A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study of the Efficacy and Safety of Lemborexant in Chinese Subjects With Insomnia Disorder
Phase: PHASE3
Conditions: Sleep Initiation and Maintenance Disorders
Sponsor: Eisai Co., Ltd.

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Revision History
Previous Version:  V5.0 (per Amendment 04)
Current Version:  V6.0 (per Amendment 05)
Date of Revisions:  28 Jun 2022
Change
Rationale
Affected Section(s)
Added conditional permission to use 
local laboratories for clinical 
laboratory tests instead of the central 
laboratory only when the central 
laboratory cannot be used due to an 
unavoidable reason (eg, lockdown).
To monitor the subject’s safety 
properly even in the case where the 
central laboratory cannot be used.

Section 9.5.1.5.3

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Previous Version:  V4.0 (per Amendment 03)
Current Version:  V5.0 (per Amendment 04)
Date of Revisions:  17 Sep 2020
Change
Rationale
Affected Section(s)
Added to evaluate Insomnia Severity 
Index (ISI) total number in Secondary
Objective
To evaluate insomnia severity

Synopsis–Objectives

Synopsis–Statistical 
Methods

Section 8.1

Section 9.7.1
Added time window for TEAEs
For clarification

Section 9.7.1.8.2
Revised date of birth to date of birth 
(or age) in demographic information 
For clarification

Section 9.5.1.1

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Previous Version:  V3.0 (per Amendment 02)
Current Version:  V4.0 (per Amendment 03)
Date of Revisions:  18 Jun 2020
Change
Rationale
Affected Section(s)
Add one annotation about adult age in
Taiwan in Inclusion Criteria 
To meet the requirement of Taiwan 
authority

Synopsis–Inclusion 
Criteria

Section 9.1

Section 9.3.1
Removed “child-resistant” in 
investigational products
Tablets will be packaged in regular 
blister cards.

Section 9.3.2
Revised volume of sample collection
For clarification

Table 2
Removed the number of subjects
(percentage)/events with TEAEs of 
cataplexy and related events from 
Safety Analysis Set
Per the deletion of Adjudication 
Committee

Section 9.7.1.8.2
The medical monitor assigned for this 
study has been changed.
Administrative change

Signature page

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Previous Version:  V2.0 (per Amendment 01)
Current Version:  V3.0 (per Amendment 02)
Date of Revisions:  12 Feb 2020
Change
Rationale
Affected Section(s)
Added moderate hepatic impairment
in Exclusion Criteria (#7)
Per the comments from FDA and 
PMDA.

Synopsis–Exclusion 
Criteria

Section 9.3.2
Removed alcohol consumption in 
electronic sleep diary
The alcohol consumption will only 
be self-reported by subjects

Synopsis-Assessments
Added Serum pregnancy test (β-hCG)
and Urine pregnancy test in Table 3
For clarity.

Table 3
Corrected a typo in Section 9.5.5
For clarity.

Section 9.5.2.1

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Previous Version:  V1.0 (original protocol)
Current Version:  V2.0 (per Amendment 01)
Date of Revisions:  11 Sep 2019
Change
Rationale
Affected Section(s)
Revised approximate number of sites 
from 20 to 30.
To facilitate study enrollment.

Synopsis–Sites

Section 6
Changed two study doses
(lemborexant 5 mg, 10 mg) to one 
study dose (lemborexant 10 mg).
See. Section 9.4.4.

Synopsis–Objectives

Synopsis–Study Design

Synopsis–Study 
Treatments

Section 9.1

Section 9.2

Section 9.4.4
Primary objective, changed from 
sSOL by sleep diary to LPS by PSG.
To incorporate feedback from 
regulatory China authority.

Synopsis–Objectives

Section 8.1
Revised secondary objectives and 
exploratory objectives.  Added 
change from baseline in BDI-II and 
BAI as exploratory objectives.
Per study objectives change and to 
explore the effects of treatment on 
BDI-II and BAI.

Synopsis–Objectives

Section 8.3
Revised total number of expected 
screened subjects from 1000 to 700.
To align with the revised study 
design and to reflect current screen
failure rate.

Synopsis–Number of 
Subjects

Section 9.3
Added inclusion criteria (#7 and #9) 
and exclusion criteria (#14) relating 
PSG.
To align with the revised primary 
objective (LPS by PSG).

Synopsis–Inclusion 
Criteria

Synopsis–Exclusion 
Criteria

Section 9.3.1

Section 9.3.2
Deleted Adjudication Committee.
This committee is not required for
China.

Synopsis–Study Design

Section 9.2
Added PSG in assessment.
To align with the revised primary 
objective.

Section 9.5.2.1
Revised statistical methods.
To align with revised primary 
objective, revised objectives, and 
one study dose.

Synopsis–Statistical 
Methods

Section 9.7.1
Revised sample size rationale.
To align with revised primary 
objective, revised objectives, and 
one study dose.

Synopsis–Sample Size 
Rationale

Section 9.7.2
Added updated information.
Add updated data of Study 303 and 
regulation.

Section 7.1

Section 7.2
Updated retention period
Per requirement of sponsor’s policy.

Section 11.6
Revised the detailed
Inclusion/Exclusion Criteria
Schedule.
For clarity.

