. 
11.1.1 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 MANAGEMENT AND STORAGE OF RECORDS 
CRO shall be in charge of implementing data management operation independently 
from Medical Affairs department of the sponsor. Adverse events, medical history, and 
concurrent conditions shall be coded using MedDRA. Drugs shall be translated using 
the WHO Drug Dictionary. 
12.1 
Case Report Form 
The principal investigator fr investigator shall complete a CRF for each research subject 
who has signed the informed consent form. 
The sponsor or its designee shall provide study sites with access authorization to the 
electronic CRF. Before use of the electric CRF 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 made 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 investigator or its designee shall ensure the accuracy and completeness of the CRF, 
and provide an electronic signature on the relevant page of the case report form. The 
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. 
• 
Severity, degree, the causal relationship with the study drug, control drug, or the 
study procedures, outcome 
When the principal investigator or investigator changes or corrects the content of the 
CRF after having submitted it to the sponsor, the form for change and correction of a 
CRF provided by the sponsor (Data Clarification Form) 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. 
The sponsor or the designee shall confirm that the CRF has been made appropriately in 
conformity with the procedure defined for each research. The sponsor or the designee 
shall read the medical record or in-hospital record related to the research subject to 
ensure the accuracy of the CRF. The completed CRF shall be the property of the 


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sponsor, and the principal investigator or investigator shall not disclose the information 
to a third party without written permission from the sponsor. 
12.2 
Storage of Records 
The principal investigator or the chief executive of study site shall store the following 
materials, 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 research subject ID 
number list, research subjects' medical records, clinical research work sheet, original 
signed and dated informed consent forms, {CRFs (copy), change and modification 
record of the CRF (copy)/ an electronic copy of the electronic CRFs with audit trails, 
and the drug management records, etc. The principal investigator and the chief 
executive of the study site shall appropriately retain the material/information related to 
this study for at least 5 years from the date of reporting the end of the research 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. 


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13.0 
STATISTICAL METHODS 
Statistical analysis will be performed by the responsible biostatistician and his/her 
designee (i.e., biostatistician of a contract research organization independent of the 
sponsor). The sponsor is not involved in the analysis of this study. 
13.1 
Statistical and Analytical Plans 
The biostatistician will prepare the initial version of a statistical analysis plan before 
informed consent of the first participant. The statistical analysis plan will specify 
detailed definitions of the endpoints and analytical methods to address all study 
objectives. 
13.1.1 Analysis sets 
The analysis set for this study will be the "Full Analysis Set," which is defined as all 
participants given at least one dose of the study drug. 
13.1.2 Analysis of demographic and other baseline characteristics  
Major demographic and other baseline characteristics in the Full Analysis Set will be 
summarized. 
13.1.3 Efficacy analysis 
[Primary endpoint] 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study 
treatment period) to the end of the treatment period 
*: Mean value from the past 7 days 
[Analytical methods] 
In the Full Analysis Set, the change in actigraphy-measured sleep latency from baseline 
to the end of the treatment period will be summarized by calculation of summary 
statistics (i.e., number of participants, mean, standard deviation, maximum, minimum, 
and quartiles; hereinafter the same) and a two-sided 95% confidence interval for the 
mean, and assessed using the one-sample t-test. 
[Secondary endpoints] 
• 
Change in sleep diary-measured sleep latency* from baseline to the end of the 
treatment period 
• 
Change in actigraphy-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 


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• 
Change in actigraphy-measured nocturnal wake time* from baseline to the end of 
the treatment period 
• 
Change in actigraphy-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured sleep efficiency* from baseline to the end of the 
treatment period 
• 
Change in sleep diary-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 
• 
Change in sleep diary-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured daytime activity level* from baseline to the end of 
the treatment period 
*: Mean value from the past 7 days 
 
[Analytical methods] 
In the Full Analysis Set, the individual secondary endpoints will be summarized by 
calculation of summary statistics and two-sided 95% confidence interval for the mean, 
and assessed using the one sample t-test. 
 
[Other endpoints] 
• 
Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, 
number of nocturnal awakenings, sleep efficiency, and daytime activity level 
• 
Diary-measured sleep latency, total nocturnal sleep time, and number of nocturnal 
awakenings 
• 
PGI 
• 
HAM-D17 
• 
3DSS 
13.1.4 Methods of data conversion and handling of missing data 
Details will be specified in the statistical analysis plan prepared separately. 
13.1.5 Significance level and confidence coefficient 
Significance level: 5% (two-sided testing) 


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Confidence coefficient: 95% (two-sided estimation)  
13.1.6 Safety analysis 
[Safety endpoints] 
• 
Adverse events 
• 
Body weight 
[Analytical methods] 
The safety will be analyzed in the Full Analysis Set as follows:  
Treatment-Emergent Adverse Events (TEAEs), defined as adverse events occurring 
after the start of study drug administration, will be coded to the Medical Dictionary for 
Regulatory Activities (MedDRA) terms, and summarized by Preferred Term (PT) and 
System Organ Class (SOC) with frequency tabulation. 
Frequency tabulation will be generated for the following: 
• 
All TEAEs 
• 
TEAEs related to the study drug 
• 
All TEAE by severity 
• 
TEAEs realted to the study drug by severity 
• 
TEAEs leading to discontinuation of study treatment 
• 
Serious TEAEs 
For body weight and vital signs, the measurements at each time point of evaluation will 
be summarized using frequency tabulation. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size  
The sample size is set to 30 in light of feasibility of this study to investigate the effect of 
ramelteon in insomnia patients with depression. This planned sample size is not based 
on statistical power calculation. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the Study Site 
The sponsor or its designee shall perform periodic monitoring of study sites during the 
research to confirm that the research is conducted in accordance with all specifications 
in the research 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 research 
subject ID numbers, medical records of the research subjects, and signed and dated 
original consent forms to confirm that the research is appropriately conducted in 
compliance with the research protocol. Also, confirm the consistency between CRF and 
the related source documents. The principal investigator, investigator, and other 
personnel involved in the research shall spare sufficient time to facilitate monitoring 
procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the quality 
monitoring plan. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the Research Protocol.  
The principal investigator or investigator shall record all deviations from Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, and research 
protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief 
executive of the study site for the clinical research 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 the IEC. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site may be research subject to audits by the sponsor or its designee. 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 clinical research. In 
addition, this research may be inspected by regulatory agencies, including those of 
foreign governments (e.g., the Food and Drug Administration [FDA], the United 


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Kingdom Medicines and Healthcare products Regulatory Agency [MHRA]). If the 
study site is contacted for an 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 research-related source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants 
(i.e., research subjects) according to the research protocol, and the ethical principles that 
have their origin in the Declaration of Helsinki, Ethical Guidelines for Medical and 
Health Research Involving Human Subjects. Each investigator will conduct the study 
according to regulatory requirements and in accordance with "Responsibilities of the 
Investigator" in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations 
For implementation or continuation of this study, the principal investigator will provide 
the head of the medical institution with this protocol, a copy of the informed consent 
form and other documents required by applicable regulations. The head of the medical 
institution will then request a review to be done by the institutional review board etc. 
regarding essential items for proper implementation of the clinical study, including 
whether the protocol is compliant with the Ethical Guidelines for Medical and Health 
Researches Involving Human Participants. Documentation of approval of the 
institutional review board etc. and agreement of the head of the medical institution must 
be obtained by the principal investigator before implementation or continuation of the 
study.  
The study site shall observe all requirements that the Ethical Review Board, etc. 
prescribe. The requirements may include notifications to committees such as the IEC, 
for example, revision of the research protocol, revision of the informed consent form 
and information sheet, reports on safety in accordance with the regulatory requirements, 
reports on status of implementation of the research at intervals determined by a study 
site committee such as the Ethics Review Committee, and submission of the study 
completion report. 
15.2 
Conflict of Interests 
Prior to the conduction of this clinical research, the investigators involved in this 
clinical research shall ensure appropriate management of any conflicts (COI) in the 
conduct of the research in accordance with the rules of the study site.15)-19) 
The study site shall comply with all requirements specified by a committee such as the 
Ethics Review Committee, including the COI self-statement form, the research protocol, 
and the informed consent form and information sheet. 


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15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Research Subjects 
The informed consent and information sheet form shall contain specific requirements of 
the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and all applicable laws and regulations. The informed 
consent form and information sheet shall specify the use of personal information and 
medical information of research subjects in this clinical research (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 research, its objectives, and 
potential risks and benefits. The informed consent form will detail the requirements of 
the participant and the fact that research 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 research subject information sheet by the committee 
such as the IEC. 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 research subjects. The principal investigator or 
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 the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects 
(or the representatives) have (1) an opportunity to inquire about the research and (2) 
sufficient time to decide on their participation. If a potential research subject (or their 
representative) decides he or she is willing to participate in the research, then the 
informed consent form must be signed and dated by the potential research subject (or 
the representative) prior to entering into the research as a subject. The principal 
investigator or investigator shall instruct the potential research subject (or 
representative) to sign using their legal names, not nicknames, using a blue or black ball 
point ink pen. Also the principal investigator or investigator shall sign and date the 
informed consent form prior to entering into the research. 
Once signed, the original informed consent form shall be retained by the principal 
investigator or investigator. The principal investigator or investigator shall record the 
date that the potential research subject signed the informed consent form in the subject's 


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medical record. A copy of the signed informed consent form shall be given to the 
research subject. 
The principal investigator or investigator shall follow the same procedure as for 
obtaining the initial consent when newly obtaining re-consent from the concerned 
research subject (or the representative) when the informed consent form is revised. The 
date of obtaining new consent shall be recorded in the research subject's medical record, 
and a copy of the revised consent form shall be provided to the research subject. 
15.4 
Personal Information of the Research Subjects 
The sponsor or the designee shall affirm the principle of the protection of research 
subjects' private/personal information. Throughout this study, research subject ID 
numbers shall be used to link the subject's source data to the sponsor's research database 
and research-related documents. Limited information on research subjects such as 
gender, age, and date of birth may be used within the scope of all applicable laws and 
regulations for identification of research subjects and confirmation of accuracy of 
research subject ID number. 
For verification of the conduct of the research in compliance with this protocol and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects, the 
sponsor shall require the principal investigator to provide the research sponsor's 
designee, representatives of regulatory authorities, designated auditors, and committees 
such as the Ethical Review Board direct access to research subjects' original medical 
records (source data or documents), including laboratory test results, ECG results, 
admission and discharge records during a subject's research participation, and autopsy 
reports.  
The principal investigator or investigator shall obtain specific authorization of the 
research subject as part of the informed consent process for access to research subject's 
original medical records by research sponsor's designee and representatives of 
regulatory authorities (see Section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or 
investigator shall delete information that may lead to identification of an individual 
(name and address of research subject, other personal information not recorded on the 
CRF of the research subject). 


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15.5 
Consultation Windows for the Research Subjects or Persons Related to the 
Research Concerned 
The principal investigator shall establish a contact service to respond to inquiries 
concerning this clinical research from research subjects or concerned people. Details of 
the contacts for inquiries will be described in the ICF. 
15.6 
Financial Burden or Reward to the Research Subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for 
medical treatment not covered by health insurance as research expenses. 
The research 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 clinical research to the research subjects at each visit from the 
research funds. Details of the financial burden on the research subjects and rewards 
shall be described in the informed consent form and information sheet. 
15.7 
Benefits and Inconveniences to the Research Subjects 
15.7.1 Benefits to research subjects 
Participation in this study is expected to allow more detailed characterization of the 
pathological condition of insomnia based on objective measurements, leading to 
selection of more appropriate treatment in individual patients. 
15.7.2 Inconveniences to research subjects 
Certain insomnia medications will be restricted during participation in this study.  
15.8 
Attribution of Research Results and Access Rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. In 
addition, secondary use (metaanalysis, etc.) of the data obtained in this clinical research 
may be possible if used in such a way that the data shall not be linked to personal 
identification information. 
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. 


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15.9 
Reporting of Results, Publication, Disclosure, and Clinical Research 
Registration Policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the 
chief executive of the study site and provide the sponsor with all the results and data 
obtained from the research. Only the sponsor may disclose the research information to 
other principal investigators, investigators or regulatory authorities during the research 
period, except when required by laws and regulations. The sponsor shall be responsible 
for publication of the research protocol and research-related results (including the public 
web site) except for other cases permitted in the research contract. 
During research period and after the end of research, the sponsor or its designee should 
promptly summarize the results and present it to medical journals and academic 
conferences, etc. The sponsor may publish any data or information obtained from the 
research (including data and information provided by the principal investigator) without 
obtaining agreement of the principal investigator. 
The investigator or the subinvestigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this research at an academic 
conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a 
timely manner and to comply with applicable laws, regulations, and guidelines, Takeda 
Pharmaceutical Company Limited shall register all clinical research being conducted in 
patients around the world at public trial registration sites, including at least the 
website(s) of ClinicalTrials.gov and Japan Pharmaceutical Information Center Clinical 
Trials Information (JAPIC), before initiation of the clinical research. On such websites, 
the research location (city, country), subject recruitment status, and contact information 
for Takeda Pharmaceutical Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the research results, irrespective of 
the nature of the results, at the public trial registration sites of Clinical Trials.gov and 
JAPIC in accordance with applicable laws and regulations. 


