Clinical trial NCT05594589
Conditions: Sleep Initiation and Maintenance Disorders
Keywords: Lemborexant E2006 Dayvigo
Sponsor: Eisai Co., Ltd.
Start date: 2022-11-30; Completion date: 2024-05-24
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of the study is to evaluate the treatment difference between lemborexant 5 milligram (mg) (LEM5) and placebo (PBO) on latency to persistent sleep (LPS) using polysomnography (PSG) on Day 30.

Detailed description:

Arms: arm 1: Participants will receive one LEM5 tablet, orally, once daily for 30 nights (Day 1 up to Day 30) on each night approximately 5 minutes before participants intend to try to sleep. arm 2: Participants will receive one lemborexant 10 mg (LEM10) tablet, orally, once daily for 30 nights (Day 1 up to Day 30) on each night approximately 5 minutes before participants intend to try to sleep. arm 3: Participants will receive one lemborexant-matched PBO tablet, orally, once daily for 30 nights (Day 1 to Day 30) on each night approximately 5 minutes before participants intend to try to sleep.
Interventions: intervention 1: Lemborexant intervention 2: PBO
Intervention descriptions: intervention 1: Lemborexant oral tablet. intervention 2: Lemborexant-matched PBO tablet.

Protocol documents:
Prot_000.pdf: 
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REVISION HISTORY
Previous Version:  V3.0 (per Amendment 02)
Current Version:  V4.0 (per Amendment 03)
Date of Revisions:  14 Sep 2023
Change
Rationale
Affected Protocol Sections
Changed the laboratory for
bacteria in urine tests from the 
central laboratory to local 
laboratories.
To monitor the subject’s safety
properly.
Section 9.5.1.4.3


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Previous Version:  V2.0 (per Amendment 01)
Current Version:  V3.0 (per Amendment 02)
Date of Revisions:  28 Sep 2022
Change
Rationale
Affected Protocol Sections
Analysis Sets Per Protocol
(PP), added a brief description 
clarifying that the evaluability 
criteria will be determined 
before database lock and will 
be specified in the SAP.
To meet the regulatory advice 
from MFDS
Section 2 – Analysis Sets
Section 9.7.1.2
Specified that a centralized 
randomization technique will 
be used as the allocation 
method.
To clarify the allocation 
method.
Section 9.4.3
Corrected language about a 
timing of blood sampling
Correction
Section 9.5.1.3.1
Section 9.5.1.4.3
Corrected volume per sample 
collection for blood samplings
Correction
Section 9.5.1.4.3
Section 9.5.2.1
Revised the title of Sponsor.
For Sponsor’s organizational 
changes
SPONSOR SIGNATURE 
PAGE
Removed language from some 
definitions of grading for 
laboratory values
To define the gradings by 
values only
Section 12, Appendix 1
P




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Previous Version:  V1.0 (original protocol)
Current Version:  V2.0 (per Amendment 01)
Date of Revisions:  12 May 2021
Change
Rationale
Affected Protocol Sections
PSG” to “had LPS data from the 
PSG on Day 30”
Analysis Sets of PP, added a 
brief description that details of 
the evaluability criteria will be 
determined 
before 
database 
lock and will be specified in the 
SAP.
To meet the regulatory advice 
from MFDS
Section 2 – Analysis Sets
Section 9.7.1.2
Efficacy Analyses, added a 
brief description that the main 
analysis group for the primary 
endpoint is FAS
To meet the regulatory advice 
from MFDS
Section 2 – Efficacy Analyses
Section 9.7.1.6
Revised sample size rationale
To meet the regulatory advice 
from MFDS
Section 2
–
Sample Size 
Rationale
Section 9.2.4
Section 9.7.2
Updated worldwide marketing
authorization status
Update
Section 7.1
Updated 
prohibited 
concomitant medications
Update
Section 12, Appendix 3
CCI


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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-J082-204
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study to Assess the Pharmacodynamics of 
Lemborexant in Korean Subjects with Insomnia Disorder 
Sponsor
Eisai Co., Ltd. 
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112-8088, Japan
Sponsor’s 
Investigational 
Product Name:
E2006/lemborexant
Indication:
Insomnia
Phase:
2
Approval Date:
V1.0
V2.0
V3.0
V4.0
14 Sep 2020 (original protocol)
12 May 2021 (per Amendment 01)
28 Sep 2022 (per Amendment 02)
14 Sep 2023 (per Amendment 03)
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study to Assess 
the Pharmacodynamics of Lemborexant in Korean Subjects with Insomnia Disorder
Investigators
To be determined
Sites
Approximately 9 Sites in South Korea (revised per Amendment 01)
Study Period and Phase of Development
First subject in to last subject out: Approximately 12 months 
Phase 2
Objectives
Primary Objective
•
To evaluate, using polysomnography (PSG), the treatment difference between lemborexant 
5 mg (LEM5) and placebo (PBO) on latency to persistent sleep (LPS) on Day 30 (revised per 
Amendment 01)
Secondary Objectives
•
To evaluate, using PSG, the treatment difference between lemborexant 10 mg (LEM10) and 
PBO on LPS on Day 30 (revised per Amendment 01)
•
To evaluate, using PSG, the treatment difference between LEM5 and PBO on sleep efficiency 
(SE) on Day 30 (revised per Amendment 01)
•
To evaluate, using PSG, the treatment difference between LEM10 and PBO on SE on Day 30
(revised per Amendment 01)
•
To evaluate safety and tolerability of lemborexant following multiple doses
•
To evaluate the pharmacokinetics of lemborexant
Exploratory Objectives
Study Design
A multicenter, multiple dose, randomized, double-blind, placebo-controlled, parallel-group study in 
Korean subjects with insomnia disorder.  Subjects will be randomized to LEM5, LEM10 or PBO in 
a ratio of 2:2:1 and will receive study drug for 30 days.(revised per Amendment 01)
Study Procedures
The study will consist of 2 phases:  Prerandomization Phase and Randomization Phase.
CCI


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The Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 days:  a 
Screening Period, a Run-in Period, and a Baseline Period.  The Randomization Phase will comprise 
a Treatment Period during which subjects will be treated for 30 nights, and a minimum 28-day 
Follow-up Period before an End of Study (EOS) Visit.
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At the 1st 
visit, informed consent will be obtained after the study has been fully explained to each subject and 
before the conduct of any screening procedures or assessments.  A medical, psychiatric, and sleep 
history interview, physical examination, serum pregnancy test (females of childbearing potential 
only), urine drug test, assessment of suicidality, questioning regarding adverse events (AEs), 12-
lead electrocardiogram (ECG), vital signs, weight, height, viral screen, clinical hematology, 
chemistry analysis and urinalysis will be conducted for evaluation of eligibility criteria, and will 
include confirmation that the subject meets diagnostic criteria for insomnia disorder, and further, 
that the subject complains of difficulties with sleep onset with or without problems with sleep 
maintenance and/or awakening earlier in the morning.  Screening assessments will include the 
Insomnia Severity Index (ISI), the Beck Depression Inventory - II (BDI), Beck Anxiety Inventory 
(BAI), and the Sleep Disorders Screening Battery (SDSB) that consists of STOPBang and 
International Restless Legs Scale (IRLS).
All eligible subjects will be provided with a paper sleep diary and site staff will instruct subjects to 
complete the diary each morning within 1 hour after morning wake time and will emphasize the 
importance of doing so.  Subjects will also be reminded of study restrictions pertaining to timing of 
meals and caffeine/alcohol use.
After subjects have completed the sleep diary on at least 7 consecutive mornings, subjects will 
undergo the 2nd Screening Visit (Visit 2).  This visit must occur between Day –17 and Day –10.  
On this night on which PSG is recorded, subjects will arrive at the clinic in the evening with 
sufficient time before bedtime to complete sleep diary review for continued eligibility with regard 
to sleep timing, duration of time spent in bed, and frequency of nights with symptoms of insomnia, 
check-in procedures, any scheduled assessments, and preparations (eg, electrode montage 
placement) for the PSG recordings. Subjects who continue to meet the eligibility criteria will then 
prepare check-in for PSG recording. After check-in has been completed, subjects will then 
undergo an 8-hour PSG recording, to start at the median habitual bedtime (MHB) as calculated 
from the sleep diary entries.  The PSG recording will include channels in the electrode montage to 
screen for symptoms of sleep apnea and periodic limb movement disorder (PLMD).  Subjects who 
continue to meet the eligibility criteria will then be dispensed PBO tablets (single-blind) and will 
enter the Run-in Period.  In addition, at check-in before all visits at which PSG is to be recorded, 
subjects will undergo a urine drug test and urine pregnancy test (females of childbearing potential 
only), and questioning regarding AEs.
Run-in Period
The Run-in Period will begin when eligible subjects are dispensed PBO tablets and will continue 
until the Baseline Period on Day 1.  During the Run-in Period, all subjects will take PBO each 
night approximately 5 minutes before bedtime (defined as the time the subject intends to try to fall 
asleep).  They will be reminded that they must remain in bed for at least 7 hours each night and 
maintain a regular bedtime and waketime throughout the study, according to the schedule 
determined by the study site and the subject.  They will also be reminded that they must follow 
study restrictions with regard to timing of meals, and use of caffeine and alcohol.
Subjects will return to the clinic between Day –10 and Day –5.  Subjects who are still eligible will 
have PSG recording.  In the evening, before the PSG recording, the safety assessments including 
questioning AEs and vital signs assessment will be conducted and a urine drug test and urine 


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pregnancy test (females of childbearing potential only) will be performed.  Study personnel will 
administer study drug to subjects approximately 5 minutes before their scheduled bedtime, which 
will be at the same MHB as used for the 2nd Screening Visit.  Subjects will undergo an 8-hour 
PSG.  The PSG recording will be reviewed for continued eligibility, and it will also provide the 
baseline values for PSG-derived endpoints for subjects who are randomized.  Subjects may then 
leave the clinic after the investigator determines that it is safe for them to do so. Subjects will 
continue to take study drug at home approximately 5 minutes before bedtime.  They will again be 
reminded that they must remain in bed for at least 7 hours each night, maintain a regular bedtime 
throughout the study, and follow study restrictions with regard to timing of meals and use of 
caffeine and alcohol.
Baseline and Treatment Period
On Day 1, the Run-in Period will end, and the Baseline Period will begin.  Subjects will return to 
the clinic for this visit. Subjects will be questioned about study drug compliance. Safety 
assessments including questioning regarding AEs, 12-lead ECG, vital signs, weight, clinical 
hematology and chemistry analysis, urinalysis will be conducted.  In addition, subjects should 
undergo a urine drug test and urine pregnancy test (females of childbearing potential only).  
Subjects who complete the Baseline Period and continue to meet the eligibility criteria will be 
randomized, and will begin the Treatment Period.
The Treatment Period will begin on Day 1 immediately after the Baseline Period and study drug 
will be administered before bedtime for the next 30 nights.  Subjects will be randomized in a 
double-blind manner, to receive study drugs, LEM5, LEM10 or PBO.
Study drug will be dispensed to subjects.  Subjects will be instructed to take lemborexant or PBO
at home in the evening immediately (ie, within 5 minutes) before bedtime on approximately the 
same schedule as during the Run-in period.
On Day 14, site staff will call subjects to check AEs, concomitant therapy, and drug compliance.
In addition, subjects will be reminded to take study drug each night approximately 5 minutes 
before bedtime and to remain in bed for at least 7 hours each night and maintain a regular bedtime 
and waketime throughout the study, according to the schedule determined by the study site and the 
subject. They will also be reminded that they must follow study restrictions with regard to timing 
of meals, and use of caffeine and alcohol. If any AE is clinically significant and requires follow-
up, an unscheduled visit may be arranged per investigator’s decision.
On Day 30, subjects will return to the clinic. Subjects will be questioned about study drug 
compliance and AEs. A urine drug test and urine pregnancy test (females of childbearing potential 
only) will be performed.  A PK blood sample will be collected predose and study drug will be 
administered approximately 5 minutes before the subject’s MHB.  A PSG will be conducted at the 
same time and with the same electrode montage as the PSG during the Run-in Period.  On the 
morning of Day 31, PK samples will be obtained.  Safety assessments including questioning 
regarding AEs, physical examination, 12-lead ECG, vital signs, clinical hematology, chemistry 
analysis and urinalysis will be conducted.  After the investigator determines that it is safe for them 
to do so, subjects will be discharged from the clinic.
Follow-Up Period and End of Study Visit
The Follow-up Period will begin when the subjects leave the clinic at the end of the Treatment 
Period.  Subjects will cease to take study drug.
Approximately 28 days after completion of the Treatment Period subjects will return to the clinic 
for the EOS Visit.  At the EOS Visit, in addition to safety assessment including questioning 
regarding AEs, physical examination, 12-lead ECG, vital signs, clinical hematology, chemistry 
analysis and urinalysis, a urine drug test and urine pregnancy test (females of childbearing potential 


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only) will be conducted.  After the End of Study Visit, subjects’ participation in the study will be 
finished.
Premature Discontinuation of Study Drug
A subject who prematurely discontinues taking study drug should return to the clinic as soon as 
practicable after discontinuing study drug (preferably within 7 days), to complete the Early 
Termination (ET) Visit.  If the subject discontinues from the study due to an AE, the subject must 
complete an ET Visit and all AEs, regardless of relationship to study drug or procedure, should be 
collected at beginning from the time the subject signs the study ICF through the last visit.  In 
addition, subjects who withdraw due to an AE should undergo a urine drug test and urine 
pregnancy test (females of childbearing potential only).
Additional Study Information
The estimated study duration for each subject on study is anticipated to be a maximum of 93 days 
consisting of the Screening Period plus Run-in Period plus Baseline Period maximum of 35 days 
plus Treatment Period plus Follow-up Period and EOS Visit maximum of 58 days.  A subject who 
completes the Treatment Period (assessments through discharge from the clinic on Day 31) will be 
considered to have completed the study.
Number of Subjects
Approximately 60 Korean subjects with insomnia disorder will be randomized to treatment (LEM5 
[24 subjects], LEM10 [24 subjects], and PBO [12 subjects]).(revised per Amendment 01)
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Korean male or female, age 19 to 80 years, at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria 
for Insomnia Disorder, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty getting to sleep 
with or without difficulty staying asleep and/or awakening earlier in the morning than 
desired despite adequate opportunity for sleep (Note that if the complaint is limited to 
difficulty staying asleep and/or awakening earlier in the morning, the subject is not 
eligible)

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Subjective Sleep Onset Latency (sSOL) typically ≥30 minutes on at least 3 nights per week in 
the previous 4 weeks at Screening
4.
ISI score ≥13 at Screening
5.
Regular time in bed between 6.5 and 9.0 hours at Screening
6.
At 2nd Screening Visit (Visit 2):  Confirmation (via Sleep Diary) of a regular bedtime, defined 
as the time the subject attempts to sleep, between 21:00 and 24:00 on at least 5 of the final 7 
nights and regular waketime, defined as the time the subject gets out of bed for the day, 
between 05:00 and 09:00 on at least 5 of the final 7 nights
7.
Confirmation of current insomnia symptoms, as determined from responses on the sleep diary 
on the 7 most recent mornings before the PSG during Screening Period (Visit 2), such that 
sSOL ≥30 minutes on at least 3 of the 7 nights


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8.
Confirmation of sufficient duration of time spent in bed, as determined from responses on the 
sleep diary on the 7 most recent mornings before the 2nd Screening Visit (Visit 2), such that 
there are no more than 2 nights with time spent in bed duration <7 hours or >10 hours
9.
During Run-in period, objective (PSG) evidence of insomnia as follows:

SE ≤85%; and

LPS ≥30 minutes
10. Provide written informed consent
11. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 
7 hours each night
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG].  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before the 1st 
dose of study drug
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device or intrauterine hormone-releasing system (IUS)
◦
a contraceptive implant
◦
an oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on the 
same dose of the oral contraceptive throughout the study and for 28 days after study 
drug discontinuation.)
◦
have a vasectomized partner with confirmed azoospermia

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
It is permissible that if a highly effective method of contraception is not appropriate or 
acceptable to the subject, then the subject must agree to use a medically acceptable method of 
contraception, ie, double-barrier methods of contraception such as latex or synthetic condom 
plus diaphragm or cervical/vault cap with spermicide.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral 
tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month 
before dosing).
3.
Any history of a medical or psychiatric condition that in the opinion of the investigator(s) 
could affect the subject’s safety or interfere with the study assessments
4.
A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG.  A history of 
risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT 
Syndrome) or the use of concomitant medications that prolonged the QTcF interval
5.
Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
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6.
Any lifetime suicidal behavior
7.
Evidence of clinically significant disease (eg, cardiac; respiratory including chronic obstructive 
pulmonary disease, acute and/or severe respiratory depression; gastrointestinal; moderate and 
severe hepatic impairment; renal including severe renal impairment; neurological including 
myasthenia gravis; psychiatric disease; or malignancy within the past 5 years other than 
adequately treated basal cell carcinoma) or chronic pain that in the opinion of the 
investigator(s) could affect the subject’s safety or interfere with the study assessments.  
Subjects for whom a sedating drug would be contraindicated for safety reasons because of the 
subject’s occupation or activities
8.
Hypersensitivity to lemborexant or to their excipients
9.
Scheduled for surgery during the study that requires general anesthesia or administration of 
prohibited medications
10. Known to be human immunodeficiency virus (HIV) positive
11. Active viral hepatitis (B or C) as demonstrated by positive serology
12. History of drug or alcohol dependency or abuse within approximately the last 2 years
13. A current diagnosis of sleep-related breathing disorder including obstructive sleep apnea (with 
or without continuous positive airway pressure [CPAP] treatment), periodic limb movement 
disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy, or an 
exclusionary score on screening instruments to rule out individuals with symptoms of certain 
sleep disorders other than insomnia as follows:

STOPBang score ≥5 (revised per Amendment 01)

IRLS ≥16
14. Apnea-Hypopnea Index >15 or Periodic Limb Movement with Arousal Index >15 as measured 
on the PSG at the 2nd Screening Visit
15. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
16. Reports a history of sleep-related violent behavior, or sleep driving, or any other complex 
sleep-related behavior (eg, making phone calls or preparing and eating food while sleeping)
17. For subjects who underwent diagnostic PSG within 1 year before informed consent:

Age 19 to 64 years: Apnea hypopnea Index ≥10, or Periodic Limb Movements with 
Arousal Index ≥10