Appendix 2

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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2006-J086-311
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study of the Efficacy and Safety of 
Lemborexant in Chinese Subjects with Insomnia Disorder
Sponsor:
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
JP
Investigational 
Product Name:
E2006/lemborexant
Indication:
Insomnia
Phase:
3
Approval Date:
V1.0
02 Aug 2018 (original protocol)
V2.0
V3.0
V4.0
V5.0
V6.0
11 Sep 2019 (per Amendment 01)
12 Feb 2020 (per Amendment 02)
18 Jun 2020 (per Amendment 03)
17 Sep 2020 (per Amendment 04)
28 Jun 2022 (per Amendment 05)
GCP Statement:
This study is to be performed in full compliance with China Good 
Clinical Practice (C-GCP) and all applicable 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, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study of the Efficacy 
and Safety of Lemborexant in Chinese Subjects with Insomnia Disorder
Investigators
TBD
Sites
Up to 30 sites in China mainland and Taiwan
Study Period and Phase of Development
24 months
Phase 3
Objectives
Primary Objective (revised per Amendment 01)
•
To confirm using polysomnography (PSG) that lemborexant 10 mg (LEM10) is superior to placebo (PBO) 
on objective sleep onset as assessed by latency to persistent sleep (LPS) during the last 2 nights of 1 month 
of treatment in subjects with insomnia disorder
Secondary Objectives (revised per Amendment 04)
•
To evaluate LEM10 compared to PBO on sleep efficiency as assessed by objective sleep efficiency (SE) 
during the last 2 nights of treatment
•
To evaluate LEM10 compared to PBO on sleep maintenance as assessed by objective wake after sleep 
onset (WASO) during the last 2 nights of treatment
•
To evaluate LEM10 compared to PBO on sleep maintenance as assessed by subjective sleep onset latency 
(sSOL), subjective sleep efficiency (sSE), subjective wake after sleep onset (sWASO) over the last 7 nights 
of 1 month of treatment
•
To evaluate the efficacy of LEM10 compared to PBO on sleep (LPS, WASO, SE) as measured by PSG 
during the first 2 nights of treatment
•
To evaluate the safety and tolerability of lemborexant
•
To evaluate the effect of lemborexant compared to PBO on insomnia severity and daytime functioning, as 
assessed by the Insomnia Severity Index (ISI)
•
To evaluate rebound insomnia following completion of treatment with lemborexant 
•
To evaluate morning residual sleepiness during treatment and following completion of treatment with 
lemborexant
Exploratory Objectives (revised per Amendment 01)
•
To explore the effects of LEM10 and PBO on subjective quality of sleep
•
To evaluate the effects of LEM10 and PBO on sleep architecture
•
To explore the effects of LEM10 and PBO on Beck Depression Inventory-II (BDI-II) and Beck Anxiety 
Inventory (BAI)
•
To summarize plasma concentrations of lemborexant and its metabolites M4, M9, and M10

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Study Design
E2006-J086-311 is a multicenter, randomized, double-blind, PBO-controlled, parallel-group study of 
lemborexant 10 mg for 30 nights in Chinese subjects (age 18 years or older) who have insomnia disorder.
(revised per Amendment 01)
The study will have 2 phases: the Prerandomization Phase and the 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 14-day Follow-Up Period before an End of Study 
(EOS) Visit.
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will undergo routine safety 
assessments at specified visits, including questioning regarding adverse events (AEs), 12-lead
electrocardiogram (ECG), vital signs, weight, height (once at Visit 1), clinical hematology and chemistry 
analysis and urinalysis.  At each visit from Screening to the EOS Visit, subjects will also undergo a urine drug 
screen.
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At the first 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 will be 
conducted, and will include confirmation that the subject meets diagnostic criteria for insomnia disorder, and 
further, that the subject complains of difficulties with sleep onset, sleep maintenance and/or early morning 
awakening. Screening assessments will include the ISI, as well as the BDI-II and BAI, STOPBang and 
International Restless Legs Scale (IRLS), collectively called the Sleep Disorders Screening Battery (SDSB).
All eligible subjects will be provided with an electronic device on which they will complete the sleep diary.  
Subjects will be trained in the use of this device.  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.  The sleep 
diary entries will be reviewed by site staff at least weekly throughout the study to ensure subject compliance 
with completion of the sleep diary and to ensure that study restrictions are met pertaining to duration of time 
spent in bed.  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, provided that the sleep diary 
entries indicate continued eligibility with regard to sleep timing, duration of time spent in bed, and frequency of 
nights with symptoms of insomnia, subjects will undergo the second Screening Visit (Visit 2a). (Subjects who 
are not eligible based on sleep diary entries will return to the clinic for debriefing purposes and to return study 
equipment.) This visit must occur between Day –18 and Day –12. On this and all nights on which PSG is 
recorded, subjects will arrive at the clinic in the evening with sufficient time before bedtime to complete check-
in procedures, any scheduled assessments, and preparations (eg, electrode montage placement) for the PSG 
recordings. 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). The PSG will be reviewed for inclusion criteria related to the presence of insomnia and absence of 
symptoms of sleep apnea and/or 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. (revised per Amendment 01)
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.