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15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any injury 
resulting from participation in the research according to local regulations applicable to 
the study site. The sponsor or its designee shall buy an insurance policy to compensate 
for health injury in research subjects 


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16.0 
REFERENCES 
1. Furihata R, Uchiyama M, Takahashi S, The association between sleep problems 
and perceived health status: a Japanese nationwide general population survey. 
Sleep Med. 2012;13(7):831-7. 
2. Patient Survey 2011 (Disease and Injury). Statistics and Information Department, 
Minister's Secretariat, Ministry of Health Labour and Welfare; 2011 
3. Kawakami N. [Major depression in Japan and the world -- State-of-art in 
epidemiology]. J Clin Exper Med. 2006;219:925-929. 
4. Sunderajan P, Gaynes BN, Wisniewski SR, et al. Insomnia in patients with 
depression: a STAR*D report. CNS Spectr. 2010;15:394-404. 
5. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with 
fluoxetine in patients with insomnia coexisting with major depressive disorder. 
Biol Psychiatry. 2006;59:1052-1060. 
6. Emens J, Lewy A, Kinzie JM, Arntz D, Rough J. Circadian misalignment in 
major depressive disorder. Psychiatry Res. 2009; 15;168(3):259-61. 
7. Driesen K, Jansen NW, van Amelsvoort LG, Kant I. The mutual relationship 
between shift work and depressive complaints--a prospective cohort study. Scand 
J Work Environ Health. 2011;37(5):402-10. 
8. Ueda H. Clinical usefulness of ramelteon in the treatment of insomnia with 
mental disorder. Jpn J Clin Psychopharmacol. 2014;17:65-73. 
9. Gross PK, Nourse R, Wasser TE. Ramelteon for insomnia symptoms in a 
community sample of adults with generalized anxiety disorder: an open label 
study. J Clin Sleep Med. 2009;5:28-33. 
10. Nakazaki K, Kitamura S, Motomura Y, et al. Validity of an algorithm for 
determining sleep/wake states using a new actigraph. J Physiol Anthropol. 
2014;33:31.  
11. Hamilton M. Development of a rating scale for primary depressive illness. Br J 
Soc Clin Psychol. 1967;6:278-296 
12. Matsumoto Y, Uchimura N, Ishida T, Toyomasu K, Hoshiko M, Kushino N, et al. 
[The cut-off point of the 3 Dimensional Sleep Scale (3DSS)--day workers 
version--based on the Pittsburgh Sleep Quality Index (PSQI)]. Sangyo Eiseigaku 
Zasshi. 2015;57:140-143. 
13. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia 
Classification Algorithm of Suicide Assessment (C-CASA): classification of 


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suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. 
Am J Psychiatry. 2007;164(7):1035-43. 
14. Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the 
assessment of suicidality in youth. CNS Spectr. 2007;12(2):156-62. 
15. Report of the Working Group on Conflict of Interest (Ministry of Education, 
Culture, Sports, Science and Technology dated November 1, 2002). 
16. 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). 
17. Guidelines on the Management of Conflict of Interest (COI) in Health and 
Labour Sciences Study (March 31, 2008). 
18. Guidelines for management of COI in medical study (COI Committee of Japan 
Association of Medical Sciences, February 2011). 
19. 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, August 2011). 
 
 
 
 
 
 
 


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Protocol 
 
 
 
 
The exploratory study to investigate the effect of Ramelteon  
for insomnia patients with major depressive disorder by using actigraphy 
 
 
 
 
 
 
 
 
 
 
Sponsor  
Takeda Pharmaceutical Company Limited  
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668 
Study Number 
Ramelteon-4002 
Version Number 
Version 1.0 
Study Drug  
Ramelteon 
Date 
March 29, 2016 
 
 
 


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Amendment History:  
Date 
Amendment Number 
Applicable Sites 
March 29, 2016 
Initial version 
All study sites  
 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered 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 research subjects to whom the drug may be administered. 
Furthermore, the information is only intended for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
STUDY ADMINISTRATIVE INFORMATION AND STUDY 
PRINCIPLES 
1.1 
Contact Information and Responsibilities for Study-Related Activities 
See the attachment. 
1.2 
Clinical Study Principals 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
•The ethical principles that have their origin in the Declaration of Helsinki. 
•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). 
•All applicable laws and regulations, including, without limitation, data privacy laws 
and conflict of interest guidelines. 


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TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND STUDY 
PRINCIPLES ...................................................................................................... 3 
1.1 
Contact Information and Responsibilities for Study-Related Activities .......... 3 
1.2 
Clinical Study Principals................................................................................ 3 
2.0 
STUDY SUMMARY .......................................................................................... 9 
3.0 
ABBREVIATIONS ........................................................................................... 13 
4.0 
INTRODUCTION ............................................................................................. 14 
4.1 
Background ................................................................................................. 14 
4.2 
Rationale for the Proposed Study ................................................................. 14 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 15 
5.1 
Objectives.................................................................................................... 15 
5.1.1 Primary objective ................................................................................... 15 
5.1.2 Secondary objective ............................................................................... 15 
5.2 
Endpoints .................................................................................................... 15 
5.2.1 Primary endpoint ................................................................................... 15 
5.2.2 Secondary endpoints .............................................................................. 15 
5.2.3 Other endpoints...................................................................................... 16 
6.0 
STUDY DESIGN .............................................................................................. 17 
6.1 
Study Design ............................................................................................... 17 
6.2 
Rationale for the Study Design .................................................................... 18 
6.3 
Premature Termination of Entire Clinical Research or Premature 
Termination of Clinical Research at a Study Site ......................................... 19 
6.3.1 Premature termination criteria of entire clinical research ........................ 19 
6.3.2 Criteria for premature termination of study sites..................................... 19 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site ............................................ 19 
6.4 
Procedures for Protocol Revision ................................................................. 19 
7.0 
SELECTION AND WITHDRAWAL CRITERIA ............................................. 21 
7.1 
Inclusion Criteria ......................................................................................... 21 
7.2 
Exclusion Criteria ........................................................................................ 22 
7.3 
Prohibited Medications and Therapies ......................................................... 23 


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7.4 
Management of Study Participants ............................................................... 23 
7.5 
Criteria for Discontinuation or Withdrawal of a Research Subject ................ 24 
7.6 
Procedures for Discontinuation of Individual Research Subjects .................. 25 
8.0 
TREATMENT .................................................................................................. 26 
8.1 
Study Drug .................................................................................................. 26 
8.1.1 Study drug ............................................................................................. 26 
8.1.2 Overdose ............................................................................................... 26 
8.2 
Prescription of the Study Drug ..................................................................... 26 
8.3 
Prescription of Antidepressant Medication ................................................... 27 
8.4 
Non-pharmacological Insomnia Treatment .................................................. 27 
9.0 
STUDY PLAN .................................................................................................. 28 
9.1 
Study Procedures ......................................................................................... 28 
9.1.1 Informed consent ................................................................................... 28 
9.1.2 Demographic data, medical history and prior medication ....................... 28 
9.1.3 History of insomnia ............................................................................... 28 
9.1.4 History of Depression ............................................................................ 28 
9.1.5 Physical examination ............................................................................. 29 
9.1.6 Body weight, height and Body Mass Index (BMI).................................. 29 
9.1.7 Actigraphy ............................................................................................. 29 
9.1.8 Sleep diary ............................................................................................. 29 
9.1.9 17-item Hamilton Rating Scale for Depression (HAM-D17) .................. 30 
9.1.10 Patient Global Impression (PGI) ............................................................ 30 
9.1.11 3 Dimensional Sleep Scale (3DSS) ........................................................ 30 
9.1.12 Columbia Suicide Severity Rating Scale (C-SSRS) ................................ 30 
9.1.13 Concomitant medications ....................................................................... 31 
9.1.14 Concurrent conditions ............................................................................ 31 
9.1.15 Pregnancy .............................................................................................. 31 
9.1.16 Documentation of withdrawals before study treatment ........................... 31 
9.2 
Monitoring of Treatment Compliance in Participants ................................... 32 
9.3 
Schedule of Examinations and Observations ................................................ 32 
9.3.1 Start of the run-in period (VISIT 1) ........................................................ 32 


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9.3.2 Start of the study treatment period (VISIT 2) ......................................... 33 
9.3.3 Treatment period (VISIT 3) ................................................................... 33 
9.3.4 At completion (VISIT 4) or withdrawal ................................................. 34 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENT .................................... 35 
10.1 
Definitions ................................................................................................... 35 
10.1.1 Adverse events ....................................................................................... 35 
10.1.2 Considerations for Adverse Events......................................................... 35 
10.1.3 Serious adverse events ........................................................................... 37 
10.1.4 Severity of adverse events ...................................................................... 38 
10.1.5 Causality of adverse events .................................................................... 38 
10.1.6 Date of onset .......................................................................................... 38 
10.1.7 Date of resolution .................................................................................. 39 
10.1.8 Actions taken for the study drug............................................................. 39 
10.1.9 Outcome ................................................................................................ 40 
10.2 
Procedures ................................................................................................... 40 
10.2.1 Collection and reporting of adverse events ............................................. 40 
10.2.2 Collection and reporting of serious adverse events ................................. 41 
10.2.3 Reporting of additional information concerning adverse events .............. 42 
10.3 
Follow-up of Serious Adverse Events .......................................................... 42 
10.3.1 Reporting of serious adverse events to Ethics Review Committee and 
regulatory authorities ............................................................................. 42 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ...................................... 44 
11.1.1 Steering Committee ............................................................................... 44 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS .............................. 45 
12.1 
Case Report Form ........................................................................................ 45 
12.2 
Storage of Records....................................................................................... 46 
13.0 
STATISTICAL METHODS .............................................................................. 47 
13.1 
Statistical and Analytical Plans .................................................................... 47 
13.1.1 Analysis sets .......................................................................................... 47 
13.1.2 Analysis of demographic and other baseline characteristics .................... 47 
13.1.3 Efficacy analysis .................................................................................... 47 


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13.1.4 Methods of data conversion and handling of missing data ...................... 48 
13.1.5 Significance level and confidence coefficient ......................................... 48 
13.1.6 Safety analysis ....................................................................................... 49 
13.2 
Interim Analysis and Criteria for Early Termination .................................... 49 
13.3 
Determination of Sample Size...................................................................... 49 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 50 
14.1 
Monitoring of the Study Site ........................................................................ 50 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the Research Protocol.................................. 50 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections .................... 50 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH ........................................ 52 
15.1 
Approval of the Ethical Review Board, etc. ................................................. 52 
15.2 
Conflict of Interests ..................................................................................... 52 
15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Research Subjects ........................................................................................ 53 
15.4 
Personal Information of the Research Subjects............................................. 54 
15.5 
Consultation Windows for the Research Subjects or Persons Related to 
the Research Concerned ............................................................................... 55 
15.6 
Financial Burden or Reward to the Research Subjects .................................. 55 
15.7 
Benefits and Inconveniences to the Research Subjects ................................. 55 
15.7.1 Benefits to research subjects .................................................................. 55 
15.7.2 Inconveniences to research subjects ....................................................... 55 
15.8 
Attribution of Research Results and Access Rights ...................................... 55 
15.8.1 Attribution of research results ................................................................ 55 
15.8.2 Data access rights .................................................................................. 55 
15.9 
Reporting of Results, Publication, Disclosure, and Clinical Research 
Registration Policy ...................................................................................... 56 
15.9.1 Reporting of results, publication and disclosure ..................................... 56 
15.9.2 Clinical research registration .................................................................. 56 
15.9.3 Clinical trial results disclosure ............................................................... 56 
15.10 Insurance and compensation for injury ......................................................... 57 
16.0 
REFERENCES .................................................................................................. 58 


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LIST OF TABLES 
Table 10.a 
Takeda Medically Significant AE List ................................................... 37 
LIST OF FIGURES 
Figure 6.a 
Schematic of Study Design .................................................................... 17 
LIST OF APPENDICES 
TABLE 10.A 
TAKEDA MEDICALLY SIGNIFICANT AE LIST ......................... 37 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: Ramelteon 
Study title: The exploratory study to investigate the effect of Ramelteon for insomnia patients 
with major depressive disorder by using actigraphy 
Protocol number: Ramelteon-4002 (293/NRP-003)  
Clinical study design: Multicenter, open-label study  
Objective: To investigate explanatorily the effect of ramelteon 8 mg once daily for 8 weeks in treatment 
for insomnia patients with depression by using actigraphy. 
Study Population: Insomnia patients with major depressive disorder 
Planned number of research subjects: 30 
Number of study sites: Approximately 5 
medical institutions 
Dose and method of administration: 
Ramelteon 8 mg once daily orally at bedtime  
Route of administration: Oral 
Duration of treatment: 8 weeks 
Duration of evaluation: 9 weeks 
(Run-in period for 1 weeks and treatment 
period for 8 weeks)  
Main criteria for inclusion: 
1. Patients with sleep-onset insomnia on ≥3 days per week for ≥4 consecutive weeks at the time of 
informed consent  
2. Patients with a diagnosis of depression according to the DSM-5 
3. Men or women aged ≥20 and <65 years at the time of informed consent  
4. Outpatients  
5. Patients with the 17-item Hamilton Rating Scale for Depression (HAM-D17) score(s) meeting either 
of the following at the start of the run-in period and the start of the study treatment period:  
- a score of 2 for the “6: Insomnia Early” item  
- a score of 1 for the “6: Insomnia Early” item with a subtotal score of ≥3 for the “7: Insomnia 
Middle” and “8: Insomnia Late” items  
6. Patients with a total HAM-D17 score of ≤16 at the start of the run-in period and the start of the study 
treatment period 
7. Patients on stable antidepressant medication, defined as no change of antidepressant agents for at 
least 8 weeks before informed consent and no change in the dosage for at least 4 weeks before 
informed consent  
8. Patients who maintain a routine sleep schedule in daily life, defined as going to bed between 21:00 
and 1:00 on ≥4 days a week  


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9. Patients in whom the run-in period actigraphy shows sleep latency ≥30 minutes and total nocturnal 
sleep time ≤6.5 hours on ≥3 days 
10. Patients who, in the opinion of the principal investigator or investigator, are capable of understanding 
the contents of the study and complying with study requirements 
11. Patients capable of signing and dating the informed consent form in person before any study 
procedures 
Main criteria for exclusion: 
1. Patients with a history of hypersensitivity to ramelteon or melatonin  
2. Patients with severe liver disorder 
3. Patients who took oral ramelteon within 4 weeks before informed consent  
4. Patients who took any oral insomnia medications (including investigational drugs and unapproved 
drugs) within 2 weeks before the study treatment period  
5. Shift workers or night workers  
6. Patients with current or past history of psychiatric or neurological diseases other than depression  
7. Patients with a score of ≥1 for the HAM-D17 “11: Suicide” item at the start of the run-in period or 
the start of the study treatment period, or with any suicide attempts within 24 weeks before or during 
the run-in period  
8. Pregnant women, nursing mothers, or women who plan to become pregnant or donate eggs before the 
informed consent, during the study period or within 4 weeks after the end of the study  
9. Patients participating in another investigational or post-marketing clinical trial/study  
10. Other patients judged by the principal investigator or investigator to be inappropriate for participation 
in this study 
Endpoints: 
<Primary endpoint> 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study treatment 
period) to the end of the treatment period 
*: Mean value from the past 7 days 
<Secondary endpoints> 
• Change in diary-measured sleep latency* from baseline to the end of the treatment period  
• Change in actigraphy-measured total nocturnal sleep time* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured nocturnal wake time* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured number of nocturnal awakenings* from baseline to the end of 
the treatment period 
• Change in actigraphy-measured sleep efficiency* from baseline to the end of the treatment 


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period 
• Change in diary-measured total nocturnal sleep time* from baseline to the end of the treatment 
period 
• Change in diary-measured number of nocturnal awakenings* from baseline to the end of the 
treatment period 
• Change in actigraphy-measured daytime activity level* from baseline to the end of the 
treatment period 
 
 *: Mean value from the past 7 days 
<Additional endpoints> 
Efficacy endpoints 
• Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, number 
of nocturnal awakenings, sleep efficiency, and daytime activity level 
• Diary-measured sleep latency, total nocturnal sleep time, and number of nocturnal awakenings 
• PGI 
• HAM-D17 
• 3DSS 
Safety endpoints 
• Adverse events 
• Body weight 
Statistical method: 
1. Analysis Sets 
The analysis set for this study will be the "Full Analysis Set," which is defined as "all 
participants given at least one dose of the study drug." 
2. Efficacy Analysis 
 
[Primary endpoint] 
In the Full Analysis Set, the change in actigraphy-measured sleep latency from baseline to the 
end of the treatment period will be summarized by calculation of summary statistics (i.e., 
number of participants, mean, standard deviation, maximum, minimum, and quartiles; 
hereinafter the same) and a two-sided 95% confidence interval for the mean, and assessed using 
the one-sample t-test. 
[Secondary endpoints] 
In the Full Analysis Set, the individual secondary endpoints will be summarized by calculation 
of summary statistics and two-sided 95% confidence intervals for the means, and assessed using 
the one-sample t-test.  
Sample Size Justification: 
The sample size is set to 30 in light of feasibility of this study to investigate the effect of 
ramelteon in insomnia patients with depression. This planned sample size is not based on 


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statistical power calculation. 