Age ≥65 years: Apnea Hypopnea Index >15, or Periodic Limb Movements with Arousal 
Index >15
18. BDI-II score >19 at Screening
19. BAI score >15 at Screening
20. Habitually naps during the day more than 3 times per week
21. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
insomnia, or habitually consumes caffeine containing beverages after 18:00 and is unwilling to 
forego caffeine after 18:00 for the duration of his/her participation in the study.  Subjects are 
excluded if, in the previous 3 months, they had symptoms that would meet DSM-5 criteria for 
caffeine intoxication, which includes consumption of a high dose of caffeine (significantly in 
excess of 250 mg) and ≥5 of the following symptoms:  restlessness, nervousness, excitement, 
insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow 
of thought and speech, tachycardia or cardiac arrhythmia, periods of high energy, or 


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psychomotor agitation.  To be exclusionary, those symptoms must cause distress or impairment 
in social, occupational and other forms of functioning, and not be associated with other 
substance, mental disorder or medical condition
22. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or 
more than 21 drinks containing alcohol per week (males), or unwilling to limit alcohol intake 
to no more than 2 drinks per day or forego having alcohol within the 3 hours before bedtime 
for the duration of his/her participation in the study
23. Comorbid nocturia that is causing or exacerbating the insomnia
24. Used any prohibited prescription or over-the-counter concomitant medications within 1 week 
or 5 half-lives, whichever is longer, before the 1st dose of study medication (Run-in Period)
25. Used any modality of treatment for insomnia, including cognitive behavioral therapy or 
marijuana within 1 week or 5 half-lives, whichever is longer, before the 1st dose of study 
medication (Run-in Period)
26. Failed treatment with dual orexin receptor antagonist drugs (efficacy and/or safety) following 
treatment with an appropriate dose and of adequate duration in the opinion of the investigator
27. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or 
between Screening and Baseline, or plans to travel across different time zones during the study
28. Performed shift work in the 2 weeks before Screening, or between Screening and Baseline, or 
plans to do during the study
29. A positive drug test at Screening, Run-in, or Baseline, or unwilling to refrain from use of 
recreational drugs during the study
30. Currently enrolled in another clinical trial or used any investigational drug or device within 
30 days or 5 × the half-life, whichever is longer, preceding informed consent
31. Previously participated in any clinical trial of lemborexant
Study Treatments
Test drug:  Lemborexant
LEM5, LEM10 or lemborexant–matched PBO will be orally administered in tablet form
approximately 5 minutes before the time the subject intends to try to sleep.
Run-in Period
All subjects will receive 1 tablet of lemborexant–matched PBO for approximately 14 days in a 
single blind manner during the Run-in Period.
Treatment Period
All subjects will receive 1 tablet as described below, according to the treatment arm to which the 
subject has been randomized:
•
LEM5:  1 lemborexant 5 mg tablet for 30 days
•
LEM10:  1 lemborexant 10 mg tablet for 30 days
•
PBO:  1 lemborexant–matched PBO tablet for 30 days
Duration of Treatment
30 days
Concomitant Drug/Therapy
Caffeine will be permitted in limited quantities during the study.  Subjects will be advised to limit 
caffeine consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg caffeine per day.  


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They will be instructed to avoid caffeine after 13:00 on days when they are scheduled for a PSG 
recording and after 18:00 on all other days during the study.
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a 
maximum of 2 alcohol containing drinks on any given day while in the study and will be instructed 
not to consume any alcohol within 3 hours before bedtime.  Subjects must not consume any alcohol 
on days when they are scheduled for a PSG recording.
Prohibited medications (presented in the protocol) should not be used during the study.  A subject 
must not have used any prohibited prescription or over-the-counter medications within 1 week or 
5 half-lives, whichever is longer, before the 1st dose of study medication (Run-in Period).
Prohibited medications include moderate and strong cytochrome P450 (CYP3A) inhibitors and all 
CYP3A inducers.  Prohibited therapies also include: any treatment for insomnia disorder, including 
any drugs or nonpharmacological treatment such as cognitive behavioral therapy; medications that 
are used for the purpose of inducing sleep (hypnotics) or inducing wakefulness (stimulants; except 
caffeine; see above) and medications that have known sedating effects or alerting effects.  The 
prohibition applies even if the entire class to which that medication belongs is not prohibited (eg, 
anticonvulsants).
If a medication is not on the list of prohibited medications but in the opinion of the investigator 
causes or exacerbates the subject’s insomnia, it must not be used throughout the study.  If a 
medication is not specified as prohibited but is in the same class as a medication that is listed in the 
protocol, and if the investigator is uncertain whether the medication has known sedating or alerting 
effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue 
from the study, with the exception that certain prohibited medications may be used for a short 
duration (not to exceed 2 weeks) to treat an acute condition if this is agreed with the Medical 
Monitor.  Note that moderate and strong CYP3A inhibitors and all CYP3A inducers will not be 
permitted at any time for any duration during the study.
Assessments
Screening Assessments
ISI
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia. 
The dimensions evaluated are severity of: sleep onset, sleep maintenance, early-morning 
awakening problems; sleep dissatisfaction; interference of sleep difficulties with daytime 
functioning, noticeability of the sleep problems by others; and distress caused by the sleep 
difficulties. A 5-point Likert scale is used to rate each item (from 0 =no problem to 4=very severe 
problem), yielding a total score from 0 to 28.
BDI-II
The BDI-II is a 21-question multiple-choice self-report questionnaire that subjects will use to rate 
the presence, frequency, and severity of symptoms of depression using a 4-point Likert scale. 
Scores on the BDI-II range from 0 to 63, with higher scores indicating higher levels of depressive 
symptoms.
BAI
The BAI is a 21-question multiple-choice self-report inventory that subjects will use to rate the 
presence, frequency, and severity of symptoms of anxiety using a 4-point Likert scale. Scores on 
the BAI range from 0 to 63, with higher scores indicating higher levels of anxiety symptoms.
SDSB
The SDSB will include the:








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Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical examination), out-of-normal-range laboratory safety 
test variables, abnormal ECG findings, out-of-range vital signs, along with change from baseline in 
laboratory safety test variables, ECGs, and vital sign measurements, will be summarized by 
treatment group using descriptive statistics.
Interim Analyses
No interim analysis is planned for this study.
Sample Size Rationale (revised per Amendment 01)
Sample size was calculated with re-sampling simulation using Study E2006-G000-201 data in 
order to power the study to detect point estimate of mean difference below a certain threshold with 
sufficient probability. The certain threshold is defined as –0.44 as derived from the upper limit of 
95% CI of pairwise difference between LEM5 and PBO for log(LPS) from Study 201.  Using the 
mean difference to PBO of log(LPS) in LEM5 from the baseline to Days 14/15 from each 
simulation (10,000 times) that using a grid search and assuming a 2:1 ratio (LEM5:PBO), 
demonstrated the difference < –0.44 could be achieved with more than 85% power. It is assumed 
that the mean difference to PBO of log(LPS) in lemborexant groups from baseline to Day 30 in this 
study will be similar with those from baseline to Days 14/15 in Study 201. When the number of 
subjects randomized to LEM5 and PBO are 24 and 12, respectively, the number of subjects who 
complete with evaluable efficacy data will be 22 and 11, respectively.  Based on this evaluation, 
this study will provide power at 88.64% for comparing LEM5 and PBO. Since LEM10 is set as a 
reference arm, therefore the sample size for LEM10 will be 24 as the same of LEM5 above. 


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................14
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................19
5
ETHICS.......................................................................................................................22
5.1
Institutional Review Boards/Independent Ethics Committees.............................22
5.2
Ethical Conduct of the Study..............................................................................22
5.3
Subject Information and Informed Consent ........................................................23
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................23
7
INTRODUCTION.......................................................................................................24
7.1
Compound overview..........................................................................................25
7.2
Clinical Experience............................................................................................25
7.2.1
Phase 1.....................................................................................................25
7.2.2
Phase 2.....................................................................................................26
7.2.3
Phase 3.....................................................................................................27
7.3
Study Rationale..................................................................................................28
8
STUDY OBJECTIVES................................................................................................28
8.1
Primary Objective ..............................................................................................28
8.2
Secondary Objectives.........................................................................................28
8.3
Exploratory Objectives.......................................................................................28
9
INVESTIGATIONAL PLAN ......................................................................................29
9.1
Overall Study Design and Plan...........................................................................29
9.1.1
Prerandomization Phase ...........................................................................30
9.1.1.1
Screening Period...............................................................................30
9.1.1.2
Run-In Period ...................................................................................31
9.1.1.3
Baseline Period.................................................................................32
9.1.2
Randomization Phase ...............................................................................32
9.1.2.1
Treatment Period ..............................................................................32
9.1.2.2
Follow-Up Period and End of Study (EOS) Visit ..............................33
9.1.2.3
Additional study information ............................................................33
9.1.2.4
Premature Discontinuation of Study Drug.........................................33
9.2
Discussion of Study Design, Including Choice of Control Groups......................33
9.2.1
Randomization .........................................................................................33
9.2.2
Run-In......................................................................................................33
9.2.3
Pharmacodynamic Parameters..................................................................34
9.2.4
Study Duration .........................................................................................34


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9.3
Selection of Study Population ............................................................................34
9.3.1
Inclusion Criteria......................................................................................34
9.3.2
Exclusion Criteria.....................................................................................35
9.3.3
Removal of Subjects From Therapy or Assessment ..................................38
9.4
Treatments.........................................................................................................38
9.4.1
Treatments Administered..........................................................................38
9.4.2
Identity of Investigational Products ..........................................................39
9.4.2.1
Chemical Name, Structural Formula of E2006/Lemborexant ............39
9.4.2.2
Comparator Drug..............................................................................39
9.4.2.3
Labeling for Study Drug ...................................................................39
9.4.2.4
Storage Conditions ...........................................................................40
9.4.3
Method of Assigning Subjects to Treatment Groups.................................40
9.4.4
Selection of Doses in the Study ................................................................40
9.4.5
Selection and Timing of Dose for Each Subject........................................40
9.4.6
Blinding ...................................................................................................40
9.4.7
Prior and Concomitant Therapy................................................................41
9.4.7.1
Drug-Drug Interactions.....................................................................41
9.4.7.2
Prohibited Concomitant Therapies and Drugs ...................................41
9.4.7.3
Caffeine and Alcohol Restrictions.....................................................42
9.4.8
Treatment Compliance .............................................................................42
9.4.9
Drug Supplies and Accountability ............................................................43
9.5
Study Assessments.............................................................................................43
9.5.1
Assessments .............................................................................................43
9.5.1.1
Screening Assessments.....................................................................43
9.5.1.1.1
Demography ...............................................................................43
9.5.1.1.2
Medical history, Psychiatric history, and Physical examinations .44
9.5.1.1.3
Sleep disorders history and Screening battery..............................44
9.5.1.1.4
Pregnancy Tests for Women of Child Bearing Potential..............45
9.5.1.1.5
Viral Testing...............................................................................45
9.5.1.2
Efficacy Assessments .......................................................................46
9.5.1.2.1
Polysomnography .......................................................................46
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................46
9.5.1.3.1
Pharmacokinetic Assessments.....................................................46
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments................................................................................47
9.5.1.4
Safety Assessments...........................................................................47
9.5.1.4.1
Adverse Events...........................................................................47


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9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................49
9.5.1.4.3
Laboratory Measurements...........................................................50
9.5.1.4.4
Vital Signs and Weight Measurements........................................52
9.5.1.4.5
Physical Examinations ................................................................52
9.5.1.4.6
Electrocardiograms .....................................................................52
9.5.1.4.7
Other Safety Assessments ...........................................................52
9.5.1.5
Other Assessments............................................................................53
9.5.2
Schedule of Procedures/Assessments........................................................53
9.5.2.1
Schedule of Procedures/Assessments................................................53
9.5.2.2
Description of Procedures/Assessments Schedule .............................57
9.5.3
Appropriateness of Measurements............................................................57
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................57
9.5.4.1
Reporting of Serious Adverse Events................................................57
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................58
9.5.4.3
Reporting of Events Associated with Special Situations....................58
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................58
9.5.4.3.2
Reporting of Abnormal hepatic Tests of Clinical Interest ............59
9.5.4.3.3
Reporting of Study-Specific Events.............................................59
9.5.4.4
Expedited Reporting .........................................................................59
9.5.4.5
Breaking the Blind............................................................................60
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................60
9.5.5
Completion/Discontinuation of Subjects...................................................60
9.5.6
Abuse or Diversion of Study Drug............................................................61
9.5.7
Confirmation of Medical Care by Another Physician................................61
9.6
Data Quality Assurance......................................................................................61
9.6.1
Data Collection.........................................................................................61
9.6.2
Clinical Data Management .......................................................................61
9.7
Statistical Methods.............................................................................................62
9.7.1
Statistical and Analytical Plans.................................................................62
9.7.1.1
Study Endpoints................................................................................62
9.7.1.1.1
Primary Endpoint........................................................................62
9.7.1.1.2
Secondary Endpoints...................................................................62
9.7.1.1.3
Exploratory Endpoints ................................................................62
9.7.1.2
Definitions of Analysis Sets..............................................................63


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9.7.1.3
Subject Disposition...........................................................................63
9.7.1.4
Demographic and Other Baseline Characteristics..............................64
9.7.1.5
Prior and Concomitant Therapy ........................................................64
9.7.1.6
Efficacy Analyses.............................................................................64
9.7.1.6.1
Primary Efficacy Analysis...........................................................64
9.7.1.6.2
Secondary Efficacy Analyses......................................................65
9.7.1.6.3
Exploratory Efficacy Analyses....................................................65
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................65
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................65
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .....................................................................................65
9.7.1.8
Safety Analyses ................................................................................65
9.7.1.8.1
Extent of Exposure......................................................................65
9.7.1.8.2
Adverse Events...........................................................................66
9.7.1.8.3
Laboratory Values.......................................................................67
9.7.1.8.4
Vital Signs and Weight ...............................................................67
9.7.1.8.5
Electrocardiograms .....................................................................67
9.7.1.8.6
Other Safety Analyses.................................................................68
9.7.2
Determination of Sample Size ..................................................................68
9.7.3
Interim Analysis.......................................................................................68
9.7.4
Other Statistical/Analytical Issues ............................................................68
10
REFERENCE LIST.....................................................................................................69
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......70
11.1
Changes to the Protocol......................................................................................70
11.2
Adherence to the Protocol..................................................................................70
11.3
Monitoring Procedures.......................................................................................70
11.4
Recording of Data..............................................................................................71
11.5
Identification of Source Data..............................................................................71
11.6
Retention of Records..........................................................................................71
11.7
Auditing Procedures and Inspection ...................................................................72
11.8
Handling of Study Drug .....................................................................................72
11.9
Publication of Results ........................................................................................72
11.10 Disclosure and Confidentiality ...........................................................................73
11.11 Discontinuation of Study....................................................................................73
11.12 Subject Insurance and Indemnity........................................................................73
12
APPENDICES.............................................................................................................74


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LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests........................................................................50
Table 2
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments ...........................................................................................50
Table 3
Schedule of Procedures/Assessments in Study E2006-J082-204: ............54
LIST OF IN-TEXT FIGURES
Figure 1 Schematic Diagram of E2006-J082-204 Study Design.....................................30
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................75
Appendix 2
Inclusion/Exclusion Criteria Schedule ....................................................77
Appendix 3
List of Prohibited Concomitant Medications...........................................78


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve extrapolated from zero 
time to infinite time
BAI
Beck Anxiety Inventory
BDI-II
Beck Depression Inventory–II
BMI
body mass index
BP
blood pressure
CI
confidence interval
CPAP
continuous positive airway pressure
Cmax
maximum observed concentration
CPMP
Committee for Proprietary Medicinal Products
CRA
clinical research associate
CRO
Contract Research Organization
CTA
Clinical Trial Authorisation
CYP3A
cytochrome P450
DORA
dual orexin receptor antagonist
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalography
EMG
electromyography
EOS
end of study
ET
early termination
FAS
Full Analysis Set
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation


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Abbreviation
Term
IEC
Institutional Ethics Committee
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
ISI
Insomnia Severity Index
IxRS
an interactive voice and web response system 
K-GCP
Korean good clinical practice
KSS
Karolinska Sleepiness Scale
LEM5
lemborexant, 5-mg dose
LEM10
lemborexant, 10-mg dose
LNH
low-normal-high
LPS
latency to persistent sleep
LS
least square
MedDRA
Medical Dictionary for Regulatory Activities
MFDS
Ministry of Food and Drug Safety
MHB
median habitual bedtime
NDA
New Drug Application
PBO
placebo
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PLMD
periodic limb movement disorder
PP
Per Protocol
PSG
polysomnography
PT
preferred term
QTcF
QT interval corrected for heart rate by Fridericia’s formula
REM
rapid eye movement (sleep stage)
SAE
serious adverse event
SAP
statistical analysis plan
SDSB
Sleep Disorders Screening Battery
SE
objective sleep efficiency
SOC
system organ class
SOP
standard operating procedure


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Abbreviation
Term
sSE
subjective sleep efficiency
sSOL
subjective sleep onset latency
sTST
subjective total sleep time
sWASO
subjective wake after sleep onset
TEAE
treatment-emergent adverse event
TIB
time in bed
TST
total sleep time
WASO
objective wake after sleep onset


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations.  Any protocol amendment or revision to the 
ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in CRA[s], 
change of telephone number[s]).  Documentation of IRB/IEC compliance with the ICH E6 
and any local regulations regarding constitution and review conduct will be provided to the 
sponsor.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor and the head of the medical 
institution. The head of the medical institution will inform the early termination/temporary 
halt of the study by the IRB/IEC to the Ministry of Food and Drug Safety (MFDS) 
immediately and submit a detailed written explanation of the reasons for the decision.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and MFDS within the 
required timeline.  The end of the study will be the date of the last study visit for the last 
subject in the study.  
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC within the required timeline, and a detailed written explanation of the reasons for 
the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki


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
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator or designee must 
explain to each subject, the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 1st
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 9 investigational sites in South Korea. (revised per Amendment 
01)


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The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO(s)) are listed in the 
Investigator Study file or Regulatory Binder provided to each site.
7
INTRODUCTION
Insomnia is a common sleep disorder that relies on a patient-reported complaint of difficulty 
falling asleep and/or difficulty maintaining sleep, ie, frequent awakenings, difficulty 
returning to sleep after awakenings, or awakening too early with inability to return to sleep 
(Buysse, 2013). Insomnia is a serious disorder that has deleterious health consequences and 
impacts a patient’s quality of life (DiBonaventura et al, 2015).  Untreated insomnia is 
associated with an increased risk of medical and psychiatric comorbidities, as well as 
occupational risks, and is associated with significantly increased healthcare services 
utilization. The annual prevalence of insomnia symptoms in the general adult population in 
the US is estimated to be from 35% to 50% (Walsh, et al., 2011), and the prevalence of 
insomnia from 12% to 20% (Morin, et al., 2011; Roth, et al., 2011).  In an epidemiology 
study of insomnia in Korean adult population, 22.8% of subjects complained of insomnia 
(Cho, et al., 2009). 
Currently available pharmacological treatments used clinically for insomnia in Korea include 
sedative hypnotics (benzodiazepines, non-benzodiazepines GABAergics agents), sedating 
antidepressants, melatonin, and antihistamines. The analysis report of treatment pattern of 
insomnia using Health Insurance Review & Assessment Service data reported that in Korea, 
zolpidem, a non-benzodiazepine, is the most frequently prescribed drug for insomnia as in 
the US and Japan, and the number of prescriptions of drugs for insomnia continues to 
increase. However, there are significant limitations with current treatment options. There 
remains an unmet medical need for a pharmacological treatment with proven efficacy on 
both sleep onset and sleep maintenance, and with good tolerability and safety, especially in 
the elderly. Patients need to be able to conduct daily activities without residual sleepiness or 
cognitive impairment, such as driving and work. Among other serious concerns with 
available treatments for insomnia are drug-drug and drug-alcohol interactions, abuse liability, 
and tolerance/habituation effects. Other important safety risks withdrawal symptoms, 
rebound insomnia, aberrant nocturnal behavior, respiratory depression, and excessive 
daytime sleepiness.
Orexins have been shown to regulate transitions between wakefulness and sleep by 
promoting cholinergic/monoaminergic neural pathways, through interaction with two G 
protein-coupled receptors (OX1R and OX2R).  It is suggested that OX1R plays an important 
role in suppressing the instigation of non-REM sleep, while OX2R has a major role in 
promoting wakefulness.  The activation of the orexinergic system promotes wakefulness, and 
its disruption brings about sleep disturbances.  Thus, it was thought that antagonising the 
orexin system during the night might reduce excessive wakefulness, and improve sleep 
continuity (Equihua, et al., 2013).  This has now been demonstrated with several members of 
the dual orexin receptor antagonist (DORA) class, such as the approval of suvorexant and 
lemborexant in several countries including the US and Japan.  