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When subjects have completed the sleep diary on at least 7 consecutive mornings during the Run-in Period, the 
diary will be reviewed for continued eligibility. Subjects who are still eligible will return to the clinic for the 
first of 2 consecutive nights on which PSG will be recorded. The first of these 2 nights must be between Day –
10 and Day –4. In the evening, before the PSG recording, the safety assessments will be conducted. 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 second Screening Visit. Subjects will undergo an 8-hour PSG. The 
next morning, subjects will complete the sleep diary. The PSG recording will be reviewed for continued 
eligibility and subjects may then leave the clinic only after the investigator determines that it is safe for them to 
do so. Subjects will return to the clinic that evening. Study personnel will administer study drug to subjects 
approximately 5 minutes before the scheduled bedtime. A PSG will be recorded overnight. The following 
morning subjects will complete the sleep diary. The PSG recording will be reviewed for continued eligibility, 
and both PSGs during the Run-in Period will also serve as the baseline 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 and they 
will continue to complete the sleep diary each morning within 1 hour after morning wake time. 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.  Urine 
drug test will be performed as described in Section 9.5.2. (revised per Amendment 01)
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, and the ISI will be administered. Blood and urine samples will be collected for routine safety 
assessments, an ECG will be performed, and vital signs and weight will be assessed. In addition, subjects 
should undergo a urine drug test. Subjects who complete the Baseline Period and continue to meet the 
eligibility criteria will be randomized, and will begin the Treatment Period.  (revised per Amendment 01)
Treatment Period
The Treatment Period will begin on Day 1 and will continue until Day 31.  Subjects will be randomized in a 
double-blind manner, to receive LEM10, or PBO. (revised per Amendment 01)
On the evening of Day1, approximately 5 minutes before the subject’s MHB, study drug will be administered 
and an 8-hour overnight PSG will be initiated. At completion of the PSG recording the following morning 
(Day 2), subjects will complete the sleep diary. They may leave the clinic after the investigator determines that 
is safe for them to do so. On the evening of Day 2, subjects will return to the clinic. A PK blood sample will 
be collected predose and study drug will be administered approximately 5 minutes before the subject’s MHB, 
followed by an overnight PSG. On the morning of Day 3, a PK sample will be obtained and subjects will 
complete the sleep diary. Subjects may then leave the clinic after the investigator determines that it is safe for 
them to do so. Study drug will be dispensed and subjects will be provided with instructions to continue 
completing the sleep diary each morning within 1 hour of waketime and taking study drug daily at home 
according to the same schedule and with the same instructions as during the Run-in Period. On Day 29, 
subjects will return to the clinic. Study drug will be administered approximately 5 minutes before the subject’s 
MHB, followed immediately by a PSG. On the morning of Day 30, subjects will complete the sleep diary, and 
may leave the clinic after the investigator determines that it is safe for them to do so.  On the evening of Day 
30, subjects will return to the clinic. A PK blood sample will be collected predose and study drug will be 
administered approximately 5 minutes before the subject’s MHB, followed by a PSG. On the morning of Day 
31, a PK sample will be obtained. Subjects will complete the sleep diary. Then the ISI, BDI-II and BAI will be 
administered. Blood and urine samples will be collected for routine safety assessments. An ECG will be 
performed, and vital signs and weight will be assessed. Then, after the investigator determines that it is safe for 
them to do so, subjects will be discharged from the clinic.  Urine drug test will be performed as described in 
Section 9.5.2. (revised per Amendment 01)
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 but will continue to complete the sleep diary each morning until the EOS 
Visit.
At least 14 days but no more than 18 days after completion of the Treatment Period, subjects will return to the 
clinic for the EOS Visit.  At the EOS Visit, in addition to standard safety assessments, a urine drug test will be 

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conducted, and sleep diaries will be collected.  After the EOS 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 beginning from the time the subject signs the 
study informed consent form (ICF) through the last visit. All AEs must be followed for 28 days after the 
subject’s last dose, or until resolution, whichever comes first. In addition, subjects who withdraw due to an AE 
should undergo a urine drug test.
Additional Study Information
The estimated duration for each subject on study is anticipated to be a maximum of 89 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 54 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.
Number of Subjects
For overall subjects, approximately a total of 700 subjects will be screened to provide approximately 188 
overall randomized subjects. Subjects will be randomized to one of the following treatment arms: LEM10, 
PBO, in an approximate 1:1 ratio.  (revised per Amendment 01)
Inclusion Criteria
1.
Chinese male or female, age 18 years or older, at the time of informed consent (in Taiwan only subjects 
with age 20 years or older are eligible) (revised per Amendment 03)
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for 
Insomnia Disorder, as follows:
-
Complains of dissatisfaction with nighttime sleep, in the form of 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
-
Associated with complaint of daytime impairment
3.
At Screening:  History of sSOL ≥30 minutes on at least 3 nights per week in the previous 4 weeks 
AND/OR sWASO ≥60 minutes on at least 3 nights per week in the previous 4 weeks
4.
At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours
5.
At second Screening Visit (Visit 2a) and Run-in Visit (Visit 3a): Sleep diary confirms regular bedtime, 
defined as the time the subject attempts to sleep, between 21:00 and 01:00 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 10:00 
on at least 5 of the final 7 nights  (revised per Amendment 01)
6.
At Screening and Baseline: ISI score ≥15  (revised per Amendment 01)
7.
Confirmation of current insomnia symptoms, as determined from responses on the sleep diary on the 7 
most recent mornings before the first PSG during Screening Period (Visit 2a) and Run-in visit (Visit 3a), 
such that sSOL ≥30 minutes on at least 3 of the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 7 
nights  (revised per Amendment 01)
8.
At the second Screening Visit (Visit 2a) and the Run-in visit (Visit 3a):  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 Visit, such that there are no more than 2 nights with time spent in bed duration <7 hours or >10 hours  
(revised per Amendment 01)
9.
During the Run-in Period, objective (PSG) evidence of insomnia as follows:
a.
LPS average ≥30 minutes on the 2 consecutive baseline PSGs, with neither night <20 minutes and/or

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b.
WASO average ≥60 minutes on the two consecutive baseline PSGs, with neither night <45 minutes
(revised per Amendment 01)
10. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours 
each night
11. Willing not to start a behavioral or other treatment program for the treatment of insomnia during the 
subject’s participation in the study
Exclusion Criteria
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-
human chorionic gonadotropin [β-hCG] test). A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first 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 be on a stable dose of the same oral contraceptive product for 
at least 28 days before dosing and 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 Screening
6.
Any suicidal behavior in the past 10 years
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. (revised per Amendment 02) Subjects for whom a sedating drug 
would be contraindicated for safety reasons because of the subject’s occupation or activities are also 
excluded
8.
Hypersensitivity to lemborexant or to their excipients
9.
Scheduled for surgery during the study

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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