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3.0 
ABBREVIATIONS 
 
BZD 
Benzodiazepine 
COI 
Conflict of Interest 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
HAM-D 
Hamilton Rating Scale for Depression 
PGI 
Patient Global Impression  
3DSS 
3 Dimensional Sleep Scale 


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4.0 
INTRODUCTION 
4.1 
Background 
Insomnia is commonly encountered in today's medical practice in Japan, and has been 
raised as a clinical and social issue.1) Depression also shows a dramatically increasing 
trend recently2)3), partly because of changes in the working environment, and its social 
impact is becoming a growing concern. Insomnia and depression are known to be often 
comorbid4), and improvement of insomnia symptoms has been described as a key to 
successful resolution of depression.5) Insomnia is known to be associated with not only 
aging and lifestyle-related diseases, but also hypervigilance due to tension from 
excessive expectation about sleep, as well as disturbance of the bodily circadian rhythm 
due to irregular living schedule with a delayed sleep-wake cycle. Depression, on the 
other hand, is typically associated with anxiety, but is now known to be linked with 
negative influence of irregular living schedule as well. Thus, insomnia and depression 
share some same risk factors, and this can explain the high co-existence rate of these 
two disorders.6)7)  
The mainstays in the treatment of insomnia have long been benzodiazepine (BZD)-class 
hypnotics and nonbenzodiazepine-class hypnotics, both classes of which exert sedative 
and anxiolytic effects. A novel melatonin receptor agonist, ramelteon (trade name, 
Rozerem), has been available in Japan since 2010. Ramelteon can improve sleep-onset 
insomnia by working on the bodily clock mechanism and adjusting the circadian rhythm. 
Ramelteon's mechanism of action without sedative or anxiolytic properties appears to be 
of high clinical significance particularly in the treatment of insomnia patients with 
concurrent depression. 
4.2 
Rationale for the Proposed Study  
Reports have been limited on the efficacy and safety of ramelteon in insomnia patients 
with depression or other psychiatric diseases8)9), and none used objective measures. The 
present study is thus designed to use actigraphy to objectively explore the efficacy of 
ramelteon on insomnia in insomnia patients with depression. 
 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary objective 
To investigate exploratorily the effect of ramelteon 8 mg once daily for 8 weeks in 
treatment for insomnia patients with depression by using actigraphy. 
5.1.2 Secondary objective 
To investigate exploratorily the safety of ramelteon 8 mg once daily for 8 weeks in 
insomnia patients with depression. 
5.2 
 Endpoints 
5.2.1 Primary endpoint 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study 
treatment period) to the end of the treatment period 
*: Mean value from the past 7 days 
5.2.2 Secondary endpoints 
• 
Change in diary-measured sleep latency* from baseline to the end of the treatment 
period 
• 
Change in actigraphy-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 
• 
Change in actigraphy-measured nocturnal wake time* from baseline to the end of 
the treatment period 
• 
Change in actigraphy-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured sleep efficiency* from baseline to the end of the 
treatment period 
• 
Change in diary-measured total nocturnal sleep time* from baseline to the end of 
the treatment period 
• 
Change in diary-measured number of nocturnal awakenings* from baseline to the 
end of the treatment period  
• 
Change in actigraphy-measured daytime activity level* from baseline to the end of 
the treatment period 
*: Mean value from the past 7 days 


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5.2.3 Other endpoints  
(1) Efficacy 
• 
Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, 
number of nocturnal awakenings, sleep efficiency, and daytime activity level 
• 
Sleep diary-measured sleep latency, total nocturnal sleep time, and number of 
nocturnal awakenings 
• 
PGI 
• 
HAM-D17 
• 
3DSS 
(2) Safety 
• 
Adverse events 
• 
Body weight 




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6.2 
Rationale for the Study Design 
<Rationale for the study population> 
For ramelteon, a drug approved for "improvement of sleep onset difficulty in 
insomnia", data have been limited on its efficacy and safety in insomnia patients with 
psychiatric disease, and construction of the clinical evidence is desired. Among 
psychiatric diseases, depression is common and often coexists with insomnia 
symptoms. Thus, the study population is set to insomnia patients with depression. 
 
<Rationale for the study design> 
An uncontrolled, open-label design is employed in light of feasibility of this 
post-marketing clinical research, although the primary objective is to explore the 
effect of ramelteon in treating insomnia patients with a history of co-morbid 
depression. 
<Rationale for the dosage> 
The approved dosage and method of administration for ramelteon are employed. 
<Rationale for the endpoints> 
The "Guideline for Clinical Evaluation of Hypnotic Agents" (Notification No. 1213-1 
of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, 
dated December 13, 2011) recommends the use of polysomnography for objective 
efficacy evaluation in addition to the use of patient-recorded sleep logs for subjective 
efficacy evaluation. While polysomnography is a complex examination and repeated 
polysomnography can impose heavy burden on participants, actigraphy has been 
recognized to provide sleep data highly correlated with those provided by 
polysomnography and is a simple tool posing less burden to participants. Thus, 
actigraphy is selected as an objective assessment tool in this study10). For subjective 
measures, this study uses a sleep diary, as well as the Patient Global Impression 
(PGI) as an index of global improvement, and the 3 Dimensional Sleep Scale (3DSS) 
as a new tool to assess sleep dimensions including sleep phases. The HAM-D17 is 
selected for evaluation of depressive symptoms, in line with preceding studies. 
The safety will be evaluated based on adverse events, body weight. 
<Rationale for the treatment duration> 
The treatment duration is set to 8 weeks on the basis of the Japanese long-term 
clinical trial of ramelteon (24-week treatment), which demonstrated gradual 


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manifestation of the efficacy of ramelteon on sleep latency under repeated dosing 
over a certain period, and the efficacy peaked around Week 8. 
<Rationale for the sample size> 
See Section 13.3 
6.3 
Premature Termination of Entire Clinical Research or Premature 
Termination of Clinical Research at a Study Site 
6.3.1 Premature termination criteria of entire clinical research 
The sponsor should immediately discontinue the study when at least one of the 
following criteria is applicable: 
• 
When new information or other evaluation on the safety or efficacy of the study 
drug becomes available that shows a change in the known risk/benefit profile of the 
concerned compound, and risks/benefits are no longer tolerable for research subject 
participation in the study. 
• 
When there is serious deviation from ethical guidelines that may threaten safety of 
the research subjects. 
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at 
the discretion of the sponsor if the entity (e.g., principal investigator) is found in 
significant violation of the ethical guidelines, protocol, or contractual agreement, or is 
unable to ensure proper conduct of the research. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site 
In the event that the sponsor or a study site committee such as an ethics review 
committee decides to prematurely suspend or terminate the entire clinical study or 
clinical study at a study site, a study-specific procedure shall be provided by the sponsor. 
The procedure shall be followed by applicable study sites during the course of clinical 
study suspension or premature termination. 
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. 


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Upon notification, the principal investigator at each study site shall submit the revised 
contents to committees such as the IEC, as necessary according to institutional 
regulations for review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA 
7.1 
Inclusion Criteria  
Participants must fulfill all of the following criteria to be included in this study: 
1. Patients with sleep-onset insomnia on ≥3 days per week for ≥4 consecutive weeks 
at the time of informed consent 
2. Patients with a diagnosis of depression according to the DSM-5 
3. Men or women aged ≥20 and <65 years at the time of informed consent  
4. Outpatients  
5. Patients with the 17-item Hamilton Rating Scale for Depression (HAM-D17) 
score(s) meeting either of the following at the start of the run-in period and the start 
of the study treatment period:  
- a score of 2 for the “6: Insomnia Early” item  
- a score of 1 for the “6: Insomnia Early” item with a subtotal score of ≥3 for the 
“7: Insomnia Middle” and “8: Insomnia Late” items  
6. Patients with a total HAM-D17 score of ≤16 at the start of the run-in period and the 
start of the study treatment period 
7. Patients on stable antidepressant medication, defined as no change of antidepressant 
agents for at least 8 weeks before informed consent and no change in the dosage for 
at least 4 weeks before informed consent  
8. Patients who maintain a routine sleep schedule in daily life, defined as going to bed 
between 21:00 and 1:00 on ≥4 days a week  
9. Patients in whom the run-in period actigraphy shows sleep latency ≥30 minutes and 
total nocturnal sleep time ≤6.5 hours on ≥3 days 
10. Patients who, in the opinion of the principal investigator or investigator, are capable 
of understanding the contents of the study and complying with study requirements 
11. Patients capable of signing and dating the informed consent form in person before 
any study procedures 
[Rationale for the inclusion criteria] 
1: This criterion is set to exclude patients with transient insomnia.  
2: This criterion is set to specify the target study population and applicable diagnostic 
criteria.  
3: This criterion is set because both men and women need to be included for evaluation. 
The lower age limit of 20 years is set because personal voluntary consent is valid at and 
above this age. The upper age limit is set for this study to enroll participants who are 
active during daytime and thus appropriate for evaluation using actigraphy.  


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4, 6, 7: These criteria are set to determine patients whose depression symptoms have 
been mild or less and stable.   
5, 9: These criteria are set to determine patients with symptoms of sleep-onset insomnia 
during the run-in period.  
8: This criterion was set to ensure appropriate evaluation of the efficacy and safety of 
the study drug.  
10, 11: These criteria are set as essential elements for the study implementation.  
7.2 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from this study: 
1. Patients with a history of hypersensitivity to ramelteon or melatonin  
2. Patients with severe liver disorder 
3. Patients who took oral ramelteon within 4 weeks before informed consent  
4. Patients who took any oral insomnia medications (including investigational drugs 
and unapproved drugs) within 2 weeks before the study treatment period  
5. Shift workers or night workers  
6. Patients with current or past history of psychiatric or neurological diseases other 
than depression  
7. Patients with a score of ≥1 for the HAM-D17 “11: Suicide” item at the start of the 
run-in period or the start of the study treatment period, or with any suicide attempts 
within 24 weeks before or during the run-in period  
8. Pregnant women, nursing mothers, or women who plan to become pregnant or 
donate eggs before the informed consent, during the study period or within 4 weeks 
after the end of the study  
9. Patients participating in another investigational or post-marketing clinical trial/study  
10. Other patients judged by the principal investigator or investigator to be 
inappropriate for participation in this study 
[Rationale for the exclusion criteria] 
1, 2: These criteria are set in consideration of the safety of the participants. 
3 to 6: These criteria are set to ensure appropriate evaluation of the efficacy and safety 
of the study drug. 
7, 8: These criteria are set in consideration of the safety of the participants. 
9, 10: These criteria are set as essential elements for the study implementation. 


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7.3 
Prohibited Medications and Therapies  
During the study period, the principal investigator or investigator will instruct the 
participants not to take any other medications than those instructed to be taken, 
including over-the-counter drugs, without first consulting with the principal investigator 
or investigator. 
[Prohibited medications] 
Fluvoxamine maleate will be prohibited from the start of the run-in period. Insomnia 
medications other than ramelteon (including investigational drug and unapproved drugs) 
will be prohibited from at least 2 weeks before treatment period to the end of the study 
period. 
1. Fluvoxamine maleate 
2. Insomnia medications other than ramelteon (including investigational drug and 
unapproved drugs) 
[Rationale for prohibited medications] 
1. Fluvoxamine maleate is contraindicated for use with the study drug, ramelteon. 
2. Insomnia medications may prevent appropriate evaluation of the efficacy and safety 
of the study drug. 
7.4 
Management of Study Participants 
The following should be observed or instructed to the participants by the principal 
investigator and investigator. 
1. Participants should make scheduled visits and undergo physical examination by 
physician and other specified examinations (Actigraphy, Sleep Diary) . When a 
scheduled visit cannot be made, the participant should promptly contact the principal 
investigator or investigator. 
2. In the event of any symptomatic worsening or other abnormalities except scheduled 
visits, the participant should promptly contact the principal investigator or 
investigator for instructions. 
3. Participants should take the study drug as instructed by the principal investigator or 
investigator. If not, this must be reported to the principal investigator or investigator 
at the next visit. 