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7.1
Compound overview  
Lemborexant, E2006, (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3 
fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide belongs to the 
pharmacologic class of orexin receptor antagonists. Lemborexant is competitive dual 
antagonist of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, with higher affinity for 
OX2R.
Lemborexant was approved in the US on 20 December 2019 for the treatment of insomnia in 
adult patients, characterized by difficulties with sleep onset and/or sleep maintenance and in 
Japan on 23 January 2020 for the treatment of insomnia in adult patients.  In addition, 
lemborexant was approved in some other countries for the treatment of insomnia in adult 
patients.
7.2
Clinical Experience
7.2.1
Phase 1
E2006-A001-001 (Study 001):  single ascending dose study.  This study included healthy 
subjects and otherwise healthy subjects with primary insomnia.  In addition to determining 
the safety and tolerability of single doses, the study provided preliminary evidence of 
efficacy in the target patient population.
E2006-A001-002 (Study 002):  multiple ascending dose study.  This study enrolled healthy 
adult and elderly subjects, each of whom was dosed with lemborexant or placebo (PBO) at 
night.  In addition to determining the safety and tolerability of multiple doses, the study also 
provided preliminary evidence of a lack of important differences in exposure between adult 
and elderly subjects.
E2006-A001-003 (Study 003):  A multiple dose study to bridge pharmacokinetics (PK), 
pharmacodynamics (PD), safety and tolerability between Japanese and white healthy 
subjects.  This study provided evidence of a lack of important differences in exposure and 
safety between Japanese and white subjects.
E2006-A001-004 (Study 004):  metabolism-based inducer/inhibitor study.  This study 
provided data demonstrating (1) strong inhibitors of cytochrome P450 (CYP3A) lead to 
higher plasma concentrations of lemborexant; and (2) strong inducers of CYP3A lead to 
notably lower plasma concentrations of lemborexant. The study also demonstrated a weak 
effect of lemborexant on CYP2B6 activity and no effect on CYP3A activity.
E2006-A001-008 (Study 008):  food effect study.  This study demonstrated a mild food 
effect.  The Cmax was decreased by 23% and the area under the concentration-time curve 
from zero time extrapolated to infinite time (AUC0-inf) was increased by 18% following 
consumption of a high fat meal.
E2006-A001-012 (Study 012): drug-drug interaction study. These study results
demonstrated that: (1) coadministration of a moderate CYP3A inhibitor (fluconazole)


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showed a moderate interaction as demonstrated by a 1.63-fold increase in Cmax and 4.2-fold
increase in AUC of lemborexant; (2) coadministration of lemborexant had no statistically
significant effect on the PK of oral contraceptives (ethinyl estradiol and norethindrone), and
these oral contraceptives did not alter the PK of lemborexant; and (3) concomitant
administration of a gastric acid suppressant agent had a weak interaction with lemborexant as
shown by a 27% decrease in Cmax and no impact on AUC of lemborexant.
E2006-E044-106 (Study 106):  Study 106 evaluated next-morning effects of lemborexant 
compared with PBO, with zopiclone included as a positive control, by measuring adult and 
elderly participants driving performance via an on-road driving test. The primary endpoint 
was to evaluate difference from PBO of standard deviation of lateral position (SDLP) during 
an on-road driving test on the mornings following the first and last dose of drug in each 
treatment period. Lemborexant 2.5, LEM5 and LEM10 showed no statistically significant 
impairment of driving performance, as measured by mean changes in SDLP, after either 
single (Day 2) or multiple (Day 9) dose administration compared to PBO, meeting the 
study’s primary endpoint. In contrast, zopiclone 7.5 mg significantly increased mean SDLP 
as compared to PBO. 
E2006-A001-108 (Study 108): Study 108 evaluated the effect of lemborexant on postural 
stability, auditory awakening threshold and cognitive performance in healthy volunteers age 
55 years and older. Participants were administered a single dose of PBO, LEM5, LEM10, or 
zolpidem ER 6.25 mg, and had eight-hour polysomnograms at baseline and at each 
single-dose treatment.  Body sway was assessed upon awakening participants after 
approximately four hours in bed. Study demonstrated that mean change from baseline in 
postural stability during middle of the night awakening is significantly and clinically 
meaningfully less after LEM5 and LEM10 than after zolpidem ER. The next morning, 
shortly after the end of eight hours in bed, unlike zolpidem ER, neither dose of lemborexant 
had statistically significant residual effects on this measure of postural stability as compared 
to PBO.  This study also evaluated the effects of LEM5 and LEM10 on the auditory 
awakening threshold (AAT) at approximately four hours post-dose, compared to zolpidem 
ER and PBO. Neither dose of lemborexant had a statistically significant difference relative 
to PBO or zolpidem ER on the ability to awaken to an external stimulus.  There were no 
differences between PBO and LEM5 on measures of attention and memory, and subjects 
taking 10 mg performed less well than PBO in the middle of the night.  No significant 
difference was found in Power of Attention and Quality of Memory between lemborexant 
treatments and PBO in the morning.
7.2.2
Phase 2
A dose-finding study (E2006-G000-201; Study 201) was conducted in subjects who had 
insomnia disorder, with the primary objectives of identifying doses that resulted in efficacy 
but did not result in significant next-day residual sleepiness.  The doses evaluated were 1, 
2.5, 5, 10, 15, and 25 mg, administered once daily for 15 days.  The study was stopped early 
for efficacy after the prespecified success criterion for sleep efficiency (SE) was achieved 
without unacceptable next-day residual sleepiness as evaluated by the Karolinska Sleepiness 
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As measured by PSG, improvements in sleep were also demonstrated by statistically 
significant increases from baseline in SE, and by decreases from baseline in mean latency to 
persistet sleep (LPS) and wake after sleep onset (WASO).  These changes were largely 
maintained over 15 days of treatment with lemborexant as compared with PBO.  Subjective 
measures derived from sleep diary entries yielded results largely comparable to PSG-derived 
results.  Further, there was no evidence of rebound insomnia after treatment was completed, 
as measured either by PSG or sleep diary.
At doses up to 10 mg, changes from baseline in next-day sleepiness, as measured by the 
KSS, did not differ from those after PBO.  At the highest doses of 15 and 25 mg, the increase 
in KSS from baseline was statistically significantly different from PBO at some time points, 
but the increases in KSS were of small magnitude (ie, less than 1 unit on average).  Although 
there was approximately a two-fold accumulation of lemborexant in plasma over the 15 day 
Treatment Period, next-day sleepiness did not increase from the beginning to the end of 
treatment.
7.2.3
Phase 3
E2006-G000-304 (Study 304):  Study 304 was a multicenter, randomized, double-blind, 
PBO-controlled, active comparator, parallel-group study of the efficacy and safety of 
lemborexant in patients 55 years and older with insomnia disorder, conducted in North 
America and Europe. Subjects were administered PBO or one of three treatment regimens 
(LEM5, LEM10, zolpidem ER 6.25 mg).  The primary endpoint was change from baseline in 
LPS of both lemborexant doses compared to PBO, measured objectively by PSG.  The key 
secondary endpoints included change from baseline in SE, and WASO for both lemborexant 
doses compared to PBO as well as WASO in the second half of the night (WASO2H) for 
both lemborexant doses compared to zolpidem ER, after 1 month of treatment, measured 
objectively by PSG.  Study 304 achieved its primary and all of the key secondary objectives 
versus PBO and versus zolpidem ER. For additional efficacy endpoints as assessed by 
subjective sleep diary, both doses of lemborexant were statistically superior to PBO on 
subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE), subjective wake 
after sleep onset (sWASO), and subjective total sleep time (sTST), over the first 7 nights and 
the last 7 nights of treatment.
E2006-G000-303 (Study 303):  Study 303 was a 12-month multicenter, randomized, 
double-blind, PBO -controlled, parallel-group study of 2 dose levels of lemborexant in 
patients with insomnia disorder, conducted in North America, South America, Europe, Asia, 
and Oceania. During the first 6 months (Period 1), subjects were randomized to PBO, 
LEM5, or LEM10.  During the second 6 months (Period 2), LEM subjects continued their 
assigned dose, but PBO subjects were rerandomized to LEM5 or LEM10.  The primary 
endpoint was mean change from baseline in sSOL of both lemborexant doses compared to 
PBO, after 6 month of treatment, measured subjectively by sleep diary.  The key secondary 
endpoints included mean change from baseline in sSE and sWASO for both lemborexant 
doses compared to PBO, after 6 month of treatment, measured subjectively by sleep diary.  In 
Study 303, both doses of lemborexant demonstrated statistically significantly larger changes 
(positive outcome) from Study Baseline compared to PBO for both sleep onset and sleep 


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maintenance variables after 6 months of treatment. The efficacy of LEM at 6 months of
treatment persisted at 12 months.  LEM was well tolerated over 12 months.
The clinical development program established the safety, tolerability, and efficacy (both 
short- and long-term) of lemborexant versus PBO in adult and older adult subjects.  In 
addition, there was no evidence for tolerance or dependence or for rebound insomnia.
7.3
Study Rationale
According to the Guideline for bridging data issued by National Institute of Food and Drug 
Safety Evaluation (Dec, 2015) and the relevant regulation in Korea, for the new drug 
application of lemborexant in South Korea, a bridging study is required to show the 
comparability of pharmacodynamic profile of lemborexant between Korean and non-Korean 
subjects to be able to extrapolate overseas clinical data of lemborexant to Korean population. 
Therefore, this study is designed to be combine components of dose-response study E2006-
G000-201 (Study 201) with respect to ages of the patient population as well as Study 304 
with respect to duration of study and doses of lemborexant.  These components are based on 
the recommendations of MFDS.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate, using polysomnography (PSG), the 
treatment difference between lemborexant 5 mg (LEM5) and placebo (PBO) on latency to 
persistent sleep (LPS) on Day 30.  (revised per Amendment 01)
8.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate, using PSG, the treatment difference between lemborexant 10 mg (LEM10)
and PBO on LPS on Day 30 (revised per Amendment 01)

To evaluate, using PSG, the treatment difference between LEM5 and PBO on sleep 
efficiency (SE) on Day 30 (revised per Amendment 01)

To evaluate, using PSG, the treatment difference between LEM10 and PBO on SE on 
Day 30 (revised per Amendment 01)

To evaluate safety and tolerability of lemborexant following multiple doses (revised per 
Amendment 01)

To evaluate the pharmacokinetics of lemborexant
8.3
Exploratory Objectives
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, 
parallel-group study in Korean subjects with insomnia disorder.  Subjects will be randomized 
to LEM5, LEM10 or PBO in a ratio of 2:2:1 and will receive study drug for 30 days.(revised 
per Amendment 01)
The study will consist of 2 phases:  Prerandomization Phase and Randomization Phase.
The Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 
days:  a Screening Period, a Run-in Period, and a Baseline Period.  The Randomization Phase 
will comprise a Treatment Period during which subjects will be treated for 30 nights, and a 
minimum 28-day Follow-up Period before an End of Study (EOS) Visit.
The estimated study duration for each subject on study is anticipated to be a maximum of 93
days consisting of the Screening Period plus Run-in Period plus Baseline Period maximum of 
35 days plus Treatment Period plus Follow-up Period and EOS Visit maximum of 58 days.  
A subject who completes the Treatment Period (assessments through discharge from the 
clinic on Day 31) will be considered to have completed the study.
An overview of the study design is presented in Figure 1.
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All eligible subjects will be provided with a paper sleep diary and site staff will instruct 
subjects to complete the diary each morning within 1 hour after morning wake time and will 
emphasize the importance of doing so.  Subjects will also be reminded of study restrictions 
pertaining to timing of meals and caffeine/alcohol use.
After subjects have completed the sleep diary on at least 7 consecutive mornings, subjects 
will undergo the 2nd Screening Visit (Visit 2).  This visit must occur between Day –17 and 
Day –10.  On this night on which PSG is recorded, subjects will arrive at the clinic in the 
evening with sufficient time before bedtime to complete sleep diary review for continued 
eligibility with regard to sleep timing, duration of time spent in bed, and frequency of nights 
with symptoms of insomnia, check-in procedures, any scheduled assessments, and 
preparations (eg, electrode montage placement) for the PSG recordings. Subjects who 
continue to meet the eligibility criteria will then prepare check-in for PSG recording. After 
check-in has been completed, subjects will then undergo an 8-hour PSG recording, to start at 
the median habitual bedtime (MHB) as calculated from the sleep diary entries.  The PSG
recording will include channels in the electrode montage to screen for symptoms of sleep 
apnea and periodic limb movement disorder (PLMD).  Subjects who continue to meet the 
eligibility criteria will then be dispensed PBO tablets (single-blind) and will enter the Run-in 
Period.  In addition, at check-in before all visits at which PSG is to be recorded, subjects will 
undergo a urine drug test and urine pregnancy test (females of childbearing potential only),
and questioning regarding AEs.
9.1.1.2
Run-In Period
The Run-in Period will begin when eligible subjects are dispensed PBO tablets and will 
continue until the Baseline Period on Day 1.  During the Run-in Period, all subjects will take 
PBO each night approximately 5 minutes before bedtime (defined as the time the subject 
intends to try to fall asleep).  They will be reminded that they must remain in bed for at least 
7 hours each night and maintain a regular bedtime and waketime throughout the study, 
according to the schedule determined by the study site and the subject.  They will also be 
reminded that they must follow study restrictions with regard to timing of meals, and use of 
caffeine and alcohol.
Subjects will return to the clinic between Day –10 and Day –5.  Subjects who are still eligible 
will have PSG recording.  In the evening, before the PSG recording, the safety assessments 
including questioning AEs and vital signs assessment will be conducted and urine drug test 
and urine pregnancy test (females of childbearing potential only) will be performed.  Study 
personnel will administer study drug to subjects approximately 5 minutes before their 
scheduled bedtime, which will be at the same MHB as used for the 2nd Screening Visit.  
Subjects will undergo an 8-hour PSG.  The PSG recording will be reviewed for continued 
eligibility, and it will also provide the baseline values for PSG-derived endpoints for subjects 
who are randomized.  Subjects may then leave the clinic after the investigator determines that 
it is safe for them to do so. Subjects will continue to take study drug at home approximately 
5 minutes before bedtime.  They will again be reminded that they must remain in bed for at 
least 7 hours each night, maintain a regular bedtime throughout the study, and follow study 
restrictions with regard to timing of meals and use of caffeine and alcohol.