IRLS ≥16
14. Apnea-Hypopnea Index >15 or Periodic Limb Movement with Arousal Index >15 as measured on the PSG 
at the second Screening Visit  (revised per Amendment 01)
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 18 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. Excluding 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 first dose of study medication (Run-in Period). (A list of prohibited 
concomitant medications is presented in Appendix 3 of protocol)
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 first 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  (revised per 
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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 more than 3 time zones during the study (China mainland will be 
considered as 1 time zone)  (revised per Amendment 01)
28. A positive drug test at Screening, Run-in, or Baseline, or unwilling to refrain from use of recreational drugs 
during the study
29. 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
30. Previously participated in any clinical trial of lemborexant
Study Treatments
Test drug:
Lemborexant 10 mg, 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  (revised per 
Amendment 01)
Run-in Period
All subjects will receive 1 lemborexant matched PBO in a single blind manner during the Run-in Period 
approximately 5 minutes before the time the subject intends to try to sleep.  (revised per Amendment 01)
Treatment Period
All subjects will receive 1 tablet as described below, according to the treatment arm to which the subject has 
been randomized:  (revised per Amendment 01)
•
LEM10: 1 lemborexant 10 mg tablet
•
PBO: 1 placebo tablet matched to lemborexant 10 mg
Duration of Treatment
A maximum of approximately 7.5 weeks:   Up to 17 days of PBO during the Run-in Period, up to 35 days of 
randomized treatment.
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.  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.  (revised per Amendment 01)
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. A drink will be defined as 285 mL of beer, 150 mL of wine, or 25 mL 
of liquor.  Subjects must not consume any alcohol on days when they are scheduled for a PSG recording.  
(revised per Amendment 01)
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 medication (Run-in Period).
Prohibited medications include moderate and strong cytochrome P450 (CYP3A) inhibitors and all CYP3A 
inducers. (revised per Amendment 01) 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 
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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 will not be permitted at any time for any duration during the study.  (revised per Amendment 
01)
Assessments
Screening Assessments (administered only at first Screening Visit)
SDSB
The SDSB will include the:
•
StopBANG:  a list of eight questions to be answered Yes or No, which screens subjects for obstructive sleep 
apnea
•
IRLS:  a subjective scale comprising ten questions, which measures severity of symptoms of restless legs 
syndrome
Efficacy Assessments
PSG (revised per Amendment 01)
Each PSG recording will include an electrode montage with electroencephalography (EEG), electromyography 
(EMG), electrooculography, and ECG channels, for scoring of sleep parameters and sleep architecture via 
standard sleep scoring criteria. In addition, the first PSG will include channels for assessment of symptoms of 
sleep apnea and periodic limb movement disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard criteria. The PSG at the 
second Screening Visit will be used only to calculate the Apnea-Hypopnea Index and the Periodic Limb 
Movements with Arousal Index for evaluation of eligibility criteria; sleep parameters and sleep architecture will 
not be evaluated from this PSG. The 2 PSGs obtained during the Run-in Period will be used to a) determine 
eligibility and b) derive baseline PSG parameters for those subjects who are randomized.
All PSG parameters will be obtained separately for each PSG recording and averaged across the pairs of 
consecutive PSG nights.
The following parameters will be derived from all PSGs:
•
LPS: minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness
•
SE: proportion of time spent asleep per time in bed (TIB), calculated as total sleep time (TST)/interval from 
lights off until lights on
•
WASO: minutes of wake from the onset of persistent sleep until lights on
•
TST: minutes of sleep from sleep onset until terminal awakening
•   Mean duration of long awakenings (DurLongAw):  average duration of all long awakenings (with long 
awakening defined as 10 or more consecutive epochs [ie, 5 minutes or longer] scored as wake or N1, 
initiated with at least one epoch of wake, after onset of persistent sleep, and including any terminal 
awakening)
Additional sleep architecture parameters will be also calculated from each PSG, including:
•
Sleep onset latency: minutes from lights off to the first epoch of any stage of sleep (N1, N2, N3, rapid eye
movement [REM])
•
Number of awakenings after persistent sleep, with an awakening defined as at least 2 consecutive epochs of 
wakefulness; an awakening could not be interrupted by stage N1, but must have been interrupted by stage 
N2, N3, or REM
•
Number of long awakenings (with long awakening defined as 10 or more consecutive epochs [ie, 5 minutes 
or longer] scored as wake or N1, initiated with at least 1 epoch of wake, after onset of persistent sleep, and 
including any terminal awakening)
•
Percentage of stage wake and sleep stages per TIB: wake, non-REM (NREM) sleep (stages N1, N2, N3 
separately and combined), REM sleep
•
Minutes of sleep stages per TIB: wake, NREM sleep (stages N1, N2, N3), REM sleep

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•
Percentage of sleep stages per TST: NREM sleep (stages N1, N2, N3 separately and combined), REM sleep
•
Minutes of sleep stages per TST: NREM sleep (stages N1, N2, N3), REM sleep
•
REM episode frequency and duration
•
Mean REM/NREM cycle duration
•
REM latency: minutes from first epoch of sleep (N1, N2, or N3) to first epoch of REM
Each of these PSG-derived variables, with the exceptions of SE, REM episode frequency and duration, mean 
REM/NREM cycle duration, and REM latency, will also be calculated by hour and by half of the 8-hour time 
interval in bed.
Electronic Sleep Diary
The sleep diary will be completed within an hour of morning waketime on each morning of the study from 
Screening through the end of the study.  Sleep diary entries may be maintained in paper format as a backup to 
the electronic sleep diary, if necessary.  This sleep diary will yield several self-reported measures of sleep that 
will be used to determine eligibility, as well as to assess efficacy and safety.  In addition, the sleep diary will 
include questions that relate to morning sleepiness.
Sleep Parameters:
•
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 total sleep time (sTST):  derived minutes of sleep from sleep onset until the time the subject 
stopped trying to sleep for the night
•
sSE:  proportion of sTST per subjective time spent in bed, calculated as the interval from the time the 
subject reported attempting to sleep until the time the subject stopped trying to sleep for the night, and time 
spent asleep derived from subjective time spent in bed minus sWASO
Sleep architecture parameters will be calculated as described above under assessments. (revised per 
Amendment 01)
Quality of Sleep and Morning Sleepiness
The sleep diary will be used to assess the subject’s global perception of quality of sleep on the previous night 
with the following question: “How would you rate the quality of your sleep last night?”  Subjects will rate the 
quality of their sleep on a scale from 1 to 9, with 1 being extremely poor and 9 being extremely good. 
The sleep diary will be used to assess subjective ratings of morning sleepiness with the following question: 
“How sleepy/alert do you feel this morning?” Subjects will rate their sleepiness/alertness level on a scale from 1 
to 9, with 1 being extremely sleepy and 9 being extremely alert.
Insomnia Severity Index 
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 (revised per Amendment 01)
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.  Subjects with BDI-II scores 
>19 will be excluded from participation.
BAI  (revised per Amendment 01)
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.  Subjects with scores on the BAI >15 will 
be excluded from participation.
Pharmacokinetic Assessments