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4. Participants should not take any other medications than those instructed to be taken, 
including over-the-counter drugs, without first consulting with the principal 
investigator or investigator (except for emergency situations). 
5. Whenever participants visit another hospital between the informed consent and the 
end of the study, the participant should tell the physician of the other hospital that 
he/she is participating in this study. 
6. Whenever participants visit another hospital between the informed consent and the 
end of the study, the participant should report to the principal investigator or 
investigator about background for the visit and treatment details. 
7. Women of childbearing potential whose male partners are not surgically sterile must 
use appropriate contraception from the time of informed consent to the end of the 
study.  
7.5 
Criteria for Discontinuation or Withdrawal of a Research Subject 
The principal investigator or investigator shall record the main reason for 
discontinuation of protocol treatment on the case report form according to the 
classification described below. Refer to Section 9.1.12 for research subjects who 
withdraw from the research before 
1. Adverse event 
This is selected when an adverse event occurred in a study participant that requires 
premature termination to avoid an unacceptable risk to the participant’s health 
imposed by continued participation in the study; or the study participant is unwilling 
to remain in the study because of the adverse event.  
2. Major protocol deviation  
This is selected when the study participant is found not to fulfill the 
protocol-specified eligibility criteria after the start of the study treatment, or has 
failed to adhere to protocol requirements, and thus the participant’s continued 
participation in the study would pose an acceptable risk to his/her health.  
3. Lost to follow-up  
This is selected when the study participant has not returned to the study site and lost 
contact. In such instances, all attempts to contact the participant must be recorded in 
the source document.  
4. Voluntary withdrawal  
This is selected when the study participant has requested to withdraw his/her 
participation in the study. The reason for withdrawal, if provided by the participant, 
will be recorded in the case report form.  


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5. Discontinuation of the entire study  
This is selected when discontinuation of the entire study is decided by the sponsor, 
institutional review board, regulatory authority, etc. See Section 6.3.1 for details.   
6. Pregnancy 
This is selected when a female study participant is found to be pregnant.  
Note: A participant found to be pregnant must be immediately withdrawn from the 
study. For the withdrawal procedure, see Section 9.1.11.  
7. Lack of efficacy 
This is selected when the investigator or subinvestigator has judged that, because of 
lack of efficacy of study treatment, the participant’s continued participation in the 
study would pose an unacceptable risk to the participant. 
8. Sign of suicide  
This is selected when the HAM-D17 “11: Suicide” item score became ≥1; or the 
principal investigator or investigator judged that the C-SSRS results or other findings 
indicate a sign of suicide. 
9. Remission of depression 
This is selected when the participant’s depression remitted to no longer require 
antidepressant medication etc.  
10. Other  
This is selected when the principal investigator or investigator has decided 
withdrawal of the participant for any other reason. The reason must be detailed in the 
case report from. 
 
7.6 
Procedures for Discontinuation of Individual Research Subjects 
The principal investigator or investigator shall terminate a research subject's research 
participation when the research subject meets the criteria described in Section 7.5. 
Individual research subjects may discontinue their research participation without giving 
a reason at any time during the research. Should a research subject's participation be 
discontinued, the primary reason for termination shall be recorded on the CRF by the 
principal investigator or investigator. In addition, efforts shall be made to perform all 
tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
TREATMENT 
8.1 
Study Drug  
8.1.1 Study drug  
Nonproprietary name: Ramelteon [JAN] 
Chemical name: N-{2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl} 
propanamide 
Dosage: 8 mg once daily 
Method of administration: Orally at bedtime 
Duration of treatment: 8 weeks  
8.1.2 Overdose 
Overdose is defined as intentional or accidental administration of the study drug at a 
higher dose than that specified in the protocol, either by a health professional or by the 
research subject.  
To consistently collect important safety information about overdose, the principal 
investigator or investigator(s) shall record all cases of overdose on the "Overdose" page 
of the CRF, irrespective of the presence or absence of accompanying adverse event. 
Adverse events associated with overdose shall be recorded on the "Adverse events" 
page of the CRF, in accordance with the procedures described in Section 10.0, 
"ADVERSE EVENTS." 
In addition, serious adverse events associated with overdose shall be recorded in 
accordance with the procedures described in Section 10.2.2, "Collection and reporting 
of SAEs." 
In the event of overdose, the principal investigator or investigator shall treat the subject 
as required based on symptoms 
8.2 
Prescription of the Study Drug  
The principal investigator or investigator will prescribe the study drug according to the 
protocol, to participants who fulfill all of the inclusion criteria and do not meet any of 
the exclusion criteria. 


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8.3 
Prescription of Antidepressant Medication  
The oral antidepressant medication being used in each participant at the time of 
informed consent will be continued without any change to the dosage regimen during 
participation in the study. 
8.4 
Non-pharmacological Insomnia Treatment  
During the study period, non-pharmacological insomnia treatment should be added or 
changed.  
 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The principal investigator or investigator will collect data according to the following 
procedures. In principle, the same principal investigator or investigator should perform 
the examinations, observations, and evaluations in the same participant. The study 
schedule is provided in Appendix A. 
9.1.1 Informed consent 
Informed consent procedures are described in Section 15.3. 
Study procedures may be started only after informed consent is obtained from the 
participant. 
Participants who provided informed consent will be assigned participant identification 
codes for de-identification. The assigned participant identification codes will be used 
throughout the study period without changes. 
9.1.2 Demographic data, medical history and prior medication 
Demographic data will be obtained in terms of date of birth, sex, and history of alcohol 
consumption, and history of smoking. 
Medical history will be obtained in terms of any clinically relevant diseases or 
symptoms that had disappeared or resolved within 1 year before the informed consent. 
Ongoing symptoms or diseases should be regarded as concurrent conditions (see 
Section 9.1.11). 
9.1.3 History of insomnia 
Regarding current insomnia, the following data will be obtained:  
  - Date of onset 
  - Initial/Recurrence 
  - Any non-pharmacological therapy 
9.1.4 History of Depression 
Regarding the current depressive episode, the following data will be obtained: 
  - Date of onset 
  - Initial/Recurrence 
  - Any use of psychotherapy 


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9.1.5 Physical examination 
Physical examination will be performed. Findings of physical examination after the start 
of the treatment period will be compared with those before the treatment period, and 
assessed for any abnormalities that can be clinically relevant. 
9.1.6 Body weight, height and Body Mass Index (BMI) 
Body weight and height will be measured. BMI will be calculated by the sponsor, using 
the following equation: 
Body Mass Index (BMI) = Body Weight (kg) / (Height (m))2 
Height will be measured to the nearest whole number in centimeters. Body weight will 
be measured to the first decimal place in kilograms. The calculated BMI value will be 
expressed to the first decimal place. 
9.1.7 Actigraphy 
At the end of the informed consent, an actigraph will be lent to each participant. After 
full instructions on actigraphy are provided to the participants, actigraphy recording will 
be started. Patients meeting the inclusion criteria on the basis of the data in the run-in 
period will keep the actigraph, and be instructed to wear it until the end of the treatment 
period.  
Participants will be instructed to bring the actigraph at each study visit. For analysis of 
the data recorded in the actigraph, the actigraph will be connected to a computer with an 
actigraphy data analysis software installed, and the following data will be transferred to 
the analysis software: sleep latency, total nocturnal sleep time, nocturnal wake time, the 
number of nocturnal awakenings, sleep efficiency and daytime activity level (step 
counts). For each of these parameters, the validity of the measured data will be checked 
according to the “Procedures for actigraphic sleep assessment” prepared separately, and 
the data during the run-in period (Weeks -1 to 0) and the treatment period (Weeks 3 to 4 
and 7 to 8) will be recorded in the case report form. The actigraph device will be 
retrieved after completion of the actigraphy recording on the 3 occasions, or when the 
participant is withdrawn from the study.  
9.1.8 Sleep diary 
At the end of the informed consent, a sleep diary will be provided to each participant, 
with instruction on how to keep the diary during the study period. The following diary 
data during the run-in period (Weeks -1 to 0) and the treatment period (Weeks 3 to 4 
and 7 to 8) will be recorded in the case report form: sleep latency, bedtime hour, 


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awakening hour and number of nocturnal awakenings. Any missing entries, 
discrepancies, or other potentially dubious entries in the sleep diary will be checked 
with the participant, and explained in the sleep diary by the participant. Accordingly, 
necessary additions and corrections will be made to the sleep diary, and recorded in the 
case report form.  
9.1.9 17-item Hamilton Rating Scale for Depression (HAM-D17) 
The Hamilton Rating Scale for Depression (HAM-D) is a questionnaire used to rate the 
severity of depression based on general symptoms of depression, including physical 
symptoms. The rater will assess individual items on a scale from 0 to 2, 3, or 4 
depending on the items, based on an interview with the participant.6) The time frame 
assessed by the HAM-D is one week before each visit. This study will use the 17-item 
version (HAM-D17), and the scores of individual items and the total score will be 
assessed and recorded in the case report form. 
9.1.10 Patient Global Impression (PGI) 
The Patient Global Impression (PGI) is a patient-rated scale to measure the degree of 
any improvement (or worsening). Participants will rate their own condition compared 
with the run-in period (before the start of study treatment), and enter the score in the 
PGI form. The principal investigator or investigator will record the score in the case 
report form. 
9.1.11 3 Dimensional Sleep Scale (3DSS) 
The 3 Dimensional Sleep Scale (3DSS) is a patient-administered questionnaire 
developed in Japan, and used to assess sleep dimensions including sleep phases.7) At 
each visit, participants will assess their own condition within the past month and 
complete the 3DSS form. The principal investigator or investigator will record the 
results of 3DSS in the case report form. 
9.1.12 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire developed by researchers at Columbia University as a 
tool to help systematically assess suicidal ideation and behavior in the individuals 
during participation in a clinical research.13)14) The C-SSRS consists of 3 questions 
addressing suicidal behavior and 5 questions addressing suicidal ideation, with 
subquestions assessing the severity. The principal investigator or investigator will 
perform the C-SSRS assessment based on an interview with the participant. Since this is 
performed to detect any signs of suicide during the study period, the C-SSRS 
assessment results will not be recorded in the case report form.  


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9.1.13 Concomitant medications 
Concomitant medications are any psychotherapeutic drugs (Drugs for Insomnia, 
Antidepressant) that are used in addition to the study drug, and include drugs prescribed 
by doctors or over-the-counter drugs purchased by the participants. At each visit, 
participants will be interviewed about any psychotherapeutic drugs used other than the 
study drug from the time of informed consent to the end of the study  and specific 
usage (drug name). 
9.1.14 Concurrent conditions 
Concurrent conditions are defined as symptoms or diseases that are present at the time 
of the informed consent. Abnormal findings from physical examination at the start of 
the run-in period will be regarded as concurrent conditions at the discretion of the 
principal investigator or investigator. 
9.1.15 Pregnancy 
If pregnancy of a participant is found during the study, with agreement of the female 
participant, the principal investigator or investigator will inform her 
obstetrics/gynecology doctor about the fact of her participation in the clinical study at 
the onset of the pregnancy, as well as details of the study drug. 
All pregnancies reported during the study will be followed up to their outcomes by the 
principal investigator or investigator, with agreement of the participants with pregnancy. 
The outcome of pregnancy, including any premature labor, will be reported to the 
sponsor, using a designated report form. Assessment after childbirth will also be 
performed. 
9.1.16 Documentation of withdrawals before study treatment 
For all participants withdrawn before the start of study treatment after signing the 
consent form, the case report form will be completed. 
The following data will be recorded in the case report form: 
• 
Date of informed consent 
• 
Date of birth 
• 
Sex 
• 
Eligibility 
• 
Reason for withdrawal 
The main reason for the withdrawal before the start of study treatment will be recorded, 
using the following classification: 


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• 
Not fulfilling all of the inclusion criteria, or meeting any of the exclusion criteria 
• 
Major protocol deviation 
• 
Lost to follow-up 
• 
Voluntary withdrawal (The reason should be specified) 
• 
Discontinuation of the entire study 
• 
Pregnancy 
• 
Other (The reason should be specified) 
Participant identification codes assigned to the participants withdrawn before the start of 
study treatment must not be reused. 
9.2 
Monitoring of Treatment Compliance in Participants 
At each visit, the principal investigator or investigator will assess the participant's 
compliance with the study drug and antidepressant medication. The compliance status 
will be classified into 4 categories: nearly all of the prescribed doses were taken (≥90%), 
most of the prescribed doses were taken (≥70%), about half of the prescribed doses 
were taken (≥50%), or less than half of the prescribed doses were taken (<50%). 
Throughout the study period, participants will be reinstructed about medication. If poor 
compliance with the study drug after the previous visit, such as <50% of prescribed 
doses, is found and does not improve, the participant may be withdrawn as appropriate. 
9.3 
Schedule of Examinations and Observations 
The schedule for all examinations, observations, and evaluations is shown in Appendix 
A. The principal investigator or investigator will perform the following examinations, 
observations, and evaluations as scheduled. 
9.3.1 Start of the run-in period (VISIT 1) 
After informed consent, the following data will be obtained by physical examination 
and other examinations. In addition, participants will be instructed to keep a sleep diary 
and to perform actigraphy recording for 1 week before VISIT 2 (i.e., Week -1 to Week 
0). Eligibility of participants will be confirmed against the inclusion and exclusion 
criteria given in Section 7.0. For documentation of participants withdrawn during the 
run-in period, the procedures in Section 9.1.13 should be followed. 
During the run-in period, the following examinations, observations, and evaluations will 
be performed: 
• 
Informed consent 


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• 
Demographic data, medical history, prior medication, history of insomnia, 
depressive episodes  
• 
Physical examination 
• 
Height, body weight and BMI 
• 
Concurrent medications 
• 
Concurrent conditions 
• 
HAM-D17 
• 
C-SSRS (baseline) 
9.3.2 Start of the study treatment period (VISIT 2) 
At the start of administration of the study drug, the following examinations, 
observations, and evaluations will be performed. 
For participants fulfilling all of the inclusion criteria and not meeting any of the 
exclusion criteria given in Section 7.0, the principal investigator or investigator will 
instruct to start taking the study drug according to Section 6.1. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
Concurrent conditions 
• 
HAM-D17 
• 
Assessment of the actigraphy data from Week -1 to Week 0 
• 
Sleep diary 
• 
3DSS 
• 
C-SSRS (after last assessment) 
9.3.3 Treatment period (VISIT 3) 
During the treatment period (VISIT 3), the following examinations, observations, and 
evaluations will be performed.  
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
HAM-D17 
• 
Assessment of actigraphy data from Week 3 to Week 4 
• 
Sleep diary 


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• 
Adverse events 
• 
3DSS 
• 
Treatment compliance 
• 
C-SSRS (after last assessment) 
9.3.4 At completion (VISIT 4) or withdrawal 
Final visit will be made at 8 weeks after the start of study treatment, when the following 
examinations, observations, and evaluations will be performed. In withdrawn 
participants, the same examinations, observations, and evaluations will be performed at 
withdrawal from the study. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant medications 
• 
HAM-D17 
• 
Assessment of actigraphy data from Week 7 to Week 8* 
• 
Sleep diary 
• 
Adverse events 
• 
3DSS 
• 
Treatment compliance 
• 
C-SSRS(after last assessment) 
• 
PGI 
For all participants given the study drug, the study completion/withdrawal status will be 
recorded in the case report form. 
 