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9.1.1.3
Baseline Period
On Day 1, the Run-in Period will end and the Baseline Period will begin.  Subjects will 
return to the clinic for this visit. Subjects will be questioned about study drug compliance. 
Safety assessments including questioning regarding AEs, 12-lead ECG, vital signs, weight, 
clinical hematology and chemistry analysis, urinalysis will be conducted.  In addition, 
subjects should undergo a urine drug test and urine pregnancy test (females of childbearing 
potential only).
9.1.2
Randomization Phase
The Randomization Phase will comprise a Treatment Period during which subjects will be 
treated for 30 nights, and a minimum 28-day Follow-up Period before an End of Study (EOS) 
Visit.
9.1.2.1
Treatment Period
Subjects who complete the Baseline Period and continue to meet the eligibility criteria will 
be randomized, and will begin the Treatment Period.
The Treatment Period will begin on Day 1 immediately after the Baseline Period and study 
drug will be administered for the next 30 nights.  Subjects will be randomized in a 
double-blind manner, to receive study drugs, LEM5, LEM10 or PBO.
Study drug will be dispensed to subjects.  Subjects will be instructed to take lemborexant or 
PBO at home in the evening immediately (ie, within 5 minutes) before bedtime on  
approximately the same schedule as during the Run-in period.
On Day 14, site staff will call subjects to check AEs, concomitant therapy, and drug 
compliance. In addition, subjects will be reminded to take study drug each night 
approximately 5 minutes before bedtime and to remain in bed for at least 7 hours each night 
and maintain a regular bedtime and waketime throughout the study, according to the schedule 
determined by the study site and the subject. They will also be reminded that they must 
follow study restrictions with regard to timing of meals, and use of caffeine and alcohol. If 
any AE is clinically significant and requires follow-up, an unscheduled visit may be arranged 
per investigator’s decision.
On Day 30, subjects will return to the clinic. Subjects will be questioned about study drug 
compliance and AEs. A urine drug test and urine pregnancy test (females of childbearing 
potential only) will be performed.  A PK blood sample will be collected predose and study 
drug will be administered approximately 5 minutes before the subject’s MHB. A PSG will be 
conducted at the same time and with the same electrode montage as the PSG during the 
Run-In Period.  On the morning of Day 31, PK samples will be obtained.  Safety assessments 
including questioning regarding AEs, physical examination, 12-lead ECG, vital signs, 
clinical hematology, chemistry analysis and urinalysis will be conducted.  After the 
investigator determines that it is safe for them to do so, subjects will be discharged from the 
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9.1.2.2
Follow-Up Period and End of Study (EOS) Visit
The Follow-up Period will begin when the subjects leave the clinic at the end of the 
Treatment Period.  Subjects will cease to take study drug.
Approximately 28 days after completion of the Treatment Period subjects will return to the 
clinic for the EOS Visit.  At the EOS Visit, in addition to safety assessments including 
questioning regarding AEs, physical examination, 12-lead ECG, vital signs, clinical 
hematology, chemistry analysis and urinalysis, a urine drug test and urine pregnancy test 
(females of childbearing potential only) will be conducted.  After the End of Study Visit, 
subjects’ participation in the study will be finished.
9.1.2.3
Additional study information
The estimated study duration for each subject on study is anticipated to be a maximum of 93 
days consisting of the Screening Period plus Run-in Period plus Baseline Period maximum of 
35 days plus Treatment Period plus Follow-up Period and EOS Visit maximum of 58 days.  
A subject who completes the Treatment Period (assessments through discharge from the 
clinic on Day 31) will be considered to have completed the study.
9.1.2.4
Premature Discontinuation of Study Drug
A subject who prematurely discontinues taking study drug should return to the clinic as soon 
as practicable after discontinuing study drug (preferably within 7 days), to complete the Early 
Termination (ET) Visit.  If the subject discontinues from the study due to an AE, the subject 
must complete an ET Visit and all AEs, regardless of relationship to study drug or procedure, 
should be collected at beginning from the time the subject signs the study ICF through the 
last visit.  In addition, subjects who withdraw due to an AE should undergo a urine drug test
and urine pregnancy test (females of childbearing potential only).
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Randomization
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
9.2.2
Run-In
Insomnia trials are associated with PBO effects.  This study will include a PBO Run-in 
Period to exclude subjects who show a response to PBO that would render them unable to 
meet inclusion criteria.


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The Run-in Period will also help to identify and exclude subjects who are not compliant with 
the duration of time spent in bed, or restrictions on alcohol and caffeine use.  In this regard, it 
is necessary for the subjects to be taking PBO. After this minimum 7 nights of treatment, 
eligible subjects will have PSG recording at Visit 3.  These recordings will be used to further 
screen for eligibility, and will serve as baseline values for those subjects who continue to 
randomization.
9.2.3
Pharmacodynamic Parameters
Sleep parameters measured by PSG are selected as the Pharmacodynamic (PD) parameters. 
PSG involves simultaneous recording of several electrophysiological parameters (such as 
electroencephalogram) to provide objective measures of physiologic changes that are 
characteristic of the different sleep stages as well as improvement in measurements of sleep 
onset and sleep maintenance. Therefore, sleep parameters measured by PSG are both PD 
endpoints and efficacy endpoints.
9.2.4
Study Duration
In Study 201, treatment benefit of LEM5 was demonstrated at the end of treatment on Days 
14/15, however, based on the regulatory advice, 2 weeks of treatment duration are not 
sufficient.  (revised per Amendment 01)  As the result from Study 304 showed that
lemborexant effects measured by PSG observed at the start of treatment were maintained at 1 
month, thus the study duration is based on Study 304.
9.3
Selection of Study Population
Approximately 60 subjects in South Korea will be randomized to treatment (LEM5 [24 
subjects], LEM10 [24 subjects], and PBO [12 subjects]). (revised per Amendment 01)  The 
eligibility criteria are based on Study 201. Subjects who do not meet all of the inclusion 
criteria or who meet any of the exclusion criteria will not be eligible to receive study drug. A 
table providing guidelines on the order in which criteria should be assessed and at what visits 
can be found in Appendix 2.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Korean male or female, age 19 to 80 years, at the time of informed consent
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 
criteria for Insomnia Disorder, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty getting to 
sleep with or without difficulty staying asleep and/or awakening earlier in the 
morning than desired despite adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months


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
Associated with complaint of daytime impairment
3. Subjective Sleep Onset Latency (sSOL) typically ≥30 minutes on at least 3 nights per 
week in the previous 4 weeks at Screening
4. ISI score ≥13 at Screening
5. Regular time in bed between 6.5 and 9.0 hours at Screening 
6. At 2nd Screening Visit (Visit 2):  Confirmation (via Sleep Diary) of a regular bedtime, 
defined as the time the subject attempts to sleep, between 21:00 and 24:00 on at least 5 of 
the final 7 nights and regular waketime, defined as the time the subject gets out of bed for 
the day, between 05:00 and 09:00 on at least 5 of the final 7 nights.
7. Confirmation of current insomnia symptoms, as determined from responses on the sleep 
diary on the 7 most recent mornings before the PSG during Screening Period (Visit 2), 
such that sSOL ≥30 minutes on at least 3 of the 7 nights 
8. Confirmation of sufficient duration of time spent in bed, as determined from responses on 
the sleep diary on the 7 most recent mornings before the 2nd Screening Visit (Visit 2), 
such that there are no more than 2 nights with time spent in bed duration <7 hours or >10 
hours
9. During Run-in period, objective (PSG) evidence of insomnia as follows:

SE ≤85%; and

LPS ≥30 minutes 
10. Provide written informed consent
11. Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG].  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before 
the 1st dose of study drug
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device or intrauterine hormone-releasing system (IUS)
◦
a contraceptive implant
◦
an oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on 
the same dose of the oral contraceptive throughout the study and for 28 days after 
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◦
have a vasectomized partner with confirmed azoospermia

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
It is permissible that if a highly effective method of contraception is not appropriate or 
acceptable to the subject, then the subject must agree to use a medically acceptable 
method of contraception, ie, double-barrier methods of contraception such as latex or 
synthetic condom plus diaphragm or cervical/vault cap with spermicide
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing)
3.
Any history of a medical or psychiatric condition that in the opinion of the investigator(s) 
could affect the subject’s safety or interfere with the study assessments
4.
A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG.  A 
history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family 
history of long QT Syndrome) or the use of concomitant medications that prolonged the 
QTcF interval
5.
Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening 
6.
Any lifetime suicidal behavior 
7.
Evidence of clinically significant disease (eg, cardiac; respiratory including chronic 
obstructive pulmonary disease, acute and/or severe respiratory depression; 
gastrointestinal; moderate and severe hepatic impairment; renal including severe renal 
impairment; neurological including myasthenia gravis; psychiatric disease; or malignancy 
within the past 5 years other than adequately treated basal cell carcinoma) or chronic pain 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with 
the study assessments.  Subjects for whom a sedating drug would be contraindicated for 
safety reasons because of the subject’s occupation or activities
8.
Hypersensitivity to lemborexant or to their excipients
9.
Scheduled for surgery during the study that requires general anesthesia or administration 
of prohibited medications
10. Known to be human immunodeficiency virus (HIV) positive
11. Active viral hepatitis (B or C) as demonstrated by positive serology
12. History of drug or alcohol dependency or abuse within approximately the last 2 years
13. A current diagnosis of sleep-related breathing disorder including obstructive sleep apnea 
(with or without continuous positive airway pressure [CPAP] treatment), periodic limb 
movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or 
narcolepsy, or an exclusionary score on screening instruments to rule out individuals with 
symptoms of certain sleep disorders other than insomnia as follows: 

STOPBang score ≥5 (revised per Amendment 01)

IRLS ≥16


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14. Apnea-Hypopnea Index >15 or Periodic Limb Movement with Arousal Index >15 as 
measured on the PSG at the 2nd Screening Visit
15. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
16. Reports a history of sleep-related violent behavior, or sleep driving, or any other complex 
sleep-related behavior (eg, making phone calls or preparing and eating food while 
sleeping)
17. For subjects who underwent diagnostic PSG within 1 year before informed consent:

Age 19 to 64 years: Apnea hypopnea Index ≥10, or Periodic Limb Movements with 
Arousal Index ≥10

Age ≥65 years: Apnea Hypopnea Index >15, or Periodic Limb Movements with 
Arousal Index >15
18. BDI-II score >19 at Screening
19. BAI score >15 at Screening
20. Habitually naps during the day more than 3 times per week
21. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
insomnia, or habitually consumes caffeine containing beverages after 18:00 and is 
unwilling to forego caffeine after 18:00 for the duration of his/her participation in the 
study.  Subjects are excluded if, in the previous 3 months, they had symptoms that would 
meet DSM-5 criteria for caffeine intoxication, which includes consumption of a high 
dose of caffeine (significantly in excess of 250 mg) and ≥5 of the following symptoms:  
restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal 
disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or 
cardiac arrhythmia, periods of high energy, or psychomotor agitation.  To be 
exclusionary, those symptoms must cause distress or impairment in social, occupational 
and other forms of functioning, and not be associated with other substance, mental 
disorder or medical condition
22. Reports habitually consuming more than 14 drinks containing alcohol per week (females) 
or more than 21 drinks containing alcohol per week (males), or unwilling to limit alcohol 
intake to no more than 2 drinks per day or forego having alcohol within the 3 hours 
before bedtime for the duration of his/her participation in the study
23. Comorbid nocturia that is causing or exacerbating the insomnia
24. Used any prohibited prescription or over-the-counter concomitant medications within 1 
week or 5 half-lives, whichever is longer, before the 1st dose of study medication (Run-in 
Period).
25. Used any modality of treatment for insomnia, including cognitive behavioral therapy or 
marijuana within 1 week or 5 half-lives, whichever is longer, before the 1st dose of study 
medication (Run-in Period)
26. Failed treatment with dual orexin receptor antagonist drugs (efficacy and/or safety) 
following treatment with an appropriate dose and of adequate duration in the opinion of 
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27. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or 
between Screening and Baseline, or plans to travel across different time zones during the 
study
28. Performed shift work in the 2 weeks before Screening, or between Screening and 
Baseline, or plans to do during the study
29. A positive drug test at Screening, Run-in, or Baseline, or unwilling to refrain from use of 
recreational drugs during the study
30. Currently enrolled in another clinical trial or used any investigational drug or device 
within 30 days or 5 × the half-life, whichever is longer, preceding informed consent
31. Previously participated in any clinical trial of lemborexant
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
A subject who discontinues study treatment should return for an early termination (ET) Visit 
as soon as possible and will complete End-of-Study procedures (see Section 9.5.5). The 
primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition electronic 
case report form (eCRF). In addition, the date of last dose of study drug(s) will be recorded.
9.4
Treatments
9.4.1
Treatments Administered
Test drug
LEM5, LEM10 or lemborexant-matched PBO will be taken orally in tablet form each night for 
30 consecutive nights, approximately 5 minutes before the time the subject intends to try to 
sleep.
Run-In Period
All subjects will receive 1 tablet of lemborexant-matched PBO for approximately 14 days in 
a single blind manner during the Run-in Period approximately 5 minutes before the time the 
subject intends to try to sleep.
Treatment Period 
All subjects will receive 1 tablet as described below approximately 5 minutes before the time 
the subject intends to try to sleep, according to the treatment arm to which the subject has 
been randomized:

LEM5:  1 lemborexant 5 mg tablet for 30 days

LEM10:  1 lemborexant 10 mg tablet for 30 days


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
PBO:  1  lemborexant-matched PBO tablet for 30 days
9.4.2
Identity of Investigational Products
The sponsor will provide lemborexant tablets in strengths of 5, and 10 mg and 
lemborexant-matched PBO, identical in appearance.  Tablets will be packaged in blister cards 
in a double-blind manner.
Each subject will be dispensed a single card at the beginning of the Run-in Period and on 
Day 1. The subject will take 1 tablet a day; a single lemborexant or lemborexant-matched 
PBO tablet.  The PBO Run-in card will contain a 17-day supply of lemborexant-matched 
PBO tablets per day.  Each card for the Treatment Period will contain a 35-day supply of 
tablets of either lemborexant or lemborexant-matched PBO depending on the dose, in 
double-blind fashion.
9.4.2.1
Chemical Name, Structural Formula of E2006/Lemborexant

Test drug code:  E2006

Generic name:  lemborexant

Chemical name:  (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3 
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
9.4.2.2
Comparator Drug
PBO to match lemborexant 
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text in Korean that is in full regulatory 
compliance with South Korea.
The following information has to be provided:

For clinical study use only

Name, address, and contact number of the sponsor

Chemical name/drug identifier (in case of a blind study, to write side by side both active 
drug and comparator drug)

Lot number/batch number

Storage conditions, expiration date

Keep out of sight and reach of children

Reference code that can identify a clinical study

Others according to the relevant regulation


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9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or is responsible for ensuring that 
the temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
After the Baseline Period on Day 1, subjects will be randomized, in a double-blind manner, 
to receive either LEM5, LEM10 or PBO in a 2:2:1 ratio on Day 1 using a centralized 
randomization technique. (revised per Amendments 01 and 02)
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized blister card 
identification numbers.  At enrollment (and after successful completion of Baseline Period on 
Day 1), the investigator or designee will call the IxRS to register the subject information.  At 
randomization (after the Baseline Period on Day 1), the IxRS will assign each subject a 
unique 6-digit randomization number.  
9.4.4
Selection of Doses in the Study
The approved doses in the US and Japan, which is lemborexant 5 mg and 10 mg per day, are 
selected to assess pharmacodynamic profile of lemborexant in Korean subjects.
9.4.5
Selection and Timing of Dose for Each Subject
Throughout the Run-in Period and the Treatment Period, study drug will be taken at home or 
in the clinic approximately 5 minutes before the subject intends to sleep, on a time schedule 
that is consistent as possible.  Subjects should not eat a meal within 3 hours before taking the 
study drug.
9.4.6
Blinding
During the Run-in Period of the Prerandomization Phase, single blinding will be in effect 
such that the subject will be blinded to study treatment but study personnel will not be 
blinded.  During the Randomization Phase, subjects and all personnel involved with the 
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staff will be blinded to the treatment codes.  Randomization data will be kept strictly 
confidential, filed securely by an appropriate group with the sponsor or CRO and accessible 
only to authorized persons (eg, Eisai Global Safety) until the time of unblinding, per standard 
operating procedure (SOP).
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the interactive voice and web 
response system (IxRS) vendor, and the sponsor.  In the event that emergency conditions 
require knowledge of the study treatment given, the blind may be broken via the code breaker 
facility within the IxRS.  Emergency procedures for revealing drug codes are given in 
Section 9.5.4.5.  If possible, before breaking the blind, the investigator should consult with 
the sponsor to ascertain the necessity of breaking the code.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject within the last 3 months before Screening (ie, Prior Medications) or during the study,
starting at the date of informed consent, will be recorded on the Prior and Concomitant 
Medication eCRF or Non-Pharmacological Procedures eCRF.  The investigator will record 
on the Adverse Event eCRF any AE for which the concomitant medication/therapy was 
administered. If the concomitant medication/therapy is being administered for a medical 
condition present at the time of entry into the study, the investigator will record the medical 
condition on the Medical History and Current Medical Conditions eCRF.
9.4.7.1
Drug-Drug Interactions
Co administration with strong and moderate P450 (CYP3A) inhibitors may moderately 
increase exposure to lemborexant, and CYP3A inducers may markedly decrease lemborexant 
exposure.  Potential drug interactions with lemborexant are described in further detail in the 
Investigator’s Brochure; prohibited concomitant medications are described in Section 9.4.7.2
and listed in Appendix 3.
9.4.7.2
Prohibited Concomitant Therapies and Drugs
Prohibited medications (presented in Appendix 3 of protocol) should not be used during the 
study.  A subject must not have used any prohibited prescription or over-the-counter 
medications within 1 week or 5 half-lives, whichever is longer, before the first dose of study 
drug (Run-in Period). 
Prohibited medications include moderate and strong CYP3A inhibitors and all CYP3A 
inducers. Prohibited therapies also include: any treatment for insomnia disorder, including 
any drugs or non-pharmacological treatment such as cognitive behavioral therapy; 
medications that are used for the purpose of inducing sleep (hypnotics) or inducing 
wakefulness (stimulants; except caffeine; see below) and medications that have known 
sedating effects or alerting effects.  This prohibition applies even if the entire class to which 
that medication belongs is not prohibited (eg, anticonvulsants).


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If a medication is not on the list of prohibited medications but in the opinion of the 
investigator causes or exacerbates the subject’s insomnia, it must not be used throughout the 
study.  If a medication is not specified as prohibited but is in the same class as a medication 
that is listed in Appendix 3, and if the investigator is uncertain whether the medication has
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that moderate and strong CYP3A inhibitors and all CYP3A 
inducers will not be permitted at any time for any duration of use during the study.  
9.4.7.3
Caffeine and Alcohol Restrictions
Caffeine will be permitted in limited quantities during the study. Subjects will be advised to 
limit caffeine consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg caffeine 
per day.  They will be instructed to avoid caffeine after 13:00 on days when they are 
scheduled for a PSG recording and after 18:00 on all other days during the study.  
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a 
maximum of 2 alcohol containing drinks on any given day while in the study, and will be 
instructed not to consume any alcohol within 3 hours before bedtime.  Subjects must not 
consume any alcohol on days when they are scheduled for a PSG recording.  
9.4.8
Treatment Compliance
Compliance will be assessed for each study drug by examination of blister packs returned to 
the investigator at the end of the Run-in and Treatment Periods.
All subjects will be reminded of the importance of taking study medication as directed, ie, 
the correct number of tablets every night approximately 5 minutes before bedtime, and they 
will be reminded that their bedtime should be the same throughout the study. Subjects will 
be told that following these instructions about taking study medication is important for the 
treatment to be effective. Compliance will be monitored closely and determined at specific 
visits by tablet count. 
When subjects visit site for Baseline assessment, and the treatment compliance check 
indicates that a subject has missed any doses, the investigator must use clinical judgment to 
decide if the subject should continue in the study.
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRA) will review treatment compliance during site visits and at the 
completion of the study.