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A single blood sample for plasma concentrations of lemborexant and its metabolites M4, M9 and M10 will be 
taken at predefined visits.  The time and date of the 2 most recent lemborexant doses administered before each 
sample will be documented.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable 
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse events (SAEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of vital signs, 
weight and ECGs; and the performance of physical examinations.  Safety will be assessed at every clinic visit 
throughout the study, including after the last dose of study drug, and at the EOS, ET, and Unscheduled Visits.
Bioanalytical Methods
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10), will be measured using 
validated liquid chromatography-tandem mass spectrometry assay methods.
Statistical Methods
All statistical tests will be based on the 5% level of significance (2-sided).
Study Endpoints
Primary Endpoint (revised per Amendment 01)
•
Change from baseline of objective LPS during the last 2 nights of 1 month of treatment of LEM10
compared to PBO
Secondary Endpoints (revised per Amendment 04)
•
Change from baseline of objective SE during the last 2 nights of 1 month of treatment of LEM10 compared 
to PBO
•
Change from baseline objective WASO during the last 2 nights of 1 month of treatment of LEM10
compared to PBO
•
Change from baseline of sSOL during the last 7 nights of 1 month of treatment of LEM10 compared to PBO
•
Change from baseline of sSE during the last 7 nights of treatment of LEM10 compared to PBO
•
Change from baseline of sWASO during the last 7 nights of treatment of LEM10 compared to PBO
•
Change from baseline of PSG parameters (LPS, SE, WASO) over the first 2 nights of 30 nights of LEM10
compared to PBO
•
Safety and tolerability of lemborexant
•
Change from Study Baseline in insomnia severity and daytime functioning, assessed as the total score and 
from the 4 items related to daily function on the ISI after 1 month of treatment with LEM10 compared to 
PBO
•
Rebound insomnia endpoints as assessed from the sleep diary during the Follow-Up Period
•
Morning residual sleepiness during treatment and following completion of treatment
Exploratory Endpoints (revised per Amendment 01)
•
Subjective quality of sleep
•
Sleep architecture
•
Effects on Beck Depression Inventory–II and Beck Anxiety Inventory
•
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
Analysis Sets
•
The Safety Analysis Set is the group of randomized subjects who received at least 1 dose of randomized 
study drug and had at least 1 postdose safety assessment.
•
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose efficacy measurement.

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•
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with the protocol.  
Details of the evaluability criteria will be determined before database lock and treatment unblinding will be 
specified in the Statistical Analysis Plan (SAP).
•
The PK Analysis Set is the group of subjects who received at least 1 dose of randomized study drug and had 
at least one quantifiable plasma concentration of lemborexant or its metabolites, with adequately 
documented dosing history.
Efficacy Analyses
The efficacy analyses will be performed on the FAS except per protocol analysis will be performed on the PP.  
(revised per Amendment 01)
Definitions of Baseline
Baseline data are captured during the Run-in and Baseline Period. 
Analysis for the Primary Endpoint (revised per Amendment 01)
Null Hypothesis: For objective LPS, no difference exists in the mean change from Study Baseline to the last 2 
nights of Month 1 of treatment with LEM10 compared with PBO.
Alternative Hypothesis: For objective LPS, a difference exists in the mean change from Study Baseline to the 
last 2 nights of Month 1 for LEM10 compared with PBO.
The objective LPS change from Baseline (the mean of Days 1 and 2, and the mean of Day 29 and 30) will be 
analyzed using the mixed effect model repeated measurement analysis (MMRM) on the FAS. The model will 
include all data and will be adjusted for the corresponding baseline value (the means from the 2 PSG recordings 
during the Run-in Period), site, age group (<65 years old; ≥65 years old), treatment, time (Days 1/2, and Days 
29/30), and the interaction of treatment by time. Since LPS is known to be non-normally distributed, a log-
transformation will be used in the analysis.  Factor “Site” will be defined in the SAP before database lock. An 
unstructured covariance matrix will be used, and if the model fails to converge, then an autoregressive matrix 
will be used. The missing values will be imputed using a pattern mixture model utilizing multiple imputations 
(MI) assuming the missing values are missing not at random (MNAR) utilizing the complete case missing value 
pattern (CCMV-subjects who completed primary efficacy assessments without missing values).  The missing 
values for a given visit will be imputed using all available values including the retrieved measurement from the 
post-discontinuation data. The P-value, least square (LS) means and the 95% confidence interval (CI) for the 
treatment difference will also be provided.
Subgroup analyses and additional sensitivity analysis will be performed as appropriate.
The following analyses will be considered as sensitivity analyses:
•
PP analysis: The same primary efficacy analyses described above will be repeated based on PP analysis set.
•
Completer analysis: The same primary efficacy analyses described above will be repeated on subjects who 
completed all efficacy assessments and have no missing values.
•
As-treated analysis: The same primary efficacy analyses (MMRM analysis with MI for missing value 
imputation) will be repeated based on the actual treatment the subject received regardless of randomization.
•
MMRM analysis assuming missing at random (MAR): The same primary endpoint analysis described above 
will be analyzed using MMRM assuming the missing values are MAR.
•
MI Imputation assuming MNAR utilizing CCMV-4: The same MMRM method used in the primary analysis 
will be applied utilizing CCMV-4 (ie, up to 4 monotone missing patterns will be used for missing value 
imputation as follows)
Study days where results are available
1
2
29
30
Pattern 1
x
x
x
x
Pattern 2
x
x
x
–
Pattern 3
x
x
–
–
Pattern 4
x
–
–
–
x: result present; – : result missing
Secondary Efficacy Analysis (revised per Amendment 04)