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10.0 
Pretreatment Event and Adverse Event 
10.1 
Definitions 
10.1.1 Adverse events 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product (including a study drug) 
and which does not necessarily have to have a clear causal relationship with this 
treatment. 
An adverse event can therefore be any unfavorable or unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
10.1.2 Considerations for Adverse Events 
Generally unfavorable findings are described below: 
• Newly diagnosed disease or unexpected aggravation of existing symptom 
(intermittent event of an existing symptom is not considered an adverse event) 
• Requiring action or medical practice 
• Requiring invasive diagnostic treatment 
• Requiring discontinuation or a change in the dose of the study drug 
• Considered unfavorable by the investigator or the subinvestigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including 
abnormal laboratory values, abnormal ECG findings) and symptoms shall not be 
recorded as adverse events. If an adverse event could not be expressed by a diagnosis 
name, the signs or symptoms shall be recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when 
the principal investigator or investigator judges the results are clinically problematic (in 
other words, when certain action or medical practice is required, or when the principal 
investigator or the investigator judges the change has exceeded the normal physiological 
variation range of the research subject). Retest and/or continued monitoring of an 
abnormality are not considered medical practice. Also, repeated or additional 


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conduction of non-invasive tests for verification, evaluation, and monitoring of an 
abnormality are not considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying 
symptoms of a disease diagnosed as an adverse event (e.g., increased creatinine due to 
renal dysfunction, etc.), the adverse event shall be handled by its diagnosis name. 
Pre-existing conditions (at start of treatment period):  
A disease or symptoms that had been present since before the start of observation period 
shall be regarded as a concurrent disease and not an adverse event. When a concurrent 
medical condition is aggravated, the aggravation shall be determined as an adverse 
event and the investigator or the subinvestigator shall record on the CRF that the 
adverse event is an aggravation of the concurrent disease (e.g., "aggravation of 
hypertension," etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each 
episode shall be recorded as an adverse event if the episodes become more frequent, 
serious, or severe in nature. If a research subject has a chronic concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition shall be recorded as adverse 
event if the degree of the worsening exceeds that which would be expected. The 
principal investigator or investigator shall ensure that the adverse event term to be 
recorded represents the change in the condition from baseline (e.g. "worsening of…"). 
Worsening of adverse events: 
If a research subject experiences a worsening of the adverse event after a change to the 
study drug, or secondary signs and symptoms are caused by the adverse event, the 
worsening or the secondary signs and symptoms shall be recorded as a new adverse 
event on the CRF. The principal investigator or investigator shall use an adverse event 
term that explicitly means a change of the condition (e.g., "worsening of…"). 
Change of severity of adverse events: 
If the research subject experiences changes in the severity of an adverse event, the event 
shall be recorded once, at its peak severity. 
Previously planned surgery or treatment: 
Preplanned surgeries or interventions that were scheduled before study treatment shall 
not be considered adverse events. However, when the existing symptom is aggravated 
to a degree requiring emergency surgery or treatment, the condition or the event shall be 
considered an adverse event. A concurrent disease that resulted from previously planned 
surgery shall be reported as an adverse event. 


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Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a 
research subject (cosmetic surgery, etc.) shall not be considered an adverse event; 
however, it shall be recorded in the source documents. Concurrent diseases due to a 
non-urgent surgery shall be reported as an adverse event. 
The Insufficient clinical response (lack of efficacy) 
Insufficient clinical response, efficacy, or pharmacological action shall not be recorded 
as an adverse event. The principal investigator or investigator shall make the distinction 
between worsening of a pre-existing condition and lack of therapeutic efficacy. 
Overdose of the study drug 
Overdose of any medication without manifested symptoms shall not be recorded as an 
adverse event, but the overdose shall be recorded on the "Overdose" page of the CRF. 
Any manifested symptoms shall also be recorded as adverse events on the "Adverse 
events" of the CRF. 
10.1.3 Serious adverse events 
Of all the unfavorable medical events that develop with administration of drugs 
(irrespective of dose), a serious adverse event is an event that: 
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, or 
6. other medically significant condition: a medically important event that causes a 
risk to a research subject even if it is not immediately life-threatening and does 
not result in death or hospitalization, or requires an action or treatment to 
prevent the results described in 1 to 5 above. Points described in the Takeda 
Medically Significant Adverse Event List (Table 10 (a)) are included in this 
section. 
* The term "life threatening" refers to an event in which the research 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. 
Table 10.a 
Takeda Medically Significant AE List 
 


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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 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
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 adverse events 
The causal relationship of each adverse event to the study drug and control drug shall be 
classified and defined as shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). Possibly due to the study drug or control drug, although other 
factors such as underlying disease, concurrent diseases, or concomitant drugs/treatment 
are also suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug and control drug. Very likely due to other factors such 
as underlying disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.6 Date of onset 
The date of onset of adverse events shall be determined according to the following 
rules: 
Adverse event, etc. 
Date of onset 


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Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the principal investigator or 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 concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of the study 
drug administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.7 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject 
recovered (including resolution with sequelae). If a research subject died due to the 
adverse event concerned, it shall be the date of death. The adverse event shall be 
recorded as "ongoing" if the research subject has not yet recovered by the end of the 
study. 
10.1.8 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including withdrawal 
by the research subject at his/her own discretion). 
When the treatment with the study drug is continued after withdrawal from the 
study, it is defined as "Dose not changed." 
 
Dose not changed 
The dose was not changed after the onset of the adverse event. 
The study drug or control drug was discontinued, reduced, or increased because of 
another adverse event. 
The study drug was discontinued or reduced for a reason other than the adverse 
event, e.g., inadvertence of the research subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
research 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 adverse event. 


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Dose reduced  
The dose or control drug was reduced because of the adverse event (including 
dose reduction by the research subject at his/her own discretion). 
Washout  
The study drug or control drug was suspended (i.e., interrupted) by the research 
subject at his/her discretion) because of the adverse event (including 
suspension/interruption, but resumed thereafter. 
10.1.9 Outcome 
Outcome of adverse events 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 research subject died from a cause other than the concerned adverse event 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 research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 
Death 
Direct relationship between death and the concerned adverse event 
"Direct relationship" means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research 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. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Adverse events will be collected for the following periods:  
• 
Any adverse events occurring between the start of study drug administration 
and completion (or discontinuation) of the treatment period 


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10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence 
of any onset of subjective symptoms. A neutral question, such as "How have you been 
feeling since your last visit?" may be asked to collect any adverse events that occurred 
between the previous and present visits. 
The principal investigator or investigator shall follow up all research subjects 
experiencing an adverse event irrespective of the causal relationship with the study drug, 
until the symptom resolve, or any clinically significant abnormal laboratory values have 
returned to baseline or there is a satisfactory explanation for the change (permanent and 
irreversible adverse events, etc.). All adverse events shall be entered on the CRF, with 
the event term, onset date, resolution date, severity, causal relationship with the study 
drug (i.e. "Unrelated" or "Related"), action taken for the study drug, outcome, causal 
relationship with any study procedure (with specific procedure if assessed to be causally 
related), and seriousness. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the 
time when the principal investigator or investigator judges that further follow-up would 
be unnecessary. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it 
shall be reported according to the following procedures.  
At the time of onset of a serious adverse event or notification of the onset by the 
research subject, the principal investigator shall report the serious adverse event to the 
chief executive of the study site immediately, and the sponsor or CRO to whom the 
sponsor has entrusted responsibility shall notify the principal investigator of the study 
site. 
The principal investigator shall then report the serious adverse event to the sponsor (for 
the contact information, refer to the attachment) within 1 day of becoming aware of the 
event onset. Further, the investigator shall submit a formal report within 10 calendar 
days to the sponsor. 
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. 
・ Brief description of adverse event and the reason for why it was determined as 
serious 


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・ Research subject ID number 
・ Name of investigator or the subinvestigator 
・ Name of the study drug 
・ Determined causal relationship 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events 
for reporting to regulatory authorities, the investigator or the subinvestigator shall 
confirm the necessary additional information and enter in the EDC system or submit a 
report within the period specified by the sponsor. 
10.3 
Follow-up of Serious Adverse Events 
When information that was not included in the detailed report was obtained later, the 
principal investigator or investigator shall state it in the copy of the report on serious 
adverse events, or create another document and submit it to the contact address shown 
on the attached sheet. 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 IEC upon request. 
The investigator or the subinvestigator shall follow-up all serious adverse events, until 
recovery is confirmed, or the final outcome is determined.  
10.3.1 Reporting of serious adverse events to Ethics Review Committee and 
regulatory authorities 
When the chief executive of the study site receives a report of a serious adverse event 
from the investigator, the chief shall consult the Ethics Review Committee, etc., and 
notify the study sites that are conducting the clinical research through the sponsor or the 
CRO consigned by the sponsor. 
Serious adverse event reported by the principal investigator is unexpected, the chief 
executive of the study site shall prepare a written report of the unexpected serious 
adverse event containing the information reported by the principal investigator plus the 
information below, and submit the report to the Minister of Health, Labor and Welfare, 
and notify other clinical study sites. (The chief executive of the study site may report it 
to the Minister of Health, Labor and Welfare via the sponsor, and notify it to other 
clinical study sites via the sponsor.)  


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• 
Actions taken for serious adverse events 
(discontinuation of new enrollment, revision of informed consent form, 
re-consents to other research 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 serious adverse events that are subject to emergency reporting 
to regulatory authorities, the investigators, and directors of study sites. 
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 study drug 
risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The study site shall submit copies of emergency report documents to the 
Ethics Review Committee, etc. 
 
 
 
 
 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
The Steering Committee will be established for this study. 
11.1.1 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 MANAGEMENT AND STORAGE OF RECORDS 
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. Adverse events, medical history, and concurrent 
conditions shall be coded using MedDRA. Drugs shall be translated using the WHO 
Drug Dictionary. 
12.1 
Case Report Form 
The principal investigator fr investigator shall complete a CRF for each research subject 
who has signed the informed consent form. 
The sponsor or its designee shall provide study sites with access authorization to the 
electronic CRF. Before use of the electric CRF 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 made 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 investigator or its designee shall ensure the accuracy and completeness of the CRF, 
and provide an electronic signature on the relevant page of the case report form. The 
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. 
• 
Severity, degree, the causal relationship with the study drug, control drug, or the 
study procedures, outcome 
When the principal investigator or investigator changes or corrects the content of the 
CRF after having submitted it to the sponsor, the form for change and correction of a 
CRF provided by the sponsor (Data Clarification Form) 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. 
The sponsor or the designee shall confirm that the CRF has been made appropriately in 
conformity with the procedure defined for each research. The sponsor or the designee 
shall read the medical record or in-hospital record related to the research subject to 
ensure the accuracy of the CRF. The completed CRF shall be the property of the 


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sponsor, and the principal investigator or investigator shall not disclose the information 
to a third party without written permission from the sponsor. 
12.2 
Storage of Records 
The principal investigator or the chief executive of study site shall store the following 
materials, 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 research subject ID 
number list, research subjects' medical records, clinical research work sheet, original 
signed and dated informed consent forms, {CRFs (copy), change and modification 
record of the CRF (copy)/ an electronic copy of the electronic CRFs with audit trails, 
and the drug management records, etc. The principal investigator and the chief 
executive of the study site shall appropriately retain the material/information related to 
this study for at least 5 years from the date of reporting the end of the research 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. 


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13.0 
STATISTICAL METHODS 
Statistical analysis will be performed by the responsible biostatistician and his/her 
designee (i.e., biostatistician of a contract research organization independent of the 
sponsor). The sponsor is not involved in the analysis of this study. 
13.1 
Statistical and Analytical Plans 
The biostatistician will prepare the initial version of a statistical analysis plan before 
informed consent of the first participant. The statistical analysis plan will specify 
detailed definitions of the endpoints and analytical methods to address all study 
objectives. 
13.1.1 Analysis sets 
The analysis set for this study will be the "Full Analysis Set," which is defined as all 
participants given at least one dose of the study drug. 
13.1.2 Analysis of demographic and other baseline characteristics  
Major demographic and other baseline characteristics in the Full Analysis Set will be 
summarized. 
13.1.3 Efficacy analysis 
[Primary endpoint] 
Change in actigraphy-measured sleep latency* from baseline (i.e., start of the study 
treatment period) to the end of the treatment period 
*: Mean value from the past 7 days 
[Analytical methods] 
In the Full Analysis Set, the change in actigraphy-measured sleep latency from baseline 
to the end of the treatment period will be summarized by calculation of summary 
statistics (i.e., number of participants, mean, standard deviation, maximum, minimum, 
and quartiles; hereinafter the same) and a two-sided 95% confidence interval for the 
mean, and assessed using the one-sample t-test. 
[Secondary endpoints] 
• 
Change in sleep diary-measured sleep latency* from baseline to the end of the 
treatment period 
• 
Change in actigraphy-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 


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• 
Change in actigraphy-measured nocturnal wake time* from baseline to the end of 
the treatment period 
• 
Change in actigraphy-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured sleep efficiency* from baseline to the end of the 
treatment period 
• 
Change in sleep diary-measured total nocturnal sleep time* from baseline to the end 
of the treatment period 
• 
Change in sleep diary-measured number of nocturnal awakenings* from baseline to 
the end of the treatment period 
• 
Change in actigraphy-measured daytime activity level* from baseline to the end of 
the treatment period 
*: Mean value from the past 7 days 
 
[Analytical methods] 
In the Full Analysis Set, the individual secondary endpoints will be summarized by 
calculation of summary statistics and two-sided 95% confidence interval for the mean, 
and assessed using the one sample t-test. 
 