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9.4.9
Drug Supplies and Accountability
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to Good Clinical Practice (GCP) guidelines as well as local requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or a third-party contractor. This includes, 
but may not be limited to:  (a) documentation of receipt of study drugs, (b) study drugs 
dispensing/return reconciliation log, (c) study drugs accountability log, (d) all shipping 
service receipts, and (e) documentation of returns to the sponsor.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority.  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator by the subject and, together with unused study 
drugs that were shipped to the site but not dispensed to subjects, are to be returned to the 
sponsor’s designated central or local depot(s) during the study or at the conclusion of the 
study. Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements.  
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Screening Assessments
9.5.1.1.1
DEMOGRAPHY 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.


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9.5.1.1.2
MEDICAL HISTORY, PSYCHIATRIC HISTORY, AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history within 5 years, except for history of any sleep 
disorder, which should be lifetime, must be noted in the Medical History and Current 
Medical Conditions eCRF.  Lifetime psychiatric history will also be obtained.  A full 
physical examination will be performed, excluding a urogenital examination unless there are 
special circumstances and at the discretion of the investigator.  
Physical examinations (full or brief) will be performed as described in Section 9.5.1.4.5.
9.5.1.1.3
SLEEP DISORDERS HISTORY AND SCREENING BATTERY
A lifetime history of sleep disorders will be obtained only at the first Screening Visit. For 
insomnia complaints, this history will include clinical, qualitative assessment and/or 
confirmation that subjects meet diagnostic criteria for insomnia disorder. The history will 
also include information regarding habitual sleep timing, bedtime routines, and other aspects 
of sleep hygiene to determine eligibility and to exclude subjects whose insomnia symptoms 
appear to be due to poor sleep hygiene or to frequent napping, for example.
Screening battery will include the Insomnia Severity Index (ISI), the Beck Depression 
Inventory - II (BDI-II), Beck Anxiety Inventory (BAI), and the Sleep Disorders Screening 
Battery (SDSB) that consists of STOPBang and International Restless Legs Scale (IRLS).
ISI
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of 
insomnia (Bastien et al., 2001). The dimensions evaluated are severity of: sleep onset, sleep 
maintenance, early-morning awakening problems; sleep dissatisfaction; interference of sleep 
difficulties with daytime functioning, noticeability of the sleep problems by others; and 
distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each item 
(from 0 =no problem to 4=very severe problem), yielding a total score from 0 to 28.
BDI-II
The BDI-II is a 21-question multiple-choice self-report questionnaire that subjects will use to 
rate the presence, frequency, and severity of symptoms of depression using a 4-point Likert 
scale (Beck et al., 1961). Scores on the BDI-II range from 0 to 63, with higher scores 
indicating higher levels of depressive symptoms.
BAI
The BAI is a 21-question multiple-choice self-report inventory that subjects will use to rate 
the presence, frequency, and severity of symptoms of anxiety using a 4-point Likert scale
(Beck et al., 1988). Scores on the BAI range from 0 to 63, with higher scores indicating 
higher levels of anxiety symptoms.


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SDSB
For the detection of other sleep disorders, the SDSB will be administered (see below). Upon 
review of the findings, if a subject endorses more than 2 items on the Symptoms of 
Narcolepsy Screen, the study site will probe for further clinical information to ascertain 
whether the subject has a likelihood of a narcolepsy diagnosis.
The SDSB will include the following, to be administered by trained site personnel:
-
StopBANG: a list of eight questions to be answered Yes or No, which screens  
subjects for obstructive sleep apnea  (Chung et al., 2008)
-
IRLS: a subjective scale comprising ten questions, which measures severity of 
symptoms of restless legs syndrome (Abetz et al., 2006)
Sleep Diary
The paper sleep diary will be completed each morning within 1 hour after morning wake 
time from the 1st Screening Visit to the 2nd Screening Visit. This Sleep Diary will yield 
several self-reported measures of sleep and will be used to determine eligibility at the 2nd 
Screening Visit.
The following parameters will be collected and calculated from Sleep Diary:

Bedtime: the time the subject attempts to sleep

Waketime: the time the subject gets out of bed for the day

sSOL: estimated minutes from the time that the subject attempts to sleep until sleep onset

sWASO: sum of estimated minutes of wake during the night after initial sleep onset until
the time that the subject stopped trying to sleep for the night

Subjective time in bed: time from Bedtime to Waketime
9.5.1.1.4
PREGNANCY TESTS FOR WOMEN OF CHILD BEARING POTENTIAL
A serum β-hCG test will be performed at Screening for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 consecutive months.  
Subsequently, urine pregnancy tests will be conducted for these subjects as specified in the 
Schedule of Procedures/Assessments (Table 3). A dipstick will be used for urine pregnancy 
testing.  
9.5.1.1.5
VIRAL TESTING
At the Screening Visit, a 6 mL blood sample will be taken for detection of hepatitis B surface 
antigen and hepatitis C antibodies, the presence of which would be exclusionary.




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measured using validated liquid chromatography-tandem mass spectrometry assay methods.
(revised per Amendment 02)
9.5.1.3.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Not applicable.
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs); regular 
monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital 
signs and ECGs; and performance of physical examinations as detailed in Table 3. Safety 
will be assessed at every clinic visit throughout the study including after the last dose of 
study drug, and at the End of Study, ET, and Unscheduled Visits.  At telephone visit on Day 
14, AE will be confirmed by telephone.
9.5.1.4.1
ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lemborexant.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit.  Refer to Section 9.5.4.1
for the time period after the end of treatment for SAE collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 


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laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.4.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:


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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
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9.5.1.4.3
LABORATORY MEASUREMENTS
Blood and urine samples will be collected for the clinical laboratory tests as listed in Table 1.  
Clinical laboratory tests are to be performed according to the schedule in Table 3. Subjects 
should be in a seated or supine position during blood collection.
The total blood volume to be drawn for laboratory measures in the study (Table 2) will be 
indicated on the ICF.
Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and 
WBC count with differential (bands, basophils, 
eosinophils, lymphocytes, monocytes, neutrophils)
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine aminotransferase, alkaline phosphatase, 
aspartate aminotransferase, direct bilirubin, total 
bilirubin
Renal function tests
blood urea/blood urea nitrogen, creatinine
Other
albumin, calcium, cholesterol, globulin, glucose, iron, 
lactate dehydrogenase, phosphorus, total protein, 
triglycerides, uric acid
Urinalysis
bacteria, casts, crystals, epithelial cells, glucose, 
ketones, occult blood, pH, protein, RBCs, specific 
gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Table 2
Blood Sampling Schedule for All Laboratory and 
Pharmacokinetic Assessments
Volumea
per Sample 
Collection
(mL)
Collection Time points
Window 
Around 
Time 
Point
Total 
Volumea
Collected 
(mL)
Clinical 
laboratory testsb
7
(revised per 
Amendment 
02)
Screening
Day 1
Day 31
End of Study
n/a
28
(revised per 
Amendment 
02)


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Table 2
Blood Sampling Schedule for All Laboratory and 
Pharmacokinetic Assessments
Volumea
per Sample 
Collection
(mL)
Collection Time points
Window 
Around 
Time 
Point
Total 
Volumea
Collected 
(mL)
Pregnancy 
testingc
(revised per 
Amendment 02)
n/a
(revised per 
Amendment 
02)
Screening
n/a
n/a
(revised per 
Amendment 
02)
Viral tests
8.5
(revised per 
Amendment 
02)
Screening
n/a
8.5
(revised per 
Amendment 
02)
Pharmacokinetic 
sampling
(revised per 
Amendment 02)
4
Day 30 (1 time within 2 hours 
predose), 
Day 31 (2 times; 1 and 1.5 
hours after morning waketime)
(revised per Amendment 02)
+/– 15 
mins
12
Total
48.5 mL
(revised per 
Amendment 
02)
n/a: not applicable
a:
Estimated volume.
b:
Clinical laboratory tests will also be conducted at ET visits, and may also be obtained at unscheduled 
visits at the discretion of the investigator.
c:
Included in the clinical laboratory test volume (revised per Amendment 02)
With the exception of assessing for bacteria in urine tests, clinical laboratory assessments 
during the study will be performed by a central laboratory.  During the study, bacteria in 
urinalysis will be performed by a local laboratory of each site (revised per Amendment 03).  
All blood samples will be collected and sent to the central laboratory on the day of collection 
unless otherwise instructed.  Urine samples will be collected, and the split samples will be 
sent to both the central laboratory and the local laboratory on the day of collection unless 
otherwise instructed (revised per Amendment 03).  In cases of a safety concern, blood 
samples will be split (or 2 samples drawn) to allow a local laboratory analysis in addition to 
the central laboratory.  Laboratory certification as available will be included in the final 
clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1 and the eCRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event eCRF
(see Section 9.5.4.3.2).


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9.5.1.4.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]) will be obtained 
at the visits designated in the Schedule of Procedures/Assessments (Table 3) by a validated 
method.  Blood pressure and pulse will be measured after the subject has been in a sitting 
position for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person. Validated methods will be used for all vital sign 
measurements, and values will be recorded.  Height (cm), and weight (kg) will also be 
measured.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations (full or brief) will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3). At Screening and at the end-of study (EOS) visit, a
comprehensive physical examination will be conducted, including evaluations of the head, 
eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a 
complete neurological examination.  A urogenital examination will only be required in the 
presence of clinical symptoms related to this region.  At other study visits as designated in 
Table 3, a brief physical examination will be conducted to assess health status by brief 
evaluation of the head, eyes, ears, nose, throat, heart, lungs, abdomen, and extremities, and 
other physical conditions of note. Documentation of the physical examination will be 
included in the source documentation at the site. Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions eCRF. Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events eCRF.
9.5.1.4.6
ELECTROCARDIOGRAMS
ECG will be obtained as designated in the Schedule of Procedures/Assessments (Table 3).  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.4.7
OTHER SAFETY ASSESSMENTS
Urine Drug Test
A 30 mL urine sample will be collected at designated time points as specified in the Schedule 
of Procedures/Assessments (Table 3).  These samples will be tested for common drugs of 


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abuse: eg, cocaine, cannabinoids, phencyclidine, opioids (as a group), benzodiazepines, 
barbiturates, and amphetamines. A dipstick will be used for urine drug testing.
9.5.1.5
Other Assessments
Not applicable.
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments for the study.


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Table 3
Schedule of Procedures/Assessments in Study E2006-J082-204:  
Phase
Prerandomization
Randomization
Period
Screening
Run-in
Baseline
Treatment
Follo
w-up
EOS
/ETb
UNS
Visit
1a
2a
2ba
3a
3b
4
5j
6a
6b
NA
7
Day(s)
–21
–14
–13
–7
–6
1
1c
14
30
31
32-57
58
Visit window
–14/+4
–3/+4
–3/+2
NA
NA
–2/+2
–2/+5
NA
+4
Assessments
Demography
X
Informed Consent
X
Inclusion/Exclusion 
criteria
Medical/psychiatric/
sleep history
X
Comprehensive 
physical exam
X
X
Brief physical exam
X
X
Beck Depression 
Inventory - II
X
Beck Anxiety 
Inventory
X
SDSB
X
Serum pregnancy 
test
X
Urine pregnancy 
testd
X
X
X
X
X
X
Urine drug testd
X
X
X
X
X
X
Insomnia Severity 
Index
X
Sleep Diarye
Height
X
Weight
X
X
X
X
Viral screen 
(HCVAb, HBsAg)
X


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Phase
Prerandomization
Randomization
Period
Screening
Run-in
Baseline
Treatment
Follo
w-up
EOS
/ETb
UNS
Visit
1a
2a
2ba
3a
3b
4
5j
6a
6b
NA
7
Day(s)
–21
–14
–13
–7
–6
1
1c
14
30
31
32-57
58
Visit window
–14/+4
–3/+4
–3/+2
NA
NA
–2/+2
–2/+5
NA
+4
Assessments
Clinical laboratory 
tests
X
X
X
X
X
Vital signs
X
X
X
X
X
X
PK blood samplingf
X
X
12-lead ECG
X
X
X
X
X
PSGg
X
X
X
Randomization
X
Dispense study drug
X
X
Study drug 
administrationh
Retrieve unused 
study drug
X
X
Check study drug 
compliancei
X
X
X
Admission to clinic
X
X
X
Discharge from 
clinic
X
X
X
Discharge from 
study
X
Adverse events
Prior and 
concomitant 
medication
ECG = electrocardiogram, EEG = electroencephalography, EMG =electromyogram, EOG = electro-oculogram, EOS = end of study, ET = early termination, 
h = hour(s), HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, HIV = human immunodeficiency virus, NA = Not applicable, PK = 
pharmacokinetic, PSG = polysomnography, SDSB = Sleep Disorders Screening Battery, UNS = Unscheduled Visit.
a.
Eligible subjects will be scheduled for screening and baseline PSGs.
b.
Any subject who early terminates will complete End-of-Study procedures.


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c.
Subjects who complete the Baseline Period and continue to meet the eligibility criteria will be randomized and will begin the Treatment Period.
d.
A dipstick will be used for urine pregnancy testing and urine drug testing at the prespecified time points.
e.
Should be completed, within 1 hour of morning waketime, on every day of the study from Visit 1 to Visit 2 and reviewed for eligibility before initiating any 
study assessments at Visit 2.
f.
Blood samples (4 mL) will be obtained at the following timepoints:  within 2 hours predose on Day 30; 1 and 1.5 hours (1 hour and 30 minutes) after 
morning waketime on Day 31. (revised per Amendments 01 and 02)
g.
PSG recordings will include a standard montage on all PSG nights (EEG, EMG, EOG, ECG).  Diagnostic channels (respiratory effort, airflow, and leg 
EMG) will be added to the standard montage on the PSG at Visit 2.
h.
First dose of study drug (PBO) will be taken by the subject on the 1st night at home after Visit 2.  On the days that subjects were admitted to the clinic, study 
drug will be administered to the subject by clinical staff.  The 1st dose of active study drug will be taken by the subject on the evening following Visit 3.  On 
days that the subjects are not admitted to the clinic, subjects self-administer study drug.  All study drug administration must be within 5 minutes of bedtime 
(defined as the time the subject attempted to sleep).
i.
Subjects will be questioned about study drug compliance upon check-in at Visits 3, 4 and 6.  Tablet counts for study drug compliance will be done after end 
of Run-in Period and end of Treatment Period.
j.
On Day 14, site staff will call subjects to check AEs, concomitant therapy, and drug compliance. In addition, subject will be reminded to take study drug 
each night approximately 5 minutes before bedtime and to remain in bed for at least 7 hours each night and maintain a regular bedtime and waketime 
throughout the study, according to the schedule determined by the study site and the subject.  They will also be reminded that they must follow study 
restrictions with regard to timing of meals, and use of caffeine and alcohol.  If any AE is clinically significant and requires follow-up, an unscheduled visit 
may be arranged per investigator’s decision.


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9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 3.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of insomnia 
disorder.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs are standard evaluations to ensure subject 
safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported to the sponsor or the responsible CRO on a completed SAE form by 
email or fax as soon as possible but no later than 24 hours from the date the 
investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected for 28 days 
after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours
of its receipt.  If the relevant follow-up information changes the investigator’s assessment of 
causality, this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.


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The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus are considered to be an SAE 
and should be reported in the same time frame and in the same format as all other SAEs (see
Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects


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Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
and Intentional Overdose, even if asymptomatic, are always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing and whether nonserious or 
serious, should be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1).  If the event does not meet 
serious criteria, the seriousness criteria on the SAE form should be indicated as “nonserious.”  

Elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal 
AND

Elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal 
AND AT THE SAME TIME

Alkaline phosphatase lab value that is less than 2X the upper limit of normal
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
9.5.4.3.3
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 


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specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early termination procedures indicated in 
the Schedule of Procedures/Assessments (Table 3).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow up, subject choice, lack of therapeutic effect, or 
administrative/other.  Discontinuations due to noncompliance with alcohol restrictions will 
be assigned to “administrative/other”. In addition to the primary reason, the subject may 
indicate 1 or more secondary reasons for discontinuation.  Study disposition information will 
be collected on the Subject Disposition eCRF.  
A subject removed from the study for any reason may not be replaced. In some 
circumstances, a subject who screen fails before the Run-in period may be rescreened 
following consultation with the Sponsor.  Any such subject will be assigned a new subject 
identification number.


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9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug eCRF.
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.4.1.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may be conducted periodically by the sponsor’s or the CRO’s qualified compliance auditing 
team, which is an independent function from the study team responsible for conduct of the 
study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF. The investigator or designee must sign the completed CRF 
to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.


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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding and a snapshot of the 
database is obtained and released for unblinding).  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate SAP.
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint will be change from baseline of LPS on Day 30 of LEM5 compared to 
PBO. (revised per Amendment 01)
9.7.1.1.2
SECONDARY ENDPOINTS
Efficacy Endpoints

Change from baseline of LPS on Day 30 of LEM10 compared to PBO (revised per 
Amendment 01)

Change from baseline of SE on Day 30 of LEM5 compared to PBO (revised per 
Amendment 01)

Change from baseline of SE on Day 30 of LEM10 compared to PBO (revised per 
Amendment 01)
Safety Endpoints

Safety and tolerability of lemborexant
Other Endpoint

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
9.7.1.1.3
EXPLORATORY ENDPOINTS
Efficacy Endpoints
CCI


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9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
Full Analysis Set (FAS): The FAS is the group of randomized subjects who received at least 
1 dose of randomized study drug and had LPS data from the PSG on Day 30. (revised per 
Amendment 01)
Per Protocol (PP) Analysis Set: The PP Analysis Set is the FAS who received protocol-
assigned study drug and did not have a major protocol deviation that is likely to affect the 
LPS data of PSG as follows. 
•
Incorrect study drug kit dispensed
•
Study drug not administered
•
Prohibited concomitant medication
•
Primary efficacy assessment out of window
•
Missing primary efficacy assessment
•
Duplicate randomization
•
Violated inclusion/exclusion criteria
More details of the evaluability criteria will be determined before database lock and will be 
specified in the SAP.  (revised per Amendments 01 and 02)
PK Analysis Set: The PK analysis set is the group of subjects who had at least 1 quantifiable 
plasma concentration of lemborexant or its metabolites, with adequately documented dosing 
history.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
CCI


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The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination.  Subjects who prematurely discontinued from study treatment will also be 
presented and summarized by primary reason for premature treatment discontinuation.  Other 
reasons for study treatment and study terminations will also be summarized.  These 
tabulations will be produced for all randomized subjects by treatment group.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics. Continuous demographic 
and baseline variables include age, height, weight, and body mass index (BMI); categorical 
variables include sex, age group, BMI group, and race.
Characteristics of insomnia at Study Baseline will be summarized using LPS, SE, WASO, 
and ISI.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code
using the World Health Organization Drug Dictionary (WHO DD) (WHO DDE/HD Mar 
2018 or latest version).  The number (percentage) of subjects who took prior and concomitant 
medications will be summarized on the Safety Analysis Set by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and WHO DD preferred term (PT).  If the Safety 
Analysis Set and FAS differ substantially, then the prior and concomitant medication 
summaries will be repeated on the FAS. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug where study drug includes PBO during the Run-in Period.
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and are continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
The main analysis group for the primary endpoint is the FAS.  (revised per Amendment 01)  
The efficacy analyses will be performed on the FAS except per protocol analysis will be 
performed on the PP. The each variables and the difference from baseline will be used for 
summary statistics by each visit and treatments. Data will be plotted as appropriate.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Since LPS is known to be non-normally distributed, the change from baseline to Day 30 of 
LPS after log-transformation for each will also be analyzed with analysis of covariance 
(ANCOVA), with treatment and baseline (log-transformation) as fixed effects. 