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The other efficacy endpoints (change from Baseline of the following for LEM10 compared to PBO; mean 
objective SE, mean objective WASO, mean sSOL, mean sSE, and mean sWASO at the first 7 nights and last 7 
nights of treatment; ISI total number and total score of 4 items of daytime functioning after 1 month of 
treatment) will be analyzed using the MMRM, assuming the missing values are MAR.  The sSOL will be 
implemented on the log-transformation.
Subgroup analyses will be defined SAP in detail.
Rebound insomnia is defined as worsened sleep relative to Screening after study drug treatment is completed. 
Sleep diary data from the Follow-Up Period will be compared to sleep diary data from the Screening Period to 
assess whether subjects experience rebound insomnia. To assess rebound insomnia, both categorical analysis at 
the subject level and continuous analysis at the group mean level will be performed. For each of the first 3 
nights and each of the 2 weeks of the Follow-Up Period the proportion of subjects whose corresponding value 
for sSOL or sWASO exceeds the corresponding Screening Period value by 5 minutes will be summarized by 
treatment group and compared to PBO. The percentage of ‘rebounders’ between LEM10 and PBO group will 
be analyzed using a chi-square test.  To assess statistical significance using the continuous data, the data will be 
analyzed using analysis of covariance (ANCOVA). The LS mean of each of the first 3 nights and each week of 
the Follow-Up Period will be compared to the Screening Period between LEM10 and PBO. If the lower bound 
of the 95% CI of sSOL or sWASO for each of the first 3 nights and the mean of each week of the Follow-Up 
Period exceeds the upper bound of a 95% CI for the values during the Screening Period in the given treatment 
group, it will be considered strong evidence for rebound insomnia. If the LS means for sSOL and sWASO for 
the Follow-Up Period are all lower than for the Screening Period, then no rebound insomnia is suggested. 
Otherwise, the degree to which the parameters worsen, and the time point(s) at which they worsen will be 
considered to evaluate whether clinically meaningful rebound insomnia is present.
To evaluate morning residual sleepiness during study treatment and following completion of treatment, the 
change from baseline of the mean of morning sleepiness item on the sleep diary for the first 7 mornings of the 
Treatment Period, the last 7 mornings of the Treatment Period, as well as the means of the first 7 days and 
second 7 days of the Follow-Up Period will be analyzed using MMRM assuming MAR.
Exploratory Efficacy and Pharmacodynamic Analyses  
The change from Baseline for the mean score of the quality of sleep item on the sleep diary will be analyzed, to 
consider the subjective quality of sleep, using MMRM, assuming MAR for the mean of the first 7 days after 1 
month of treatment.  The change from Baseline (at Screening) for BDI-II and BAI will be analyzed using 
ANCOVA including treatment and Baseline.  Other efficacy measures will be tabulated, and may be plotted, 
but will not be statistically analyzed.
Pharmacokinetic Analysis
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 lemborexant and its metabolites M4, 
M9, and M10 plasma concentrations by dose.
Safety Analyses
Evaluations of safety will be performed on the relevant Safety Analysis Set. The incidence of AEs, out-of-
normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs and weight, 
along with change from baseline in laboratory safety test variables, ECGs, and vital sign and weight 
measurements, will be summarized by treatment group using descriptive statistics.
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed by modeling 
methods if warranted.
Details of all of analysis will be specified in the SAP.
Interim Analyses (revised per Amendment 01)
This is a fixed design.  There is no interim analysis for efficacy and no alpha spending before final analysis.  
However a blinded sample size re-estimation through estimated standard deviation based on blinded data prior 
to the completion of enrollment, may be performed if there is an indication that sample size assumptions need 
to be changed.  This blinded sample size re-estimation could be performed based on signals from external 
studies or based on review of blinded data from this study prior to completion of enrollment.

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Sample Size Rationale (revised per Amendment 01)
The sample size was considered based on LPS for each comparison between Study 201(E2006-G000-201) and 
Study 304 (E2006-G000-304).  For LEM10 on Days 29 and 30, we assume the effect size that mean difference 
divided by common standard deviation as –0.411 under logarithm transformation.  Therefore, to detect a 
difference in LPS comparing LEM10 with PBO, at least 94 subjects per group (total 188) will be needed for a 
0.05 α-level, 2-sided test and more than 80% power based on above assumption.