[Other endpoints] 
• 
Actigraphy-measured sleep latency, total nocturnal sleep time, nocturnal wake time, 
number of nocturnal awakenings, sleep efficiency, and daytime activity level 
• 
Diary-measured sleep latency, total nocturnal sleep time, and number of nocturnal 
awakenings 
• 
PGI 
• 
HAM-D17 
• 
3DSS 
13.1.4 Methods of data conversion and handling of missing data 
Details will be specified in the statistical analysis plan prepared separately. 
13.1.5 Significance level and confidence coefficient 
Significance level: 5% (two-sided testing) 


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Confidence coefficient: 95% (two-sided estimation)  
13.1.6 Safety analysis 
[Safety endpoints] 
• 
Adverse events 
• 
Body weight 
[Analytical methods] 
The safety will be analyzed in the Full Analysis Set as follows:  
Treatment-Emergent Adverse Events (TEAEs), defined as adverse events occurring 
after the start of study drug administration, will be coded to the Medical Dictionary for 
Regulatory Activities (MedDRA) terms, and summarized by Preferred Term (PT) and 
System Organ Class (SOC) with frequency tabulation. 
Frequency tabulation will be generated for the following: 
• 
All TEAEs 
• 
TEAEs related to the study drug 
• 
All TEAE by severity 
• 
TEAEs realted to the study drug by severity 
• 
TEAEs leading to discontinuation of study treatment 
• 
Serious TEAEs 
For body weight and vital signs, the measurements at each time point of evaluation will 
be summarized using frequency tabulation. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size  
The sample size is set to 30 in light of feasibility of this study to investigate the effect of 
ramelteon in insomnia patients with depression. This planned sample size is not based 
on statistical power calculation. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the Study Site 
The sponsor or its designee shall perform periodic monitoring of study sites during the 
research to confirm that the research is conducted in accordance with all specifications 
in the research 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 research 
subject ID numbers, medical records of the research subjects, and signed and dated 
original consent forms to confirm that the research is appropriately conducted in 
compliance with the research protocol. Also, confirm the consistency between CRF and 
the related source documents. The principal investigator, investigator, and other 
personnel involved in the research shall spare sufficient time to facilitate monitoring 
procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the quality 
monitoring plan. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the Research Protocol.  
The principal investigator or investigator shall record all deviations from Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, and research 
protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief 
executive of the study site for the clinical research 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 the IEC. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site may be research subject to audits by the sponsor or its designee. 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 clinical research. In 
addition, this research may be inspected by regulatory agencies, including those of 
foreign governments (e.g., the Food and Drug Administration [FDA], the United 


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Kingdom Medicines and Healthcare products Regulatory Agency [MHRA]). If the 
study site is contacted for an 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 research-related source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants 
(i.e., research subjects) according to the research protocol, and the ethical principles that 
have their origin in the Declaration of Helsinki, Ethical Guidelines for Medical and 
Health Research Involving Human Subjects. Each investigator will conduct the study 
according to regulatory requirements and in accordance with "Responsibilities of the 
Investigator" in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations 
For implementation or continuation of this study, the principal investigator will provide 
the head of the medical institution with this protocol, a copy of the informed consent 
form and other documents required by applicable regulations. The head of the medical 
institution will then request a review to be done by the institutional review board etc. 
regarding essential items for proper implementation of the clinical study, including 
whether the protocol is compliant with the Ethical Guidelines for Medical and Health 
Researches Involving Human Participants. Documentation of approval of the 
institutional review board etc. and agreement of the head of the medical institution must 
be obtained by the principal investigator before implementation or continuation of the 
study.  
The study site shall observe all requirements that the Ethical Review Board, etc. 
prescribe. The requirements may include notifications to committees such as the IEC, 
for example, revision of the research protocol, revision of the informed consent form 
and information sheet, reports on safety in accordance with the regulatory requirements, 
reports on status of implementation of the research at intervals determined by a study 
site committee such as the Ethics Review Committee, and submission of the study 
completion report. 
15.2 
Conflict of Interests 
Prior to the conduction of this clinical research, the investigators involved in this 
clinical research shall ensure appropriate management of any conflicts (COI) in the 
conduct of the research in accordance with the rules of the study site.15)-19) 
The study site shall comply with all requirements specified by a committee such as the 
Ethics Review Committee, including the COI self-statement form, the research protocol, 
and the informed consent form and information sheet. 


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15.3 
Informed Consent and Information Sheet, and the Agreement of the 
Research Subjects 
The informed consent and information sheet form shall contain specific requirements of 
the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and all applicable laws and regulations. The informed 
consent form and information sheet shall specify the use of personal information and 
medical information of research subjects in this clinical research (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 research, its objectives, and 
potential risks and benefits. The informed consent form will detail the requirements of 
the participant and the fact that research 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 research subject information sheet by the committee 
such as the IEC. 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 research subjects. The principal investigator or 
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 the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects 
(or the representatives) have (1) an opportunity to inquire about the research and (2) 
sufficient time to decide on their participation. If a potential research subject (or their 
representative) decides he or she is willing to participate in the research, then the 
informed consent form must be signed and dated by the potential research subject (or 
the representative) prior to entering into the research as a subject. The principal 
investigator or investigator shall instruct the potential research subject (or 
representative) to sign using their legal names, not nicknames, using a blue or black ball 
point ink pen. Also the principal investigator or investigator shall sign and date the 
informed consent form prior to entering into the research. 
Once signed, the original informed consent form shall be retained by the principal 
investigator or investigator. The principal investigator or investigator shall record the 
date that the potential research subject signed the informed consent form in the subject's 


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medical record. A copy of the signed informed consent form shall be given to the 
research subject. 
The principal investigator or investigator shall follow the same procedure as for 
obtaining the initial consent when newly obtaining re-consent from the concerned 
research subject (or the representative) when the informed consent form is revised. The 
date of obtaining new consent shall be recorded in the research subject's medical record, 
and a copy of the revised consent form shall be provided to the research subject. 
15.4 
Personal Information of the Research Subjects 
The sponsor or the designee shall affirm the principle of the protection of research 
subjects' private/personal information. Throughout this study, research subject ID 
numbers shall be used to link the subject's source data to the sponsor's research database 
and research-related documents. Limited information on research subjects such as 
gender, age, and date of birth may be used within the scope of all applicable laws and 
regulations for identification of research subjects and confirmation of accuracy of 
research subject ID number. 
For verification of the conduct of the research in compliance with this protocol and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects, the 
sponsor shall require the principal investigator to provide the research sponsor's 
designee, representatives of regulatory authorities, designated auditors, and committees 
such as the Ethical Review Board direct access to research subjects' original medical 
records (source data or documents), including laboratory test results, ECG results, 
admission and discharge records during a subject's research participation, and autopsy 
reports.  
The principal investigator or investigator shall obtain specific authorization of the 
research subject as part of the informed consent process for access to research subject's 
original medical records by research sponsor's designee and representatives of 
regulatory authorities (see Section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or 
investigator shall delete information that may lead to identification of an individual 
(name and address of research subject, other personal information not recorded on the 
CRF of the research subject). 


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15.5 
Consultation Windows for the Research Subjects or Persons Related to the 
Research Concerned 
The principal investigator shall establish a contact service to respond to inquiries 
concerning this clinical research from research subjects or concerned people. Details of 
the contacts for inquiries will be described in the ICF. 
15.6 
Financial Burden or Reward to the Research Subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for 
medical treatment not covered by health insurance as research expenses. 
The research 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 clinical research to the research subjects at each visit from the 
research funds. Details of the financial burden on the research subjects and rewards 
shall be described in the informed consent form and information sheet. 
15.7 
Benefits and Inconveniences to the Research Subjects 
15.7.1 Benefits to research subjects 
Participation in this study is expected to allow more detailed characterization of the 
pathological condition of insomnia based on objective measurements, leading to 
selection of more appropriate treatment in individual patients. 
15.7.2 Inconveniences to research subjects 
Certain insomnia medications will be restricted during participation in this study.  
15.8 
Attribution of Research Results and Access Rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. In 
addition, secondary use (metaanalysis, etc.) of the data obtained in this clinical research 
may be possible if used in such a way that the data shall not be linked to personal 
identification information. 
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. 


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15.9 
Reporting of Results, Publication, Disclosure, and Clinical Research 
Registration Policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the 
chief executive of the study site and provide the sponsor with all the results and data 
obtained from the research. Only the sponsor may disclose the research information to 
other principal investigators, investigators or regulatory authorities during the research 
period, except when required by laws and regulations. The sponsor shall be responsible 
for publication of the research protocol and research-related results (including the public 
web site) except for other cases permitted in the research contract. 
During research period and after the end of research, the sponsor or its designee should 
promptly summarize the results and present it to medical journals and academic 
conferences, etc. The sponsor may publish any data or information obtained from the 
research (including data and information provided by the principal investigator) without 
obtaining agreement of the principal investigator. 
The investigator or the subinvestigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this research at an academic 
conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a 
timely manner and to comply with applicable laws, regulations, and guidelines, Takeda 
Pharmaceutical Company Limited shall register all clinical research being conducted in 
patients around the world at public trial registration sites, including at least the 
website(s) of ClinicalTrials.gov and Japan Pharmaceutical Information Center Clinical 
Trials Information (JAPIC), before initiation of the clinical research. On such websites, 
the research location (city, country), subject recruitment status, and contact information 
for Takeda Pharmaceutical Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the research results, irrespective of 
the nature of the results, at the public trial registration sites of Clinical Trials.gov and 
JAPIC in accordance with applicable laws and regulations. 


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15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any injury 
resulting from participation in the research according to local regulations applicable to 
the study site. The sponsor or its designee shall buy an insurance policy to compensate 
for health injury in research subjects 


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16.0 
REFERENCES 
1. Furihata R, Uchiyama M, Takahashi S, The association between sleep problems 
and perceived health status: a Japanese nationwide general population survey. 
Sleep Med. 2012;13(7):831-7. 
2. Patient Survey 2011 (Disease and Injury). Statistics and Information Department, 
Minister's Secretariat, Ministry of Health Labour and Welfare; 2011 
3. Kawakami N. [Major depression in Japan and the world -- State-of-art in 
epidemiology]. J Clin Exper Med. 2006;219:925-929. 
4. Sunderajan P, Gaynes BN, Wisniewski SR, et al. Insomnia in patients with 
depression: a STAR*D report. CNS Spectr. 2010;15:394-404. 
5. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with 
fluoxetine in patients with insomnia coexisting with major depressive disorder. 
Biol Psychiatry. 2006;59:1052-1060. 
6. Emens J, Lewy A, Kinzie JM, Arntz D, Rough J. Circadian misalignment in 
major depressive disorder. Psychiatry Res. 2009; 15;168(3):259-61. 
7. Driesen K, Jansen NW, van Amelsvoort LG, Kant I. The mutual relationship 
between shift work and depressive complaints--a prospective cohort study. Scand 
J Work Environ Health. 2011;37(5):402-10. 
8. Ueda H. Clinical usefulness of ramelteon in the treatment of insomnia with 
mental disorder. Jpn J Clin Psychopharmacol. 2014;17:65-73. 
9. Gross PK, Nourse R, Wasser TE. Ramelteon for insomnia symptoms in a 
community sample of adults with generalized anxiety disorder: an open label 
study. J Clin Sleep Med. 2009;5:28-33. 
10. Nakazaki K, Kitamura S, Motomura Y, et al. Validity of an algorithm for 
determining sleep/wake states using a new actigraph. J Physiol Anthropol. 
2014;33:31.  
11. Hamilton M. Development of a rating scale for primary depressive illness. Br J 
Soc Clin Psychol. 1967;6:278-296 
12. Matsumoto Y, Uchimura N, Ishida T, Toyomasu K, Hoshiko M, Kushino N, et al. 
[The cut-off point of the 3 Dimensional Sleep Scale (3DSS)--day workers 
version--based on the Pittsburgh Sleep Quality Index (PSQI)]. Sangyo Eiseigaku 
Zasshi. 2015;57:140-143. 
13. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia 
Classification Algorithm of Suicide Assessment (C-CASA): classification of 


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CONFIDENTIAL 
suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. 
Am J Psychiatry. 2007;164(7):1035-43. 
14. Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the 
assessment of suicidality in youth. CNS Spectr. 2007;12(2):156-62. 
15. Report of the Working Group on Conflict of Interest (Ministry of Education, 
Culture, Sports, Science and Technology dated November 1, 2002). 
16. 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). 
17. Guidelines on the Management of Conflict of Interest (COI) in Health and 
Labour Sciences Study (March 31, 2008). 
18. Guidelines for management of COI in medical study (COI Committee of Japan 
Association of Medical Sciences, February 2011). 
19. 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, August 2011). 
 
 

SAP_000.pdf: 
 
 
Title: The exploratory study to investigate the effect of Ramelteon for insomnia patients 
with major depressive disorder by using actigraphy 
 
NCT Number: NCT02669082 
Statistical analysis plan Approve Date: 26-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. 


 
 
 
 
 
The exploratory study to investigate the effect of Ramelteon  
for insomnia patients with major depressive disorder by using actigraphy 
(Protocol number: Ramelteon-4002) 
 
Statistical Analysis Plan 
(Ver.2.0: 26 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 .......................................................................................... 3 
6. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS ..... 6 
6.1. Subject Disposition ......................................................................................................... 6 
6.2. Demographics and Other Baseline Characteristics ............................................................. 8 
6.3. Study Drug Compliance and Exposure ............................................................................ 10 
7. 
EFFICACY EVALUATIONS ........................................................................................ 11 
7.1. Primary Endpoint and the Analytical Methods .................................................................. 11 
7.2. Secondary Endpoints and the Analytical Methods ............................................................. 11 
7.3. Other Analyses .............................................................................................................. 12 
8. 
SAFETY EVALUATION.............................................................................................. 15 
8.1. Evaluation of Adverse Event .......................................................................................... 15 
8.2. Other Evaluation ........................................................................................................... 17 
9. 
LISTING ....................................................................................................................... 17 
10. CONSIDERATIONS on STATISTICAL ANALYSIS ................................................. 18 
10.1. Adjustments for Covariates .......................................................................................... 18 
10.2. Handling of Dropouts or Missing Data .......................................................................... 18 
10.3. Criteria for Interim Analysis and Early Discontinuation ................................................. 18 
10.4. Multicenter Studies ..................................................................................................... 18 
10.5. Multiple Comparisons/Multiplicity ............................................................................... 18 
10.6. Examination of Subgroups ........................................................................................... 18 
11. REVISION HISTORY ................................................................................................. 19 
 


 
1 
 
1. 
DEFINITIONS of TERMS 
・ TEAE: Treatment-emergent adverse event 
・ Summary Statistics: Number of subjects, mean, standard deviations (SDs), maximum values, 
minimum values and quartiles 
・ Treatment Group: Ramelteon group 
 
2. 
TIME WINDOW 
[Actigraphy, Sleep diary] 
Since the response data of actigraphy and sleep diary at each time point are the mean of data 
which collected in the previous 7 days, a set of data before each time point will be evaluated if 
they meet in the time window. For example, if a set of data belongs to the both time windows at 
week 4 and week 8, a set of data will be divided into two groups, which are for Week 4 and 
Week 8. 
When there are two or more sets of data in the same time window, the one with the nearest visit 
date to the reference date will be selected, and if the time differences from the reference date are 
the same, the later data will be adopted. 
 