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9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 23.0 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data 
listing of all SAEs will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.


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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and treatment group using descriptive statistics.  
Qualitative parameters listed in Section 9.5.1.4.3 will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline to each postbaseline visit 
and to end of treatment will be reported using shift tables.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS AND WEIGHT
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse,
respiratory rate, temperature, weight) and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
ECG assessments will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  Descriptive statistics for ECG parameters and changes 
from baseline will be presented by visit and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) during the treatment period will be summarized.  Clinically 
abnormal ECG results in QTcF will be categorized as follows:


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Absolute QTcF interval prolongation:

QTcF interval >450 ms

QTcF interval >480 ms

QTcF interval >500 ms
Change from baseline in QTcF interval:

QTcF interval increases from baseline >30 ms

QTcF interval increases from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
Not applicable.
9.7.2
Determination of Sample Size
Sample size was calculated with re-sampling simulation using Study E2006-G000-201 data 
in order to power the study to detect point estimate of mean difference below a certain 
threshold with sufficient probability. The certain threshold is defined as –0.44 as derived 
from the upper limit of 95% CI of pairwise difference between LEM5 and PBO for log(LPS) 
from Study 201.  Using the mean difference to PBO of log(LPS) in LEM5 from the baseline 
to Days 14/15 from each simulation (10,000 times) that using a grid search and assuming a 
2:1 ratio (LEM5:PBO), demonstrated the difference < –0.44 could be achieved with more 
than 85% power. It is assumed that the mean difference to PBO of log(LPS) in lemborexant 
groups from baseline to Day 30 in this study will be similar with those from baseline to Days 
14/15 in Study 201. When the number of subjects randomized to LEM5 and PBO are 24 and 
12, respectively, the number of subjects who complete with evaluable efficacy data will be 
22 and 11, respectively.  Based on this evaluation, this study will provide power at 88.64% 
for comparing LEM5 and PBO. Since LEM10 is set as a reference arm, therefore the sample 
size for LEM10 will be 24 as the same of LEM5 above.  (revised per Amendment 01)
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.


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10 REFERENCE LIST
Abetz L, Arbuckle R, Allen RP, Garcia-Borreguero D, Hening W, Walters AS, et al.  The 
reliability, validity and responsiveness of the International Restless Legs Syndrome Study 
Group rating scale and subscales in a clinical-trial setting.  Sleep Med. 2006;7:340–9.
Bastien CH, Vallières A, Morin CM.  Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research.  Sleep Med 2001;2:297-307.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring 
depression. Arch. Gen. Psychiatry. 1961;4(6):561–71.
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: 
Psychometric properties J Consult Clinical Psychol. 1988;56: 893–7.
Buysse DJ. Insomnia. JAMA. 2013 Feb 20;309(7):706-16.
Cho YW, Shin WC, Yun CH, Hong SB, Kim JH, Earley CJ. Epidemiology of Insomnia in 
Korean Adults: Prevalence and Associated Factors. J Clin Neurol. 2009 Mar;5(1):20-3. 
Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, et al.  STOP 
Questionnaire A Tool to Screen Patients for Obstructive Sleep Apnea.  Anesthesiology 
2008;108:812–21.
DiBonaventura M, Richard L, Kumar M, Forsythe A, Flores NM, Moline M. The association 
between insomnia and insomnia treatment side effects on health status, work productivity, 
and healthcare resource use. PLoS ONE. 2015 Oct 1;10:e0137117.
Equihua AC, De La Herran-Arita AK, and Drucker-Colin R. Orexin receptor antagonists as 
therapeutic agents for insomnia. Front Pharmacol. 2013 Dec;4:163.
Morin CM, LeBlanc M, Bélanger L, Ivers H, Mérette C, Savard J. Prevalence of insomnia 
and its treatment in Canada. Can J Psychiatry. 2011 Sep;56(9):540-8.
Roth T, Coulouvrat C, Hajak G, Lakoma MD, Sampson NA, Shahly V, et al. Prevalence and 
perceived health associated with insomnia based on DSM-IV-TR; International Statistical 
Classification of Diseases and Related Health Problems, Tenth Revision; and Research 
Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition criteria: 
results from the America Insomnia Survey. Biol Psychiatry. 2011 Mar 15;69(6):592-600.
Walsh JK, Coulouvrat C, Hajak G, Lakoma MD, Petukhova M, Roth T, et al. Nighttime 
insomnia symptoms and perceived health in the America Insomnia Survey (AIS). Sleep. 
2011;34(8):997-1011.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator and
the head of the medical institution will allow the CRA to inspect the clinical, laboratory, and 
pharmacy facilities to assure compliance with GCP and local regulatory requirements.  The 
CRFs and subject’s corresponding original medical records (source documents) are to be 
fully available for review by the sponsor’s representatives at regular intervals.  These reviews 
verify adherence to study protocol and data accuracy in accordance with local regulations.  
All records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:  

Clinic, office, or hospital charts


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
Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, ECGs, EEGs, polysomnographs) regardless of how these images are stored, 
including microfiche and photographic negatives

Medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

eCRF components (eg, questionnaires) that are completed directly by subjects and serve 
as their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents, Investigator and Site Information Form. ICFs, and IRB/IEC correspondence).  
The site should plan to retain study documents, as directed by the sponsor, for at least 15 
years following the completion of the study.


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It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor or designated contractor.  Drug supplies must be kept in an appropriate secure 
area (eg, locked cabinet) and stored according to the conditions specified on the drug labels.  
The investigator (or a designated pharmacist) must maintain an accurate record of the 
shipment and dispensing of the study drug in a drug accountability ledger, a copy of which 
must be given to the sponsor at the end of the study.  An accurate record of the date and 
amount of study drug dispensed to each subject must be available for inspection at any time.  
The CRA will visit the site and review these documents along with all other study conduct 
documents at appropriate intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.


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11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Appendix 2
Inclusion/Exclusion Criteria Schedule
Appendix 3
List of Prohibited Concomitant Medications


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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L
N/A
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
N/A
Alkaline phosphatase 
>ULN – 2.5ULN
>2.5 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULNl
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 - 3.0baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN
>2.5 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
>500 mg/dL;
>27.8 mmol/L;
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
>7.0 mmol/L
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
N/A
<3.0 – 2.5 mmol/L
<2.5 mmol/L
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L; 
>155 – 160 mmol/L
>160 mmol/L
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL
≤0.59 mmol/L
N/A
N/A
>10 mg/dL
>0.59 mmol/L
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: January 5, 2018.
(revised per Amendments 01 and 02)


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Appendix 2
Inclusion/Exclusion Criteria Schedule
Inclusion/exclusion criteria (Section 9.3.1 and Section 9.3.2) will be obtained at study visits 
as shown below.
Visit Name
V1, V2a
V3a
V5a
Screening
Run-in
Treatment
Baseline
Inclusion Criterion Number
1, 2, 3, 4, 5, 6, 7, 8, 
10, 11
5, 9
None
Exclusion Criterion Number
1 – 30
1, 20, 21, 22, 23, 
24, 25, 27, 28, 29
1, 9, 20, 21, 22, 27, 
28, 29


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Appendix 3
List of Prohibited Concomitant Medications
If a medication is not presented in the list below, but does fit into a class of medications 
noted in the list, the medical monitor must be consulted to determine whether it is permitted.
Category
Medication
Anticholinergics (centrally-acting)
–
Anticonvulsants with known sedating effects
Barbiturates 
Benzodiazepines 
GABA analogues 
Hydantoins 
Phenyltriazines
Antidepressants with known sedating effects
Amitriptyline
Clomipramine
Desipramine
Doxepin
Imipramine
Mirtazapine
Nefazodone
Nortriptyline
Protriptyline (revised per Amendment 01)
Trazodone
Trimipramine
Antihistamines (centrally-acting H1, including 
over the counter)
Diphenhydramine HCl
Carbinoxamine 
Doxylamine 
Dimenhyrinate 
Triprolidine 
Bromopheniramine 
Chlorphemamine 
Hydroxazine
Antihistamines with known sedating effects
Non-sedating, eg, loratadine is not 
prohibited
Anxiolytics with known sedating effects
Lorazepam 
Alprazolam 
Buspirone
Moderate CYP3A inhibitors
Aprepitant
Ciprofloxacin
Conivaptan
Crizotinib


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Category
Medication
Cyclosporine 
Diltiazem
Dronedarone 
Erythromycin 
Fluconazole
Fluvoxamine 
Imatinib
Tofisopam
Verapamil
Strong CYP3A inhibitors
Boceprevir
Clarithromycin
Cobicistat
Danoprevir and ritonavir
Elvitegravir and ritonavir
Grapefruit juice
Idelalisib
Indinavir and ritonavir
Itraconazole
Ketoconazole
Lopinavir and ritonavir
Nefazodone
Nelfinavir
Paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)
Posaconazole
Ritonavir
Saquinavir and ritonavir
Telaprevir
Tipranavir and ritonavir 
Telithromycin
Troleandomycin
Voriconazole
CYP3A inducers
Apalutamide
Armodafinil
Bosentan
Carbamazepine
Efavirenz
Enzalutamide


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Category
Medication
Etravirine
Mitotane
Modafinil
Phenytoin
Rifampin
Rufinamide
St. John’s wort
Phenobarbital
Primidone
Hypnotics
Melatonin 
Prescribed or OTC
Herbal preparations with sedating effects
Semen Ziziphi Spinosae
Caulis Polygoni Multiflori
Tuckahoe
Fructus Gardeniae
Polygala tenuifolia
Angelica sinensis
Bupleuri Radix
Licorice
Rehmannia glutinosa
Salvia miltiorrhiza
Ligusticum chuanxiong
Or any other herbal medication that fit into 
this class by investigator’s judgement
MAOIs
Tranylcypromine (revised per Amendment 
01)
Phenelzine (revised per Amendment 01)
Isocarboxazid. (revised per Amendment 
01)
Norepinephrine and dopamine reuptake 
inhibitors (NDRIs)
Bupuropion (revised per Amendment 01)
Opioid Analgesics
–
Muscle relaxants (centrally-acting) with known 
sedating effects
GABA analogues 
Hydantoins 
Phenyltriazines
Stimulants
Amphetamines 
Modafinil 
Armodafinil
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Category
Medication
Other
Warfarin, heparin, ticlopidine
Non-stimulant diet pills
Systemic isoretinoin
Systemic glucocorticoids
Tryptophan


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SPONSOR SIGNATURE PAGE
Study Protocol Number:
E2006-J082-204
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study to Assess the Pharmacodynamics of 
Lemborexant in Korean Subjects with Insomnia Disorder
Investigational Product 
Name:
E2006/lemborexant
Chief Portfolio Officer, 
Eisai Co., Ltd.
Signature
Date


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-J082-204
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study to Assess the Pharmacodynamics of 
Lemborexant in Korean Subjects with Insomnia Disorder 
Investigational Product
Name:
E2006/lemborexant
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Clinical Study Report 
E2006-J082-204 
 
16.1.9 
Documentation of Statistical Methods 
Listed below are all versions of the Statistical Analysis Plan for this study. The corresponding 
documents are provided on the following pages. 
Statistical Analysis Plan 
Version 
Date 
Revised original 
2.0 
03 Jul 2024 
Original  
1.0 
18 Jan 2023 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2006-J082-204 
Study Protocol 
Title: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study to Assess the Pharmacodynamics of 
Lemborexant in Korean Subjects with Insomnia Disorder 
Date: 
3/ Jul/ 2024 
Version: 
Version.2.0 
 
 
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Major Revisions to Version 2.0 
Date of Revisions: 3 Jul 2024 
Change 
Rationale 
Affected Sections 
Added a word of “randomized” to 
“study drug” in the definition of 
Safety Analysis Set. 
To clarify the definition of Safety 
Analysis Set. 
Section 5.2.1 
Added the LPS analysis based on 
non-log transformed data. 
To evaluate original unit for LPS 
as a sensitivity analysis. 
Section 5.4.1 
Deleted the summary of urinalysis 
parameters. 
Provide only data listings to make 
consistent with the approach in 
the precedent studies.  
Section 5.6.3 
Defined the exploratory analyses 
for polysomnography parameters. 
To clarify the exploratory 
analyses for other 
polysomnography parameters. 
Section 5.8 
Major Revisions to Version .0 
Date of Revisions: 12 JAN 2023 
Change 
Rationale 
Affected Sections 
Deleted a word of “major” from 
“a major protocol deviation” in 
the definition of Per Protocol 
Analysis Set. 
Protocol deviation that is likely to 
affect the LPS data of PSG is not 
limited to major protocol 
deviation. 
Section 5.2.1 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objective ..........................................................................................7 
3.1.2 
Secondary Objectives .....................................................................................7 
3.1.3 
Exploratory Objectives ..................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................7 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ..............................................................................................9 
5.1 
Study Endpoints .......................................................................................................9 
5.1.1 
Primary Endpoint ...........................................................................................9 
5.1.2 
Secondary Endpoints .....................................................................................9 
5.1.3 
Exploratory Endpoints .................................................................................10 
5.2 
Study Subjects ........................................................................................................10 
5.2.1 
Definitions of Analysis Sets.........................................................................10 
5.2.2 
Subject Disposition ......................................................................................11 
5.2.3 
Protocol Deviations ......................................................................................11 
5.2.4 
Demographic and Other Baseline Characteristics .......................................12 
5.2.5 
Prior and Concomitant Therapy ...................................................................12 
5.2.6 
Treatment Compliance .................................................................................13 
5.3 
Data Analysis General Considerations ..................................................................13 
5.3.1 
Pooling of Centers........................................................................................13 
5.3.2 
Adjustments for Covariates..........................................................................13 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................13 
5.3.4 
Examination of Subgroups ...........................................................................13 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................13 
5.3.6 
Other Considerations ...................................................................................13 
5.4 
Efficacy Analyses ..................................................................................................14 
5.4.1 
Primary Efficacy Analyses ..........................................................................14 
5.4.2 
Secondary Efficacy Analyses ......................................................................14 
5.4.3 
Other Efficacy Analyses ..............................................................................15 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................15 
5.5.1 
Pharmacokinetic Analyses ...........................................................................15 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....15 
5.6 
Safety Analyses ......................................................................................................15 
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5.6.1 
Extent of Exposure .......................................................................................15 
5.6.2 
Adverse Events ............................................................................................15 
5.6.3 
Laboratory Values ........................................................................................16 
5.6.4 
Vital Signs ....................................................................................................17 
5.6.5 
Electrocardiograms ......................................................................................18 
5.6.6 
Other Safety Analyses ..................................................................................18 
5.7 
Other Analyses .......................................................................................................19 
5.8 
Exploratory Analyses .............................................................................................19 
5.9 
Extension Phase Analyses......................................................................................19 
6 
INTERIM ANALYSES ...................................................................................................20 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................20 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................20 
8.1 
Visit Window .........................................................................................................20 
8.2 
Baseline Assessment ..............................................................................................20 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................20 
9.1 
Pharmacokinetic Data Handling ............................................................................20 
9.1.1 
Lower Limit of Quantification of Lemborexant and its metabolites M4, 
M9, and M10 Plasma Concentration ...........................................................20 
9.1.2 
Below Limit of Quantification Handling for Calculating Summary 
Statistics of Lemborexant and its metabolites M4, M9, and M10 Plasma 
Concentration ...............................................................................................20 
9.1.3 
Handling of Anomalous Concentration Values ...........................................21 
9.1.4 
General Rules for Presentation of Drug Concentrations ..............................21 
10 STATISTICAL SOFTWARE ..........................................................................................21 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................21 
12 REFERENCES ................................................................................................................21 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AR 
autoregressive covariance matrix 
ATC 
anatomical therapeutic class 
BAI 
Beck Anxiety Inventory 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
EOS 
end of study  
FAS 
full analysis set 
IRLS 
International Restless Legs Scale 
ISI 
Insomnia Severity Index 
LEM5 
lemborexant 5 mg 
LEM10 
lemborexant 10 mg 
LLOQ 
Lower Limit of Quantification 
LPS 
latency to persistent sleep 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PBO 
Placebo 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PSG 
Polysomnography 
QTcF 
corrected QT interval by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard deviation 
SE 
sleep efficiency 
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Abbreviation 
Term 
SI 
Système International 
SDSB 
Sleep Disorder Screening Battery 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TIB 
time in bed 
TST 
total sleep time 
WASO 
wake after sleep onset 
WHO DD 
World Health Organization Drug Dictionary 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol 
E2006-J082-204.  
SAP is based on protocol (V4.0) (14-Sep-2023).  
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To evaluate, using polysomnography (PSG), the treatment difference between lemborexant 
5 mg (LEM5) and placebo (PBO) on latency to persistent sleep (LPS) on Day 30. 
3.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate, using PSG, the treatment difference between lemborexant 10 mg (LEM10) 
and PBO on LPS on Day 30 
• 
To evaluate, using PSG, the treatment difference between LEM5 and PBO on sleep 
efficiency (SE) on Day 30  
• 
To evaluate, using PSG, the treatment difference between LEM10 and PBO on SE on 
Day 30 
• 
To evaluate safety and tolerability of lemborexant following multiple doses 
• 
To evaluate the pharmacokinetics of lemborexant 
3.1.3 
Exploratory Objectives 
3.2 
Overall Study Design and Plan 
This study is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, 
parallel-group study in Korean subjects with insomnia disorder.  Subjects will be randomized 
to LEM5, LEM10 or PBO in a ratio of 2:2:1 and will receive study drug for 30 days. 
The study will consist of 2 phases:  Prerandomization Phase and Randomization Phase. 
The Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 
days:  a Screening Period, a Run-in Period, and a Baseline Period.  The Randomization Phase 
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4 
DETERMINATION OF SAMPLE SIZE 
The sample size was calculated with re-sampling simulation using Study 201 (E2006-G000-
201) data in order to power the study to detect point estimate of mean difference below a 
certain threshold with sufficient probability.  The certain threshold is defined as –0.44 as 
derived from the upper limit of 95% CI of pairwise difference between LEM5 and PBO for 
log(LPS) from Study 201.  Using the mean difference to PBO of log(LPS) in LEM5 from the 
baseline to Days 14/15 from each simulation (10,000 times) that using a grid search and 
assuming a 2:1 ratio (LEM5: PBO), demonstrated the difference < –0.44 could be achieved 
with more than 85% power.  It is assumed that the mean difference to PBO of log(LPS) in 
lemborexant groups from baseline to Day 30 in this study will be similar with those from 
baseline to Days 14/15 in Study 201.  When the number of subjects randomized to LEM5 
and PBO are 24 and 12, respectively, the number of subjects who complete with evaluable 
efficacy data will be 22 and 11, respectively.  Based on this evaluation, this study will 
provide power at 88.64% for comparing LEM5 and PBO.  Since LEM10 is set as a reference 
arm, therefore the sample size for LEM10 will be 24 as the same of LEM5 above. 
5 
STATISTICAL METHODS 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using SAS software or other validated statistical software as required. 
All descriptive statistics for continuous variables will be reported using number of 
observations (n), mean (arithmetic unless otherwise specified), standard deviation (SD), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum.  Categorical 
variables will be summarized as number and percentage of subjects. 
Treatment groups will be defined as PBO, LEM5, LEM10, and LEM total Treatment arms 
will be defined as PBO, LEM5, and LEM10. 
All statistical tests will be based on the 5% level of significance (two-sided).   
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
The primary endpoint will be change from baseline of LPS on Day 30 of LEM5 compared to 
PBO. 
5.1.2 
Secondary Endpoints 
Efficacy Endpoints  
• Change from baseline of LPS on Day 30 of LEM10 compared to PBO  
• Change from baseline of SE on Day 30 of LEM5 compared to PBO  
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• Change from baseline of SE on Day 30 of LEM10 compared to PBO 
Safety Endpoints  
• Safety and tolerability of lemborexant 
Other Endpoint 
• Plasma concentrations of lemborexant and its metabolites M4, M9, and M10 
 