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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................20
5
ETHICS.......................................................................................................................23
5.1
Institutional Review Boards/Independent Ethics Committees.............................23
5.2
Ethical Conduct of the Study..............................................................................23
5.3
Subject Information and Informed Consent ........................................................24
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................24
7
INTRODUCTION.......................................................................................................25
7.1
Indication...........................................................................................................25
7.1.1
Current Therapeutics Options ...................................................................25
7.1.2
Lemborexant (E2006)...............................................................................25
7.1.2.1
Mechanism of Action........................................................................25
7.1.2.2
Clinical Experience With Lemborexant.............................................26
7.1.2.2.1
Phase 1 .......................................................................................26
7.1.2.2.2
Phase 2 .......................................................................................28
7.1.2.2.3
Phase 3 .......................................................................................28
7.2
Study Rationale..................................................................................................29
8
STUDY OBJECTIVES................................................................................................30
8.1
Primary Objective (revised per Amendment 01).................................................30
8.2
Secondary Objectives (revised per Amendment 04) ...........................................30
8.3
Exploratory Objectives (revised per Amendment 01) .........................................31
9
INVESTIGATIONAL PLAN ......................................................................................31
9.1
Overall Study Design and Plan...........................................................................31
9.1.1
Prerandomization Phase ...........................................................................33
9.1.1.1
Screening Period...............................................................................33
9.1.1.2
Run-In Period ...................................................................................33
9.1.1.3
Baseline Period.................................................................................34
9.1.2
Randomization Phase ...............................................................................34
9.1.2.1
Treatment Period ..............................................................................34
9.1.2.2
Follow-Up Period and End of Study Visit .........................................35
9.1.2.3
Premature Discontinuation of Study Drug.........................................35
9.2
Discussion of Study Design, Including Choice of Control Groups......................36
9.2.1
Randomization .........................................................................................36
9.2.2
Run-In......................................................................................................36

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9.2.3
Study Duration .........................................................................................36
9.3
Selection of Study Population ............................................................................36
9.3.1
Inclusion Criteria......................................................................................37
9.3.2
Exclusion Criteria.....................................................................................38
9.4
Treatments.........................................................................................................41
9.4.1
Treatments Administered..........................................................................41
9.4.2
Identity of Investigational Products ..........................................................41
9.4.2.1
Chemical Name, Structural Formula of E2006/Lemborexant ............41
9.4.2.2
Comparator Drug..............................................................................42
9.4.2.3
Labeling for Study Drug ...................................................................42
9.4.2.4
Storage Conditions ...........................................................................42
9.4.3
Method of Assigning Subjects to Treatment Groups.................................42
9.4.4
Selection of Doses in the Study (revised per Amendment 01)...................43
9.4.5
Selection and Timing of Dose for Each Subject........................................43
9.4.6
Blinding ...................................................................................................43
9.4.7
Prior and Concomitant Therapy................................................................43
9.4.7.1
Drug-Drug Interactions.....................................................................44
9.4.7.2
Prohibited Concomitant Therapies and Drugs ...................................44
9.4.7.3
Caffeine and Alcohol Restrictions.....................................................44
9.4.8
Treatment Compliance .............................................................................45
9.4.9
Drug Supplies and Accountability ............................................................45
9.5
Study Assessments.............................................................................................46
9.5.1
Assessments .............................................................................................46
9.5.1.1
Demography.....................................................................................46
9.5.1.2
Screening and Baseline Assessments ................................................46
9.5.1.2.1
Medical History and Physical Examinations................................46
9.5.1.2.2
Sleep Disorders History and Screening Battery ...........................46
9.5.1.2.3
Viral Testing...............................................................................47
9.5.1.2.4
Pregnancy Tests for Women of child Bearing Potential...............47
9.5.1.3
Efficacy Assessments .......................................................................47
9.5.1.3.1
Polysomnography (PSG) (revised per Amendment 01) ...............47
9.5.1.3.2
Electronic Sleep Diary ................................................................48
9.5.1.3.3
Insomnia Severity Index..............................................................49
9.5.1.3.4
Beck Depression Inventory-II .....................................................49
9.5.1.3.5
Beck Anxiety Inventory..............................................................50
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................50
9.5.1.4.1
Pharmacokinetic Assessments.....................................................50

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9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments................................................................................50
9.5.1.5
Safety Assessments...........................................................................50
9.5.1.5.1
Adverse Events...........................................................................50
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................52
9.5.1.5.3
Laboratory Measurements...........................................................53
9.5.1.5.4
Vital Signs and Weight Measurements........................................55
9.5.1.5.5
Physical Examinations ................................................................55
9.5.1.5.6
Electrocardiograms .....................................................................56
9.5.1.5.7
Other Safety Assessments ...........................................................56
9.5.2
Schedule of Procedures/Assessments........................................................56
9.5.2.1
Schedule of Procedures/Assessments................................................56
9.5.2.2
Description of Procedures/Assessments Schedule .............................60
9.5.3
Appropriateness of Measurements............................................................60
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................60
9.5.4.1
Reporting of Serious Adverse Events................................................60
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................61
9.5.4.3
Reporting of Events Association with Special Situations...................62
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................62
9.5.4.3.2
Reporting of Study-Specific Events.............................................62
9.5.4.4
Expedited Reporting .........................................................................62
9.5.4.5
Breaking the Blind............................................................................62
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................63
9.5.5
Completion/Discontinuation of Subjects...................................................63
9.5.6
Abuse or Diversion of Study Drug............................................................64
9.5.7
Confirmation of Medical Care by Another Physician................................64
9.6
Data Quality Assurance......................................................................................64
9.6.1
Data Collection.........................................................................................64
9.6.2
Clinical Data Management .......................................................................64
9.7
Statistical Methods.............................................................................................65
9.7.1
Statistical and Analytical Plans.................................................................65
9.7.1.1
Study Endpoints (revised per Amendment 04) ..................................65
9.7.1.1.1
Primary Endpoint........................................................................65
9.7.1.1.2
Secondary Endpoints...................................................................65