Assessment time point 
Reference Date 
Time window 
Days after the first 
administration 
At the start of the treatment 
period 
(baseline) 
Day 1 
Day -7 to Day 1 
Week 4 of the treatment 
period 
Day 29 
Day 2 to Day 32 
Week 8 of the treatment 
period 
Day 57 
Day 33 to Day 60 
At the end of the treatment 
period 
The latest set of the data group 
during the treatment period 
Day 2 to Day 60 
 
The day before the first day of the administration will be referred to as Day -1, and the first day 
of administration as Day 1. 
 
 


 
2 
 
 
[PGI, HAM-D17, 3DSS, Weight] 
When there are two or more data in the same time window, the one with the nearest assessment 
date to the reference date will be selected, and if the time differences from the reference date are 
the same, the later data will be adopted. 
Assessment time point 
Reference Date 
Time window 
Days after the first 
administration 
At the start of the treatment 
period 
(baseline) 
Day 1 
Day -7 to Day 1 
Week 4 of the treatment 
period 
Day 29 
Day 2 to Day 32 
Week 8 of the treatment 
period 
Day 57 
Day 33 to Day 60 
At the end of the treatment 
period 
The latest day during the 
treatment period 
Day 2 to Day 60 
 
The day before the first day of the administration will be referred to as Day -1, and the first day 
of administration as Day 1. 
 
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) 
・ Level of significance 
5% (two-sided) 
 
 


 
3 
 
・ 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 
 [Actigraphy] 
・ Daily variation of sleep latency will be calculated at each assessment time point as follows: 
Maximum value of sleep latency – minimum value of sleep latency 
 [Sleep Diary] 
・ Total nocturnal sleep time will be derived at each assessment time point as follows: 
(Awaking hour – bedtime hour) – sleep latency 
・ Daily variation of sleep latency will be calculated at each assessment time point as follows: 
Maximum value of sleep latency – minimum value of sleep latency 
 [HAM-D17] 
・ HAM-D17 total score (excluding sleep related score): 
HAM-D17 total score – total score of sleep related score (question number 06, 07, 08) 
・ HAM-D17 total score (sleep related score only): 
Total score of sleep related score (question number 06, 07, 08) 
 [Demographic Characteristics] 
・ Disease Duration (year) 
Duration of insomnia or depression = (date of first dose – onset date of insomnia or 
depression + 1) / 365.25 
For calculation, the onset date is regarded as the first of the month. 
 
 


 
4 
 
[3DSS] 
3DSS Questionnaire Instructions 
・ Choose the best number which describes yourself over the past one month.  
・ The question is for your daily life, and you don’t need to consider any special cases.  
・ Please fill in the number, or mark it.  
・ Pen, pencil, marker pen can be used.  
・ If you correct your answer, please erase it or mark “x” on your previous answer.  
No. 
 
Strongly 
Agree 
Agree Disagree 
Strongly 
Disagree 
1 
I sleep for less than 6 hours on 
weekdays. 
[1] 
[2] 
[3] 
[4] 
2 
I cannot get enough sleep even though I 
want to. 
[1] 
[2] 
[3] 
[4] 
3 
I go to bed at a fixed, regular time on 
weekdays and weekends. 
[1] 
[2] 
[3] 
[4] 
4 
I wake up at a fixed, regular time on 
weekdays and weekends. 
[1] 
[2] 
[3] 
[4] 
5 
I have a well-balanced breakfast every 
day. 
[1] 
[2] 
[3] 
[4] 
6 
It takes me more than 30 minutes to fall 
asleep. 
[1] 
[2] 
[3] 
[4] 
7 
I wake up more than twice a night. 
[1] 
[2] 
[3] 
[4] 
8 
I wake up earlier than usual (for over 2 
hours), and cannot fall asleep again. 
[1] 
[2] 
[3] 
[4] 
9 
I don’t sleep soundly. 
[1] 
[2] 
[3] 
[4] 
10 
I worry that I cannot fall asleep. 
[1] 
[2] 
[3] 
[4] 
11 
I don’t feel free from sleepiness or 
fatigue when I wake up. 
[1] 
[2] 
[3] 
[4] 
12 
I feel sleepy not only in the afternoon, 
but also in the morning and/or evening. 
[1] 
[2] 
[3] 
[4] 
13 
I often doze off. 
[1] 
[2] 
[3] 
[4] 
14 
“Morningness” is better suited to me 
than “Eveningness”. 
[1] 
[2] 
[3] 
[4] 


 
5 
 
No. 
 
Strongly 
Agree 
Agree Disagree 
Strongly 
Disagree 
15 
What time do you wake up on 
weekdays? 
[1] --> 6 A.M. or earlier 
[2] --> Around 6:30 A.M. 
[3] --> Around 7 A.M. 
[4] --> Later than 7 A.M. 
[1] 
[2] 
[3] 
[4] 
 
・ Phase scale score 
Phase scale score is the total score of the question number 3, 4, 5, 14 and 15, and each score 
is assigned according to the answers as below. 
[1]=3, [2]=2, [3]=1, [4]=0 
・ Quality scale score 
Quality scale score is the total score of the question number 6 to 10, and each score is 
assigned according to the answers as below. 
[1]=0, [2]=1, [3]=2, [4]=3 
・ Quantity scale score 
Quantity scale score is the total score of the question number 1, 2, 11, 12 and 13, and the 
score for each answer is assigned as below. 
[1]=0, [2]=1, [3]=2, [4]=3 
 
[TEAE] 
・ A TEAE is an adverse event for which the date of onset occurred after the first dose of study 
drug.  
[Non-serious TEAE] 
・ Non-serious TEAE is an adverse event experienced by more than 5 % of subjects, excluding 
serious AE (defined in the section 10.1.3 in the protocol).  
 
 


 
6 
 
6. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS 
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. 
 
6.1.2. Eligibility of Subjects 
Analysis set: All subjects who are obtained informed consent 
Analysis Items: Randomization into the treatment period of 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  
6.1.3.1. Status at the End of Study 
Analysis set: All subjects who enter the treatment period 
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.  
 
 


 
7 
 
6.1.4. Protocol Deviations and Analysis Datasets 
6.1.4.1. Protocol Deviations  
6.1.4.1.1 Protocol Deviations on the treatment period  
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 
6.1.4.2.1 Datasets Analyzed 
Analysis set: All subjects who enter the treatment period 
Analysis Items: Protocol deviations [Inclusion, Exclusion] 
Full Analysis Set 
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 deviations will be counted for each deviation. 
(2) The number of subjects in Full Analysis Set and the percentage will be 
calculated based on the subjects who enter the treatment period. 
 
 


 
8 
 
6.2. Demographics and Other Baseline Characteristics 
6.2.1. Distribution of Demographics 
Analysis set: All subjects who are given at least one dose of the study drug 
Analysis Items:  
Age (years) 
[Min<= - <65, 65<= - <=Max] 
Gender 
[Male, Female] 
Height (baseline) (cm) 
[Min<= - <150, 150<= - <160, 160<= - <170,  
170<= - <=Max] 
Weight (baseline) (kg) 
[Min<= - <40.0, 40.0<= - <50.0, 
50.0<= - <60.0, 60.0<= - <70.0, 70.0<= - <=Max] 
BMI (baseline) (kg/m2) 
[Min<= - <18.5, 18.5<= - <25.0, 25.0<= - <=Max] 
Alcohol consumption per week 
[0 day, 1-2 days, 3-5 days, 6-7 days] 
Daily smoking status 
 [Non-smoking, Less than 20 cigarettes, 20 cigarettes 
or more] 
Insomnia 
・ Duration of disease (years) 
・ Initial episode/recurrence 
[Initial episode, Recurrence] 
・ Non-pharmacological therapy [Yes, No] 
Depression 
・ Duration of disease (years) 
・ Initial episode/recurrence 
[Initial episode, Recurrence] 
・ Psychotherapy 
[Yes, No] 
Sleep latency by actigraphy (baseline) 
Sleep latency by sleep diary (baseline)  
Total nocturnal sleep time by actigraphy (baseline) 
Nocturnal wake time by actigraphy (baseline) 
Number of nocturnal awakenings by actigraphy (baseline) 
Sleep efficiency by actigraphy (baseline) 
Total nocturnal sleep time by sleep diary (baseline) 
Number of nocturnal awakenings by sleep diary (baseline) 
Daytime activity level by actigraphy (steps) (baseline) 


 
9 
 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The number of subjects and the percentage will be calculated for 
discrete variables, and summary statistics will be calculated for 
continuous variables. 
 
6.2.2. Medical History and Concurrent Medical Conditions 
Analysis set: All subjects who are given at least one dose of the study drug 
Analysis Items: Medical history, Concurrent medical conditions 
Analysis Methods: History events and concurrent medical conditions will be coded 
using the MedDRA dictionary and tabulated by System 
Organ Class (SOC) and Preferred Term (PT). SOCs will be 
sorted in alphabetical order, and PTs will be sorted in 
decreasing frequency order. 
(1) The number of subjects and the percentage will be calculated for 
medical history by SOC/PT. 
(2) The number of subjects and the percentage will be calculated for 
medical conditions by SOC/PT. 
Subjects with one or more events within a level of MedDRA term is 
counted only once in that level. 
 
6.2.3. Medication History and Concomitant Medications 
Analysis set: All subjects who are given at least one dose of the study drug 
Analysis Items: Medication history 
Previous use of hypnotics 
[Yes (previous use of Benzodiazepine hypnotics, previous use of 
Non-benzodiazepine hypnotics, previous use of other hypnotics), No] 
Concomitant Medications 
Analysis Methods: The number of subjects and the percentage will be calculated for 
the above analysis items. Medications will be coded using the 
WHO (World Health Organization) Drug. Coded medications 
will be sorted in decreasing frequency order. Medications 
used more than once within a subject will be counted only 
once for the coded medication. 
 


 
10 
 
6.3. Study Drug Compliance and Exposure 
6.3.1. Study Drug Compliance 
Analysis set: All subjects who are given at least one dose of the study drug. 
Analysis Items: 
Study drug compliance [Properly (90% or more), Generally (70% or more), Half 
(50% or more), Less than half (less than 50%)]  
Antidepressants Compliance [Properly (90% or more), Generally (70% or more), 
Half (50% or more), Less than half (less than 50%)]  
Change of antidepressants dosage regimen [Yes, no] 
Time point: Week 4, Week 8 
Analysis Methods: For the above analysis items, the following analysis will be 
performed.  
(1) The number of subjects and the percentage will be calculated for each 
category. 
 
6.3.2. Study Drug Exposure 
Analysis set: All subjects who are given at least one dose of the study drug. 
Analysis Items:  
Duration of study drug exposure (days) [1<=-<29, 29<=-<58, 58<=-<=Max] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) The number of subjects and the percentage will be calculated for 
discrete variables, and summary statistics will be calculated for 
continuous variables. 
 
 


 
11 
 
7. 
EFFICACY EVALUATIONS 
7.1. Primary Endpoint and the Analytical Methods 
7.1.1. Change from Baseline in Sleep Latency by Actigraphy 
Analysis set: Full Analysis Set 
Analysis items: Sleep latency by actigraphy 
Time point: Baseline, Week 4, Week 8, End of the treatment period 
Analysis methods: For the above analysis items, the following analysis will be 
performed. 
(1) As the analyses for primary endpoint, summary statistics and 
two-sided 95% confidence interval (CI) of the mean will be calculated 
for both change and percentage change from baseline to the end of 
treatment period, and one sample t-test will be conducted to assess the 
change within a subject. The same analyses as described above will be 
performed for change and percentage change at Week 4 and Week 8. 
In addition, mean plots with +/- SD for change and percentage change 
will be displayed at each time point. 
(2) For change and percentage change from baseline to each time point, 
case plots will be illustrated at each time point. 
(3) For observed value at each time point, case plots will be displayed, 
and summary statistics and two-sided 95% CI of the mean will be 
calculated. Mean plots with +/- SD will be also displayed at each time 
point. 
 
7.2. Secondary Endpoints and the Analytical Methods 
7.2.1. Secondary Endpoints and the Analytical Methods 
Analysis set: Full Analysis Set 
Analysis items:  
Sleep latency by actigraphy 
Total nocturnal sleep time by actigraphy 
Nocturnal wake time by actigraphy 
Number of nocturnal awakenings by actigraphy 
Sleep efficiency by actigraphy 
Total nocturnal sleep time by sleep diary 
Number of nocturnal awakenings by sleep diary 
Daytime activity level by actigraphy (steps) 
 
 


 
12 
 
Time Point: Baseline, Week 4, Week 8, End of the treatment period 
Analysis Methods: For the above analysis items, the same analyses as described in 
7.1.1. will be performed for secondary endpoints. 
 