5.1.3 
Exploratory Endpoints 
Efficacy Endpoints 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 dose of randomized 
study drug and had at least 1 postdose safety assessment. 
Full Analysis Set (FAS): The FAS is the group of randomized subjects who received at least 
1 dose of randomized study drug and had LPS data from the PSG on Day 30. 
Per Protocol (PP) Analysis Set: The PP Analysis Set is the FAS who received protocol-
assigned study drug and did not have a protocol deviation that is likely to affect the LPS data 
of PSG as follows.  
• 
Incorrect study drug kit dispensed 
• 
Protocol-assigned study drug not administered 
• 
Prohibited concomitant medication 
• 
Primary efficacy assessment out of window 
• 
Missing primary efficacy assessment 
• 
Duplicate randomization 
• 
Violated inclusion/exclusion criteria 
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PK Analysis Set: The PK analysis set is the group of subjects who had at least 1 quantifiable 
plasma concentration of lemborexant or its metabolites, with adequately documented dosing 
history. 
The number of subjects randomized, the number and the percentage of subjects included in 
each analysis set will be presented by each treatment group.  The reasons for exclusion from 
each analysis set will be summarized by each treatment group.  Subject listing of analysis set 
and reasons for exclusion from FAS, PP Analysis Set, PK Analysis Set and Safety Analysis 
Set will be provided. 
 
5.2.2 
Subject Disposition 
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized for all enrolled subjects (subjects who signed informed consent).  
Screen failure data will be listed.   
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination.  Subjects who prematurely discontinued from study treatment will also be 
presented and summarized by primary reason for premature treatment discontinuation.  Other 
reasons for study treatment and study terminations will also be summarized.  These 
tabulations will be produced for all randomized subjects by each treatment group. 
5.2.3 
Protocol Deviations 
Protocol deviations will be identified, reviewed and documented by the clinical team prior to 
database lock/treatment unblinding.  All protocol deviations will be categorized according to 
important/minor and standard classifications including but not limited to the following: 
• GCP-related deviations 
- 
Failure to obtain informed consent / ICF absent 
- 
Study-specific procedures / data captured before subject signed ICF 
• Eligibility criteria 
- 
Subject was enrolled while all inclusion criteria were not met. 
- 
Subject was enrolled while an exclusion criteria was met. 
• IMP deviations 
- 
Subject received less than 80% or more than 120% of the total number of doses that 
should have been administered in study period.  
• Prohibited concomitant medications / procedure 
- 
Subjects who received prohibited concomitant therapies and/or drugs in study 
protocol 9.4.7.2 during the study by the last dose of study drug. 
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Important protocol deviations will be summarized for category by each treatment group.  In 
addition, COVID-19 related deviations will also be summarized by each treatment group.  
Subject listing of important protocol deviation and COVID-19 related deviation will be 
provided. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, weight, and body mass index (BMI); categorical 
variables include sex (male and female), age group (< 65 years,   \HDUV), BMI group (< 
18.5, 18.5  25.0, 25.0  30.0,  30.0), and race. 
Characteristics of insomnia at Study Baseline will be summarized using LPS, SE WASO, 
TST from PSG ISI (items 1 to 7, 4 to 7), BDI-II, BAI, STOP Bang, and IRLS. 
5.2.4.1 
Medical History 
All medical histories as documented by the Medical History and Current Medical Conditions 
CRF will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
[Version 27.0]). 
The number and percent of subjects with medical history will be summarized by System Organ 
Class (SOC), preferred term for each treatment group based on Safety Analysis Set. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (WHO DD MAR24B3G). 
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Safety Analysis Set by each treatment group, Anatomical Therapeutic 
Chemical (ATC) class, and WHO DD preferred term (PT).  If a subject takes the same 
medications for the same class level or drug name, the subject will be counted only once for 
that class level or drug name. A separate summary will be provided for subjects who take 
concomitant medications during Run-in and Treatment Periods. All prior and concomitant 
medications and non-pharmacologic medications will be presented in subject data listings.  If 
the Safety Analysis Set and FAS differ substantially, then the prior and concomitant 
medication summaries will be repeated on the FAS. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug where study drug includes PBO during the Run-in Period. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and are continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  
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5.2.6 
Treatment Compliance 
Treatment compliance (in %) is defined as follows:   
100 x (total number of tablets dispensed - total number of tablets returned or lost)    
number of tablets expected to be taken  
Compliance during the Run-in and Treatment Periods will be summarized separately using 
descriptive statistics based on Safety Analysis Set Summaries will provide descriptive 
summary statistics and number (percentage) of subjects   WR  ! WR
 DQG !by each treatment group.  Subject listing of study drug compliance will 
be provided. 
5.3 
Data Analysis General Considerations 
The main analysis group for the primary endpoint is the FAS.  The efficacy analyses will be 
performed on the FAS except per protocol analysis which will be performed on the PP 
analysis set.  The values of each variable and the difference from baseline will be used for 
summary statistics by each visit and each treatment arm. 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
In the statistical models, baseline (log-transformation) of the efficacy variables will be 
applied as adjustment factor. 
5.3.3 
Multiple Comparisons/Multiplicity 
No multiplicity adjustment is planned for primary endpoint. 
5.3.4 
Examination of Subgroups 
No subgroup analysis will be performed. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
No imputation will be performed for missing data. 
5.3.6 
Other Considerations 
Not Applicable. 
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5.4 
Efficacy Analyses 
5.4.1 
Primary Efficacy Analyses 
The LPS change from baseline to Day 30 after log-transformed will be analyzed using 
analysis of covariance (ANCOVA), with treatment arms (PBO, LEM5, and LEM10) and 
baseline LPS (log-transformation) as fixed effects on the FAS.  Since LPS is known to be 
non-normally distributed, a log-transformation will be used in the analysis. 
The pairwise comparison of LEM5 compared to PBO will be applied in this analysis.  The 
least square (LS) means between LEM5 and PBO of change from baseline to Day 30 of LPS 
after log-transformed will be performed. The 95% confidence interval (CI) and P value of the 
treatment differences will be provided.  This is not confirmation study so that P value will be 
only a reference value. 
5.4.1.1 
Sensitivity Analysis 
The same primary efficacy analysis described in Section 5.4.1 will be repeated based on non-
log transformed data as a sensitivity analysis. 
5.4.1.2 
Supplemental Analysis 
PP analysis will be performed the same primary efficacy analysis described in Section 5.4.1 
based on PP analysis set. 
5.4.2 
Secondary Efficacy Analyses 
The pairwise comparison of LEM10 compared to PBO for LPS with log-transformed will be 
applied within the same model of primary efficacy analysis. The same analyses as the 
sensitivity and supplemental analyses for the primary efficacy analysis will also be 
conducted. 
The SE change from baseline to Day 30 of each active arm (LEM5 and LEM10) compared to 
PBO will be analyzed using ANCOVA, with treatment arms (PBO, LEM5, and LEM10) and 
baseline SE as fixed effects on the FAS.  The LS means between each active arm (LEM5 and 
LEM10) and PBO of change from baseline to Day 30.  The 95% CI and P value of the 
treatment differences will be provided. 
The SE described above will be repeated based on PP analysis set. 
Longitudinal plot for LPS and SE of median and LS geometric means or LS means for the 
changes from baseline will be presented by each treatment arm. 
Subject listing of individual visit results and averaged analysis results for PSG parameters 
(LPS and SE) will be provided. 
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5.4.3 
Other Efficacy Analyses 
Other efficacy analysis will be defined in 5.8 Exploratory Analyses. 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, 
and M10 plasma concentration listings.  The PK Analysis Set will be used for summaries of 
plasma concentrations of lemborexant and its metabolites M4, M9, and M10 by nominal 
sampling time and dose. 
5.5.1.1 
Plasma Concentration Analysis 
Plasma concentrations for lemborexant and its metabolites M4, M9, and M10 will be 
summarized using summary statistics (n, mean, SD, median, minimum, and maximum) by 
dose group, and nominal sampling time. 
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10 will be listed for 
each subject by dose group and actual sampling time. 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable.  
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables).  Safety variables include treatment-emergent adverse events (TEAEs), 
clinical laboratory parameters, vital signs, 12-lead ECG results.  Study Day 1 for all safety 
analyses will be defined as the date of the first dose of study drug. 
5.6.1 
Extent of Exposure 
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study 
drug will be summarized using descriptive statistics by treatment group.  Duration of 
exposure of study drug will be defined as the number of days between the date the subject 
received the first dose of study drug during Treatment Period and the date the subject 
received the last dose of study drug during Treatment Period, inclusive.  Subject listing of  
dosing and extent of exposure will be provided. 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the MedDRA.  Adverse events will be coded to the 
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MedDRA (Version 27.0) lower level term (LLT) closest to the verbatim term.  The linked 
MedDRA PT and SOC are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment (on or after the first dose of study 
drug up to 28 days after the subject’s last dose), having been absent at pretreatment 
(Baseline) or 
• Reemerges during treatment, having been present at pretreatment (before the Run-in 
Period) but stopped before treatment, or  
• Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized for Run-in Period and Treatment Period by treatment group 
separately.  The incidence of TEAEs will be reported as the number (percentage) of subjects 
with TEAEs by SOC and PT.  TEAEs by PT during Treatment Period will also be 
summarized by decreasing frequency.  A subject will be counted only once within a SOC and 
PT, even if the subject experienced more than 1 TEAE within a specific SOC and PT. The 
number (percentage) of subjects with TEAEs will also be summarized by maximum severity 
(mild, moderate, or severe). 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
and treatment-emergent non-SAEs will be summarized by MedDRA SOC and PT for each 
treatment group.  A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data 
listing of all AEs leading to discontinuation from study drug will be provided. 
5.6.3 
Laboratory Values 
Laboratory results except urinalysis parameters will be summarized using Système 
International (SI) units, as appropriate.  For all quantitative parameters listed in Section 
9.5.1.4.3 in protocol, the actual value for each visit (Screening, Day 1, Day 31, the end of 
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treatment and the end of study) and the change from baseline to Day 31, each postbaseline 
visit the end of treatment and the end of study will be summarized by visit and treatment 
group using descriptive statistics. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit, the end of treatment and the end of study.  Similar 
shift tables will also compare the baseline LNH classification to the LNH classification for 
the highest and lowest value during the Treatment period.
Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results. 
Appendix 1 in protocol (Sponsor’s Grading for Laboratory Values) presents the criteria that 
will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with 
an increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV is defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.  Percentages will be based 
on the number of subjects with both nonmissing baseline and relevant postbaseline results. 
Subject listing of laboratory results for hematology, chemistry, urinalysis, urine drug test and 
pregnancy test will be provided. 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit 
and treatment group. Analysis of changes from baseline will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results. 
In addition, clinically notable vital sign values will be identified using the criteria in Table 1.  
The clinically notable vital sign values will be summarized using frequency count at each 
visit by treatment group.  Subject listing of vital signs will be provided. 
Table 1 
Vital Sign Criteria 
 
Criterion valuea 
Change relative to 
baselinea 
Clinically notable range 
Heart rate 
! ESP 
Increase of 15 bpm 
H 
 
<50 bpm 
'HFUHDVH RI  ESP 
L 
Systolic BP 
! PP+J 
,QFUHDVH RI  PP+J 
H 
 
<90 mmHg 
'HFUHDVH RI  PP+J 
L 
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Table 1 
Vital Sign Criteria 
 
Criterion valuea 
Change relative to 
baselinea 
Clinically notable range 
Diastolic BP 
! PP+J 
,QFUHDVH RI  PP+J 
H 
 
<50 mmHg 
Decrease of  PP+J 
L 
Weight 
-- 
,QFUHDVH RI   
H 
 
-- 
'HFUHDVH RI  
L 
Respiratory Rate 
! ESP 
-- 
H 
 
< 10 bpm 
-- 
L 
BP = blood pressure, H = high, L = low. 
a. 
Clinically notable means that a value must meet the criterion value and must attain the specified magnitude 
of change relative to baseline. 
5.6.5 
Electrocardiograms 
ECG assessments will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3 in protocol).  Descriptive statistics for ECG parameters and 
changes from baseline will be presented by visit and treatment group. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) during the treatment period will be summarized.  Clinically 
abnormal ECG results in QTcF will be categorized as follows: 
Absolute QTcF interval prolongation: 
• QTcF interval ! PV 
• 47F) LQWHUYDO ! PV 
• 47F) LQWHUYDO !500 ms 
Change from baseline in QTcF interval: 
• 47F) LQWHUYDO LQFUHDVHV IURP EDVHOLQH ! ms 
• 47F) LQWHUYDO LQFUHDVHV IURP EDVHOLQH ! PV 
Subject listing of ECG will be provided. 
5.6.6 
Other Safety Analyses 
Not applicable. 
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6 
INTERIM ANALYSES 
No interim analysis is planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
Major changes of analysis plan between SAP version 1.0 to version 2.0 are listed in revision 
history. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Visit Window 
Study Day 1 is defined as the date of the first dose of study drug during the Treatment 
Period.  The nominal visit (ie, study visit captured on the CRF) will be used as the analysis 
visits in all by-visit summaries.  The Early Term visit will be considered as unscheduled visit 
and will not be included in the by-visit summary.  Where applicable, the Early Term visit 
will be used along with the Day 31 visit for completers as the End of Treatment visit for the 
safety analyses. 
8.2 
Baseline Assessment  
Unless otherwise specified, baseline measurement is the last observed measurement, 
including unscheduled assessments, prior to the first dose of study medication of treatment 
period for a given assessment. 
• ISI: Last available ISI measurement at Visit 1  
• BDI-II and BAI : Last available measurement at Visit 1 
• SDSB (STOPBang and IRLS) : Last available measurement at Visit 1 
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
9.1 
Pharmacokinetic Data Handling 
9.1.1 
Lower Limit of Quantification of Lemborexant and its metabolites M4, M9, 
and M10 Plasma Concentration 
The LLOQ of lemborexant and its metabolites M4, M9, and M10 are 0.0500 ng/mL. 
9.1.2 
Below Limit of Quantification Handling for Calculating Summary Statistics of 
Lemborexant and its metabolites M4, M9, and M10 Plasma Concentration 
When calculating the mean (or median) value for the concentration at a given time point, all 
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BLQ values are assigned as zero. 
 
9.1.3 
Handling of Anomalous Concentration Values 
Anomalous values are those that are inconsistent with known or expected PK behavior of the 
drug, but are not defined on the basis of statistical tests for outliers.  Individual concentrations 
deemed to be anomalous can be excluded from the summary statistics of Lemborexant and its 
metabolites M4, M9, and M10 Plasma Concentration.  Anomalous values are identified in the 
clinical study report (CSR).  Clear justification must be provided in the CSR for exclusion of 
any data. 
9.1.4 
 General Rules for Presentation of Drug Concentrations 
When presenting individual/raw values and summary statistics, the following rule will be 
applied: for drug concentrations, all summary statistics (mean, median, and SD) will have 3 
significant digits. 
Typical variable 
Standard 
Unit 
N 
Digit rule 
Raw 
Minimum 
Maximum 
Mean 
Median 
SD 
E2006 and its 
metabolites M4, M9, 
and M10 
concentration 
ng/mL 
X 
Significant 
digits 
3 
3 
3 
 
10 STATISTICAL SOFTWARE 
Analysis will be performed using SAS (release 9.4 or newer)  and Microsoft Excel (2010 or 
newer). 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings and graphs shells will be provided in a separate document, which will 
show the content and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
Not applicable. 
 
 
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2006-J082-204
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-
Group Study to Assess the Pharmacodynamics of Lemborexant in Korean 
Subjects with Insomnia Disorder
Date:
18 / Jan / 2023
Version:
Version 1.0
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................4
3
INTRODUCTION.........................................................................................................6
3.1
Study Objectives..................................................................................................6
3.1.1
Primary Objective ......................................................................................6
3.1.2
Secondary Objectives .................................................................................6
3.1.3
Exploratory Objectives...............................................................................6
3.2
Overall Study Design and Plan.............................................................................6
4
DETERMINATION OF SAMPLE SIZE.......................................................................9
5
STATISTICAL METHODS..........................................................................................9
5.1
Study Endpoints...................................................................................................9
5.1.1
Primary Endpoint .......................................................................................9
5.1.2
Secondary Endpoints..................................................................................9
5.1.3
Exploratory Endpoints..............................................................................10
5.2
Study Subjects ...................................................................................................10
5.2.1
Definitions of Analysis Sets......................................................................10
5.2.2
Subject Disposition...................................................................................11
5.2.3
Protocol Deviations ..................................................................................11
5.2.4
Demographic and Other Baseline Characteristics......................................11
5.2.5
Prior and Concomitant Therapy................................................................12
5.2.6
Treatment Compliance .............................................................................12
5.3
Data Analysis General Considerations................................................................12
5.3.1
Pooling of Centers....................................................................................13
5.3.2
Adjustments for Covariates ......................................................................13
5.3.3
Multiple Comparisons/Multiplicity...........................................................13
5.3.4
Examination of Subgroups........................................................................13
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................13
5.3.6
Other Considerations................................................................................13
5.4
Efficacy Analyses ..............................................................................................13
5.4.1
Primary Efficacy Analyses .......................................................................13
5.4.2
Secondary Efficacy Analyses ...................................................................13
5.4.3
Other Efficacy Analyses...........................................................................14
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................14
5.5.1
Pharmacokinetic Analyses........................................................................14
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....14
5.6
Safety Analyses..................................................................................................14
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5.6.1
Extent of Exposure...................................................................................14
5.6.2
Adverse Events.........................................................................................15
5.6.3
Laboratory Values ....................................................................................16
5.6.4
Vital Signs................................................................................................16
5.6.5
Electrocardiograms...................................................................................17
5.6.6
Other Safety Analyses ..............................................................................17
5.7
Other Analyses...................................................................................................18
5.8
Exploratory Analyses.........................................................................................18
5.9
Extension Phase Analyses..................................................................................18
6
INTERIM ANALYSES...............................................................................................18
7
CHANGES IN THE PLANNED ANALYSES ............................................................18
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................18
8.1
Visit Window.....................................................................................................18
8.2
Baseline Assessment..........................................................................................18
9
PROGRAMMING SPECIFICATIONS .......................................................................19
9.1
Pharmacokinetic Data Handling .........................................................................19
9.1.1
Lower Limit of Quantification of Lemborexant and its metabolites M4, 
M9, and M10 Plasma Concentration.........................................................19
9.1.2
General Rules for Presentation of Drug Concentrations ............................19
10
STATISTICAL SOFTWARE......................................................................................19
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................19
12
REFERENCES............................................................................................................19
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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
AR
autoregressive covariance matrix
ATC
anatomical therapeutic class
BAI
Beck Anxiety Inventory
BDI-II
Beck Depression Inventory - II
BMI
body mass index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
EOS
end of study 
FAS
full analysis set
LEM5
lemborexant 5 mg
LEM10
lemborexant 10mg
IRLS
International Restless Legs Scale
ISI
Insomnia Severity Index
LPS
latency to persistent sleep
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities
PBO
Placebo
PD
Pharmacodynamic
PK
Pharmacokinetic
QTcB
corrected QT interval by Bazett’s formula 
QTcF
corrected QT interval by Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SD
Standard deviation
SE
sleep efficiency
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Abbreviation
Term
SI
Système International
SMQ
Standardized MedDRA Queries 
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value
TIB
time in bed
TST
total sleep time
WASO
wake after sleep onset
WHO DD
World Health Organization Drug Dictionary
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3
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E2006-
J082-204.
SAP is based on protocol (V3.0) (29-Sep-2022).
3.1
Study Objectives
3.1.1
Primary Objective
To evaluate, using polysomnography (PSG), the treatment difference between lemborexant 
5 mg (LEM5) and placebo (PBO) on latency to persistent sleep (LPS) on Day 30.
3.1.2
Secondary Objectives
The secondary objectives of the study are:
•
To evaluate, using PSG, the treatment difference between lemborexant 10 mg (LEM10) 
and PBO on LPS on Day 30
•
To evaluate, using PSG, the treatment difference between LEM5 and PBO on sleep 
efficiency (SE) on Day 30
•
To evaluate, using PSG, the treatment difference between LEM10 and PBO on SE on 
Day 30
•
To evaluate safety and tolerability of lemborexant following multiple doses
•
To evaluate the pharmacokinetics of lemborexant
3.1.3
Exploratory Objectives
3.2
Overall Study Design and Plan
This study is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, 
parallel-group study in Korean subjects with insomnia disorder.  Subjects will be randomized 
to LEM5, LEM10 or PBO in a ratio of 2:2:1 and will receive study drug for 30 days.
The study will consist of 2 phases:  Prerandomization Phase and Randomization Phase.
The Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 
days:  a Screening Period, a Run-in Period, and a Baseline Period.  The Randomization Phase 
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will comprise a Treatment Period during which subjects will be treated for 30 nights, and a 
minimum 28-day Follow-up Period before an End of Study (EOS) Visit.
The estimated study duration for each subject on study is anticipated to be a maximum of 93
days consisting of the Screening Period plus Run-in Period plus Baseline Period maximum of 
35 days plus Treatment Period plus Follow-up Period and EOS Visit maximum of 58 days.  
A subject who completes the Treatment Period (assessments through discharge from the 
clinic on Day 31) will be considered to have completed the study.
An overview of the study design is presented in Figure 1.
Estimates for End of study are as follows:
•
The end of the study will be the date of the last study visit for the last subject in the study.
•
The estimated duration for each subject on study is anticipated to be a maximum of 93
days (12.7 weeks) consisting of the Screening Period plus Run-in Period plus Baseline 
Period maximum of 35 days plus Treatment Period plus Follow-Up Period and EOS Visit 
maximum of 58 days.  A subject who completes the Treatment Period (assessments 
through discharge from clinic on the morning of Day 31) will be considered to have 
completed the study.
An overview of the study design is presented in Figure 1.
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4
DETERMINATION OF SAMPLE SIZE
Sample size was calculated with re-sampling simulation using Study E2006-G000-201 data 
in order to power the study to detect point estimate of mean difference below a certain 
threshold with sufficient probability.  The certain threshold is defined as –0.44 as derived 
from the upper limit of 95% CI of pairwise difference between LEM5 and PBO for log(LPS) 
from Study 201.  Using the mean difference to PBO of log(LPS) in LEM5 from the baseline 
to Days 14/15 from each simulation (10,000 times) that using a grid search and assuming a 
2:1 ratio (LEM5:PBO), demonstrated the difference < –0.44 could be achieved with more 
than 85% power.  It is assumed that the mean difference to PBO of log(LPS) in lemborexant 
groups from baseline to Day 30 in this study will be similar with those from baseline to Days 
14/15 in Study 201.  When the number of subjects randomized to LEM5 and PBO are 24 and 
12, respectively, the number of subjects who complete with evaluable efficacy data will be 
22 and 11, respectively.  Based on this evaluation, this study will provide power at 88.64% 
for comparing LEM5 and PBO.  Since LEM10 is set as a reference arm, therefore the sample 
size for LEM10 will be 24 as the same of LEM5 above.
5
STATISTICAL METHODS
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using SAS software or other validated statistical software as required.
All descriptive statistics for continuous variables will be reported using number of 
observations (n), mean (arithmetic unless otherwise specified), standard deviation (SD), 
median, minimum and maximum.  Categorical variables will be summarized as number and 
percentage of subjects.  
All statistical tests will be based on the 5% level of significance (two-sided).  
5.1
Study Endpoints
5.1.1
Primary Endpoint
The primary endpoint will be change from baseline of LPS on Day 30 of LEM5 compared to 
PBO.
5.1.2
Secondary Endpoints
Efficacy Endpoints 
•
Change from baseline of LPS on Day 30 of LEM10 compared to PBO 
•
Change from baseline of SE on Day 30 of LEM5 compared to PBO 
•
Change from baseline of SE on Day 30 of LEM10 compared to PBO
Safety Endpoints 
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•
Safety and tolerability of lemborexant
Other Endpoint
•
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
5.1.3
Exploratory Endpoints 
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
Full Analysis Set (FAS): The FAS is the group of randomized subjects who received at least 
1 dose of randomized study drug and had LPS data from the PSG on Day 30.
Per Protocol (PP) Analysis Set: The PP Analysis Set is the FAS who received protocol-
assigned study drug and did not have a protocol deviation that is likely to affect the LPS data 
of PSG as follows. 
•
Incorrect study drug kit dispensed
•
Protocol-assigned study drug not administered
•
Prohibited concomitant medication
•
Primary efficacy assessment out of window
•
Missing primary efficacy assessment
•
Duplicate randomization
•
Violated inclusion/exclusion criteria
More details of the evaluability criteria will be determined before database lock and will be 
specified in revised SAP.
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PK Analysis Set: The PK analysis set is the group of subjects who had at least 1 quantifiable 
plasma concentration of lemborexant or its metabolites, with adequately documented dosing 
history.
The number of subjects randomized, the number and the percentage of subjects included in 
each analysis set will be presented by dose group and overall.
5.2.2
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination.  Subjects who prematurely discontinued from study treatment will also be 
presented and summarized by primary reason for premature treatment discontinuation.  Other 
reasons for study treatment and study terminations will also be summarized.  These 
tabulations will be produced for all randomized subjects by treatment group.
5.2.3
Protocol Deviations
Protocol deviations will be identified, reviewed and documented by the clinical team prior to 
database lock/treatment unblinding.  All protocol deviations will be categorized according to 
important/minor and standard classifications including but not limited to the following:
•
Failure to obtain informed consent / ICF absent
•
Study-specific procedures / data captured before subject signed ICF
•
Subject was enrolled while all inclusion criteria were not met.
•
Subject was enrolled while an exclusion criteria was met.
•
Subject received less than 80% or more than 120% of the total number of doses that 
should have been administered in study period.
Important protocol deviations will be summarized by category and treatment group.  
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, weight, and body mass index (BMI); categorical 
variables include sex, age group, BMI group, and race.
Characteristics of insomnia at Study Baseline will be summarized using LPS, SE and WASO
from PSG, ISI, BDI-II, BAI, Stop-BANG and IRLS.
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5.2.4.1
Medical History
All medical histories as documented by the Medical History and Current Medical Conditions 
CRF will be coded using the Medical Dictionary for Regulatory Activities (MedDRA
[Version 23.0 or higher]).
The number and percent of subjects with medical history will be summarized by System Organ 
Class (SOC), preferred term for each treatment group based on Safety Analysis Set.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (WHO DDE/HD Mar 
2018 or latest version).  The number (percentage) of subjects who took prior and concomitant 
medications will be summarized on the Safety Analysis Set by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and WHO DD preferred term (PT).  If the Safety 
Analysis Set and FAS differ substantially, then the prior and concomitant medication 
summaries will be repeated on the FAS. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug where study drug includes PBO during the Run-in Period.
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and are continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings.
5.2.6
Treatment Compliance
Treatment compliance (in %) is defined as follows:  
100 x (total number of tablets dispensed - total number of tablets returned or lost)   
number of tablets expected to be taken 
Compliance for each study drug will be calculated on the basis of number of tablets 
dispensed, lost and returned.  Summaries will provide descriptive summary statistics and 
number (percentage) of subjects below 80%, between 80% and 120%, and greater than 
120%.
5.3
Data Analysis General Considerations
The main analysis group for the primary endpoint is the FAS.    The efficacy analyses will be 
performed on the FAS except per protocol analysis will be performed on the PP analysis set.  
The each variables and the difference from baseline will be used for summary statistics by 
each visit and treatments.  Data will be plotted as appropriate.
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5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses.
5.3.2
Adjustments for Covariates
In the statistical models, baseline (log-transformation) of the efficacy variables will be 
applied as adjustment factor.
5.3.3
Multiple Comparisons/Multiplicity
No multiplicity adjustment is planned for primary endpoint.
5.3.4
Examination of Subgroups
No subgroup analysis will be performed.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
No imputation will be performed for missing data.
5.3.6
Other Considerations
Not Applicable.
5.4
Efficacy Analyses
5.4.1
Primary Efficacy Analyses
The LPS change from baseline to Day30 after log-transformed will be analyzed using 
analysis of covariance (ANCOVA), with treatment and baseline (log-transformation) as fixed 
effects on the FAS. The analysis will be modeled pairwise by the relevant treatment groups
for the comparison. Since LPS is known to be non-normally distributed, a log-transformation 
will be used in the analysis.
The pairwise comparison of LEM5 compared to PBO will be applied in this analysis. The 
least square (LS) means between LEM5 and PBO of change from baseline to Day30 of LPS 
after log-transformed will be performed. The 95% confidence interval (CI) and -p-value of 
the treatment differences will be provided. This is not confirmation study so that p-value will 
be only a reference value.
5.4.2
Secondary Efficacy Analyses
The pairwise comparison of LEM10 compared to PBO for LPS with log-transformed will be 
applied within the same model of primary efficacy analysis.
The SE change from baseline to Day30 of each active arm (LEM5 and LEM10) compared to 
PBO will be analyzed using ANCOVA, with treatment and baseline as fixed effects on the 
FAS. The analysis will be modeled pairwise by the relevant treatment groups for the 
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comparison. The LS means between each active arm (LEM5 and LEM10) and PBO of 
change from baseline to Day30. The 95% CI and -p value of the treatment differences will be 
provided. 
The LPS with log-transformed and SE described above will be repeated based on PP analysis 
set.
5.4.3
Other Efficacy Analyses
Other efficacy analysis will be defined in 5.8 Exploratory Analyses.
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, 
and M10 plasma concentration listings.  The PK Analysis Set will be used for summaries of 
plasma concentrations of lemborexant and its metabolites M4, M9, and M10 by nominal 
sampling time and dose.
5.5.1.1
Plasma Concentration Analysis
Plasma concentrations for lemborexant and its metabolites M4, M9, and M10 will be 
summarized using summary statistics (n, mean, SD, median, minimum, and maximum) by 
dose group, and nominal sampling time.
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10 will be listed for 
each subject by dose group and actual sampling time.
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable.
5.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables).  Safety variables include treatment-emergent adverse events (TEAEs), 
clinical laboratory parameters, vital signs, 12-lead ECG results.  Study Day 1 for all safety 
analyses will be defined as the date of the first dose of study drug.
5.6.1
Extent of Exposure
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study 
drug will be summarized using descriptive statistics by treatment group.  Duration of 
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exposure of study drug will be defined as the number of days between the date the subject 
received the first dose of study drug during Treatment Period and the date the subject 
received the last dose of study drug during Treatment Period, inclusive.  
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the MedDRA.  Adverse events will be coded to the 
MedDRA (Version 23.0 or higher) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA PT and SOC are also captured in the database.
A TEAE is defined as an AE that emerges during treatment (on or after the first dose of study 
drug up to 28 days after the subject’s last dose), having been absent at pretreatment 
(Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (before the Run-in 
Period) but stopped before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within a SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT. The number (percentage) of subjects with TEAEs will 
also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs)
and treatment-emergent non-serious adverse events (SAEs) will be summarized by MedDRA 
SOC and PT for each treatment group.  A subject data listing of all SAEs will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
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5.6.3
Laboratory Values
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3 in protocol, the actual value and the 
change from baseline to each postbaseline visit and to the end of treatment (defined as the 
last on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.4.3 in protocol will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 in protocol (Sponsor’s Grading for Laboratory Values) presents the criteria that 
will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with 
an increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as 
a postbaseline value with an increase from baseline to a grade of 3 or higher.  When 
displaying the incidence of TEMAVs, each subject may be counted once in the laboratory 
parameter high and in the laboratory parameter low categories, as applicable.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit 
and treatment group. Analysis of changes from baseline will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
In addition, clinically notable vital sign values will be identified using the criteria in Table 1.  
The clinically notable vital sign values will be summarized using frequency count at each 
visit by treatment group.  
Table 1
Vital Sign Criteria
Criterion valuea
Change relative to 
baselinea
Clinically notable range
Heart rate
>120 bpm
Increase of  15 bpm
H
<50 bpm
Decrease of  U15 bpm
L
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Table 1
Vital Sign Criteria
Criterion valuea
Change relative to 
baselinea
Clinically notable range
Systolic BP
>180 mmHg
Increase of  U20 mmHg
H
<90 mmHg
Decrease of U20 mmHg
L
Diastolic BP
>105 mmHg
Increase of U15 mmHg
H
<50 mmHg
Decrease of U15 mmHg
L
Weight
--
Increase of U7% 
H
--
Decrease of U7%
L
Respiratory Rate
>20 bpm
--
H
< 10 bpm
--
L
BP = blood pressure, H = high, L = low.
a.
Clinically notable means that a value must meet the criterion value and must attain the specified magnitude 
of change relative to baseline.
5.6.5
Electrocardiograms
ECG assessments will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3 in protocol).  Descriptive statistics for ECG parameters and 
changes from baseline will be presented by visit and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) during the treatment period will be summarized.  Clinically 
abnormal ECG results in QTcF will be categorized as follows:
Absolute QTcF interval prolongation:
•
QTcF interval >450 ms
•
QTcF interval >480 ms
•
QTcF interval >500 ms
Change from baseline in QTcF interval:
•
QTcF interval increases from baseline >30 ms
•
QTcF interval increases from baseline >60 ms
5.6.6
Other Safety Analyses
Not applicable.
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•
ISI: Last available ISI measurement at Visit 1
•
BDI-II and BAI : Last available measurement at Visit 1
•
SDSB (Stop-BANG and IRLS) : Last available measurement at Visit 1
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
9.1
Pharmacokinetic Data Handling
9.1.1
Lower Limit of Quantification of Lemborexant and its metabolites M4, M9, 
and M10 Plasma Concentration
The LLOQ of lemborexant and its metabolites M4, M9, and M10 are 0.0500 ng/mL.
9.1.2
General Rules for Presentation of Drug Concentrations
When presenting individual/raw values and summary statistics, the following rule will be 
applied: for drug concentrations, all summary statistics (mean, median, and SD) will have 3 
significant digits.
Typical variable
Standard 
Unit
N
Digit rule
Raw
Minimum
Maximum
Mean
Median
SD
E2006 and its 
metabolites M4, M9, 
and M10
concentration
ng/mL
X
Significant 
digits
3
3
3
10 STATISTICAL SOFTWARE
Analysis will be performed using SAS (release 9.4 or newer), Phoenix WinNonlin (version 
6.4 or newer), and Microsoft Excel (2010 or newer).
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study tables, listings and graphs shells will be provided in a separate document, which will 
show the content and format of all tables, listings, and graphs in detail.
12 REFERENCES
Not applicable.
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