7.3. Other Analyses 
7.3.1. Patient Global Impression of Improvement (PGI) 
Analysis set: Full Analysis Set 
Analysis items: PGI [Very much worse, Much worse, A little worse, No change, A 
little improved, Much improved, Very much improved] 
Time Point: End of the treatment period 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) The number of subjects and the percentage will be calculated for each 
category. 
7.3.2. Hamilton Rating Scale for Depression-17 (HAM-D17) 
Analysis set: Full Analysis Set 
Analysis items:  
01. Depressed mood (Sadness, hopeless, helpless, worthless) 
[0, 1, 2, 3, 4] 
02. Work and activities 
[0, 1, 2, 3, 4] 
03. Genital symptoms 
[0, 1, 2] 
04. Somatic symptoms gastrointestinal 
[0, 1, 2] 
05. Loss of weight (Rated by A or B) 
A. Rating by history 
[0, 1, 2, 3] 
B. Rating weekly by measuring weight by ward psychiatrist 
[0, 1, 2, 3] 
06. Insomnia early 
[0, 1, 2] 
07. Insomnia middle 
[0, 1, 2] 
08. Insomnia late 
[0, 1, 2] 
09. Somatic symptoms general 
[0, 1, 2] 
10. Feelings of guilt 
[0, 1, 2, 3, 4] 
11. Suicide 
[0, 1, 2, 3, 4] 
12. Anxiety psychic 
[0, 1, 2, 3, 4] 
13. Anxiety somatic 
[0, 1, 2, 3, 4] 
14. Hypochondriasis 
[0, 1, 2, 3, 4] 


 
13 
 
15. Insight 
[0, 1, 2] 
16. Retardation (Slowness of thought and speech, impaired ability to concentrate, 
decreased motor activity)  
[0, 1, 2, 3, 4] 
17. Agitation 
[0, 1, 2, 3, 4] 
HAM-D17 total score 
[0<=-<8, 8<=-<17, 17<=-<24, 24<=] 
HAM-D17 total score (except for sleep related score) 
HAM-D17 total score (sleep related score) 
 
Time Point: Baseline, Week 4, Week 8, End of the treatment period 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) The number of subjects and the percentage will be calculated for each 
category. 
(2) For HAM-D17 total score, HAM-D17 total score (except for sleep 
related) and HAM-D17 total score (sleep related), summary statistics 
will be calculated and case plots will be displayed. 
(3) For HAM-D17 total score, HAM-D17 total score (sleep related) and 
HAM-D17 total score (except for sleep related), summary statistics 
and two-sided 95% CI of the mean will be calculated for both change 
and percentage change from baseline to each time point, and one 
sample t-test will be conducted to assess the change within a subject. 
 
7.3.3. 3 Dimensional Sleep Scale (3DSS) 
Analysis set: Full Analysis Set 
Analysis items:  
01. I sleep for less than 6 hours on weekdays. 
02. I cannot get enough sleep even though I want to. 
03. I go to bed at a fixed, regular time on weekdays and weekends. 
04. I wake up at a fixed, regular time on weekdays and weekends. 
05. I have a well-balanced breakfast every day. 
06. It takes me more than 30 minutes to fall asleep. 
07. I wake up more than twice a night. 
08. I wake up earlier than usual (for over 2 hours), and cannot fall asleep again. 
09. I don’t sleep soundly. 
10. I worry that I cannot fall asleep. 
11. I don’t feel free from sleepiness or fatigue when I wake up. 


 
14 
 
12. I feel sleepy not only in the afternoon, but also in the morning and/or evening. 
13. I often doze off. 
14. “Morningness” is better suited to me than “Eveningness”. 
 
[Strongly Agree, Agree, Disagree, Strongly Disagree] for the question 1 - 14.  
15. What time do you wake up on weekdays? 
 
[6 A.M. or earlier, Around 6:30 A.M., Around 7 A.M., Later than 7 A.M.] 
Phase scale score 
Quality scale score 
Quantity scale score 
 
Time Point: Baseline, Week 4, Week 8, End of the treatment period 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) The number of subjects and the percentage will be calculated for each 
category. 
(2) For phase scale score, quality scale score and quantity scale score, 
summary statistics will be calculated and case plots will be displayed. 
(3) For phase scale score, quality scale score and quantity scale score, 
summary statistics and two-sided 95% CI of the mean will be 
calculated for both change and percentage change from baseline to 
each time point, and one sample t-test will be conducted to assess the 
change within a subject. 
 
7.3.4. Correlation between Endpoints 
Analysis set: Full Analysis Set 
Analysis items: Sleep latency by actigraphy 
Sleep latency by sleep diary 
Total nocturnal sleep time by actigraphy 
Total nocturnal sleep time by sleep diary 
Time Point: End of the treatment period 
Analysis Methods: Correlation charts between the items below will be illustrated 
and Spearman’s correlation coefficient will calculated.  
Sleep latency by actigraphy vs. sleep diary 
Total nocturnal sleep time by actigraphy vs. sleep diary 
 
 


 
15 
 
8. 
SAFETY EVALUATION 
8.1. Evaluation of Adverse Event 
8.1.1. Brief Summary of TEAE 
Analysis set: Full Analysis Set 
Analysis items: TEAE 
Category Classification:  
Causal relationship with study drug 
[related, unrelated] 
        Severity 
[Mild, Moderate, Severe] 
        Date of onset 
[1<= - <29, 29<= - <58, 58<= - <=Max] 
 
For the above analysis items, the following analyses will be performed. 
(1) Brief summary of TEAE 
1) 
All TEAEs 
2) 
TEAEs related to study drug 
3) 
TEAEs by severity 
4) 
TEAEs related to study drug by severity 
5) 
TEAEs leading to study drug discontinuation 
6) 
Serious TEAEs 
7) 
Serious TEAEs related to study drug 
8) 
Serious TEAEs leading to study drug discontinuation  
9) 
TEAEs leading to death 
10) TEAEs by date of onset  
Incidence rates will be calculated based on the following rules. 
[Frequency of Subjects] 
In case of the analysis by severity, subjects with one or more adverse events within 
a level of MedDRA term is counted only once in that level using the most severe 
incident. The denominator when calculating the incidence of adverse events is the 
number of subjects of Full Analysis Set. 
In case of the analysis by date of onset, subjects with one or more adverse events 
are counted once in each category of period when the incident occurred. The 
denominator when calculating the incidence of adverse events is the number of 
subjects who are administrated the study drug on and after the period, or the 
subjects with TEAEs on and after the period. The numerator is the number of 
subjects with TEAEs on the period.  
 
 


 
16 
 
In the analyses other than the above, subjects with one or more adverse events 
within a level of MedDRA term is counted only once in that level. The denominator 
when calculating the incidence of adverse events is the number of subjects of Full 
Analysis Set. 
8.1.2. Display of TEAE 
Analysis set: Full Analysis Set 
Analysis items: TEAE 
Category Classification:  
Causal relationship with study drug 
[related, unrelated] 
        Severity 
[Mild, Moderate, Severe] 
        Date of onset 
[1<= - <29, 29<= - <58, 58<= - <=Max] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. The data will be coded using the MedDRA dictionary and be 
summarized into SOC and PT. SOCs will be sorted in alphabetical order, 
then PTs will be sorted in decreasing frequency order. 
1) 
All TEAEs (by SOC/PT) 
2) 
TEAEs related to study drug (by SOC/PT) 
3) 
TEAEs by severity (by SOC/PT) 
4) 
TEAEs related to study drug by severity (by SOC/PT) 
5) 
TEAEs leading to study drug discontinuation (by SOC/PT) 
6) 
Serious TEAEs (by SOC/PT) 
7) 
Non-serious TEAEs (by SOC/PT) 
8) 
Serious TEAEs related to study Drug (by SOC/PT) 
9) 
Serious TEAEs leading to study drug discontinuation (by SOC/PT) 
10) TEAEs leading to death (by SOC/PT) 
11) TEAEs by date of onset (by SOC/PT) 
The number of subjects and incidence rates will be calculated in the same manner 
as mentioned in 8.1.1. 
 
 


 
17 
 
8.2. Other Evaluation 
8.2.1. Evaluation of Weight 
Analysis set: Full Analysis Set 
Analysis items: Weight 
Time Point: Baseline, Week 4, Week 8, End of the treatment period 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) Summary statistics for observed values and post-treatment changes 
(post-treatment value – baseline value) will be calculated at each time 
point. 
(2) For observed value, case plots will be illustrated at each time point. 
 
9. 
LISTING 
Listing of the following data will be presented. 
・ Demographic Data 
・ Medication History 
・ Medical History, Concurrent Medical Conditions 
・ Insomnia History 
・ Depression History 
・ Weight, BMI 
・ HAM-D17 
・ 3DSS 
・ Actigraphy 
・ Eligibility 
・ Study Drug Compliance 
・ Status at the end of Study 
・ PGI 
・ Sleep Diary 
・ Adverse Event 
・ Concomitant Medications 
・ Overdose 
 
 
 


 
18 
 
10. CONSIDERATIONS on STATISTICAL ANALYSIS 
10.1. Adjustments for Covariates 
Adjustments for covariates will not be performed. 
 
10.2. Handling of Dropouts or Missing Data 
Any imputation for missing data will not be performed. 
 
10.3. Criteria for Interim Analysis and Early Discontinuation 
No interim analyses will be performed. 
 
10.4. Multicenter Studies 
No statistical adjustments will be made to compensate for multi-center study. 
 
10.5. Multiple Comparisons/Multiplicity 
No statistical adjustments will be made for multiple comparisons. 
 
 
10.6. Examination of Subgroups 
The subgroup analyses will be performed to examine the primary endpoints using the same 
analysis methods as 7.1.1(1). The analyses will be performed for the data at the end of treatment 
period only. 
Subgroups: 
・ Medication history  
[Previous use of Benzodiazepine hypnotics, 
No previous use of Benzodiazepine hypnotics (Previous use of Non-benzodiazepine 
hypnotics),  
No previous use of Benzodiazepine hypnotics (No previous use of Non-benzodiazepine 
hypnotics and previous use of other hypnotics), 
No previous use of hypnotics] 
・ Concomitant use of Benzodiazepine anxiolytics 
[Yes, No] 
・ Concomitant use of SSRI or SNRI 
[Yes, No] 
・ Duration of insomnia  
[< 3years, 3years<=] 
・ Duration of depression  
[< 3years, 3years<=] 
・ Phase scale score in 3DSS at Baseline 
[< 9, 9<=] 
 
 
 


 
19 
 
11. REVISION HISTORY 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
1.0 
3 JUN 2016 
- 
 
2.0 
26 FEB 2018 
5.OTHER DATA HANDLING 
Add the endpoints below: 
[Actigraphy] 
・ Daily variation of sleep latency 
[Sleep Diary] 
・ Daily variation of sleep latency 
[HAM-D17] 
・ HAM-D17 total score 
(excluding sleep related score) 
・ HAM-D17 total score (sleep 
related score only) 
[Demographic Characteristics] 
・ Disease Duration (year)  
[Non-serious TEAE] 
To add the endpoints. 
 
 
 
 
6.1.3. Subject Disposition 
Modify the title below: 
(Before) 6.1.3.1. Status at the End 
of Treatment Period 
(After) 6.1.3.1. Status at the End of 
Study 
Modify the endpoint below: 
(Before) Status at the end of 
treatment 
(After) Status at the end of study 
To specify the 
contents of analysis. 
 
 
 
6.1.4.2.1. Datasets Analyzed 
Delete the underlined part below: 
For the above analysis items, the 
following analysis will be 
performed for merged treatment 
group. 
To correct the clerical 
error. 
PPD
PPD


 
20 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
 
 
 
6.2.1. Distribution of 
Demographics 
Add the endpoints below: 
Insomnia 
・ Duration of disease (years)  
・ Initial episode/recurrence 
・ Non-pharmacological therapy 
Depression 
・ Duration of disease (years)  
・ Initial episode/recurrence 
・ Psychotherapy 
To add the endpoints. 
 
 
 
 
6.2.3. Medication History and 
Concomitant Medications 
Add the endpoints below: 
Analysis items: 
Previous use of hypnotics 
[Yes (previous use of 
Benzodiazepine hypnotics, 
previous use of  
Non-benzodiazepine 
hypnotics, previous use of 
other hypnotics), No] 
To add the endpoints. 
 


 
21 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
 
 
 
7.1.1. Change from Baseline in 
Sleep Latency by Actigraphy 
(1) Add the underlined part below:  
As the analyses for primary 
endpoints, summary statistics 
and two-sided 95% confidence 
interval (CI) of the mean will 
be calculated for both change 
and percentage change from 
baseline to the end of treatment 
period 
(2) Add this section. 
(3) Add the underlined parts below: 
For observed value at each 
time point, case plots will be 
displayed, and summary 
statistics and two-sided 95% 
CI of the mean will be 
calculated. Mean plots with 
+/- SD will be also displayed 
at each time point. 
To add the endpoints 
and analysis methods. 
 


 
22 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
 
 
 
7.2.1. Secondary Endpoints and the 
Analytical Methods 
(1) Add the underlined part below:  
As the analyses for primary 
endpoints, summary statistics 
and two-sided 95% confidence 
interval (CI) of the mean will 
be calculated for both change 
and percentage change from 
baseline to the end of treatment 
period 
(2) Add this section. 
(3) Add the underlined parts below: 
For observed value at each time 
point, case plots will be 
displayed, and summary 
statistics and two-sided 95% CI 
of the mean will be calculated. 
Mean plots with +/- SD will be 
also displayed at each time 
point. 
To add the endpoints 
and analysis methods. 
 
 
 
 
7.3.2. Hamilton Rating Scale for 
Depression-17 (HAM-D17) 
Modify the categories below: 
(Before) HAM-D17 total score 
[0<=-<8, 8<=-<17, 17<=-<23, 
24<=] 
(After) HAM-D17 total score 
[0<=-<8, 8<=-<17, 17<=-<24, 
24<=] 
Add the endpoints below: 
・ HAM-D17 total score (except 
for sleep related score)  
・ HAM-D17 total score (sleep 
related score) 
To correct the clerical 
error and add the 
endpoints. 
 


 
23 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
 
 
 
7.3.3. 3 Dimensional Sleep Scale 
(3DSS) 
(2) Add the underlined parts below:  
For phase scale score, quality 
scale score and quantity scale 
score, summary statistics will 
be calculated and case plots 
will be displayed. 
(3) Add this section 
To add the endpoints. 
 
 
 
7.3.4. Correlation between 
Endpoints 
Add this whole section. 
To add the analysis. 
 
 
 
8.1.2. Display of TEAE 
7) Add this section. 
To add the analysis. 
 
 
 
9. LISTING 
Add this whole section. 
To add the analysis. 
 
 
 
10.6. Examination of Subgroups 
Add this whole section. 
To add the analysis.