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9.7.1.1.3
Exploratory Endpoints ................................................................66
9.7.1.2
Definitions of Analysis Sets..............................................................66
9.7.1.3
Subject Disposition...........................................................................66
9.7.1.4
Demographic and Other Baseline Characteristics..............................67
9.7.1.5
Prior and Concomitant Therapy ........................................................67
9.7.1.6
Efficacy Analyses.............................................................................67
9.7.1.6.1
Analysis for the Primary Endpoint (revised per Amendment 
01) ..............................................................................................68
9.7.1.6.2
Secondary Efficacy Analysis (revised per Amendment 04) .........69
9.7.1.6.3
Exploratory Efficacy and Pharmacodynamic Analyses................70
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................70
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................70
9.7.1.7.2
Pharmacodynamic Analyses........................................................70
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analysis .............................70
9.7.1.7.4
Pharmacogenomic Analyses........................................................70
9.7.1.8
Safety Analyses ................................................................................70
9.7.1.8.1
Extent of Exposure......................................................................71
9.7.1.8.2
Adverse Events...........................................................................71
9.7.1.8.3
Laboratory Values.......................................................................72
9.7.1.8.4
Vital Signs and Weight ...............................................................72
9.7.1.8.5
Electrocardiograms .....................................................................73
9.7.1.8.6
Other Safety Analyses.................................................................73
9.7.1.9
Other Analyses .................................................................................73
9.7.2
Determination of Sample Size (revised per Amendment 01).....................73
9.7.3
Interim Analysis (revised per Amendment 01)..........................................74
9.7.4
Other Statistical/Analytical Issues ............................................................74
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................74
10
REFERENCE LIST.....................................................................................................75
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......76
11.1
Changes to the Protocol......................................................................................76
11.2
Adherence to the Protocol..................................................................................76
11.3
Monitoring Procedures.......................................................................................76
11.4
Recording of Data..............................................................................................77
11.5
Identification of Source Data..............................................................................77
11.6
Retention of Records..........................................................................................77
11.7
Auditing Procedures and Inspection ...................................................................78
11.8
Handling of Study Drug .....................................................................................78

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11.9
Publication of Results ........................................................................................78
11.10 Disclosure and Confidentiality ...........................................................................79
11.11 Discontinuation of Study....................................................................................79
11.12 Subject Insurance and Indemnity........................................................................79
12
APPENDICES.............................................................................................................80
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests........................................................................54
Table 2
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments (revised per Amendment 03)..............................................54
Table 3
Schedule of Procedures / Assessments in Study E2006-J086-311 
(revised per Amendment 01 and 02) .......................................................57
Table 4
Clinically Notable Vital Sign Ranges......................................................73
LIST OF IN-TEXT FIGURES
Figure 1
Schematic Diagram of E2006-J086-311 Study Design............................32
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................81
Appendix 2
Inclusion/Exclusion Criteria Schedule ....................................................84
Appendix 3
List of Prohibited Concomitant Medications...........................................85

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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
CCMV
complete case missing value
CI
confidence interval
CMQ
customized MedDRA queries
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
DurLongAw
Mean duration of long awakenings
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalography
EMG
electromyography
EOS
end of study
ET
early termination
FAS
Full Analysis Set

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Abbreviation
Term
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation
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 
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
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MHB
median habitual bedtime
MI
multiple imputations
MMRM
mixed effect model repeated measurement
M-MSLT
modified multiple sleep onset latency test
MNAR
missing not at random
NDA
New Drug Application
NMPA
National Medical Products Administration
NREM
non-REM sleep
PBO
placebo
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PLMD
periodic limb movement disorder
PMDA
Pharmaceuticals and Medical Devices Agency
PP
Per Protocol

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Abbreviation
Term
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
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
WASO2H
wake after sleep onset in the second half of the night

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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 clinical 
research associates(s) [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.
A signed letter of 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 (or if regionally required, the head of the 
medical institution) will immediately send the notice of study suspension or termination by 
the IRB/IEC to the sponsor.
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 (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) 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.
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
•
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 Conference on Harmonisation of Pharmaceuticals for Human Use
•
A waiver from the [IRB(s)/IEC(s)] will be obtained before study initiation for 
non-US studies conducted under an Investigational New Drug (IND) application.
•
Other applicable regulatory authorities’ requirements or directives

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5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator or appropriate 
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 as well as 
contact information (phone number(s) of investigational site and name(s) of contact person).  
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 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 C-
GCP, 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 (or designee) 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) up to 30 sites in China mainland and Taiwan. (revised per Amendment 01)
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.

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7
INTRODUCTION
7.1
Indication
Insomnia is a sleep disorder characterized by difficulties with sleep onset and/or sleep 
maintenance, which is the most prominent among numerous sleep disorders known today.  In 
industrialized nations, approximately 30% of the population has symptoms and at least 6% 
meet diagnostic criteria for primary insomnia meriting treatment (Roth T, 2007).  The 
percentages of subjects in China presenting with both night-time and daytime symptoms that 
meet the diagnostic criteria of DSM-IV, were 12.1% on average across 10 countries and 
10.0% in China (Soldatos CR, et al., 2005). According to more recent research reported by 
the Chinese Sleep Research Society in 2014, 38.2% of Chinese people suffer from a sleep 
disorder, with insomnia one of the most frequent.
7.1.1
Current Therapeutics Options
Currently available pharmacological treatments used clinically in the world for insomnia 
include benzodiazepines, non-benzodiazepine GABA-releasing (GABAergics) agents, 
antidepressants, melatonin and melatonin agonists, antihistamines, etc. For National Medical 
Products Administration (NMPA) approved pharmacological treatments, there is no 
difference between approved dosages in China and globally approved dosages for insomnia 
drugs, for the most commonly used non-benzodiazepines: zolpidem (10 mg/day in both US 
and China); eszopiclone, (2 or 3 mg/day in both US and China). However, there has been 
increased awareness of the need for sleep-promoting agents with mechanisms of action 
different from GABA-A receptor positive-allosteric modulators.  Orexin neuropeptides 
(orexin A and orexin B) have been recognized as critical upstream controllers of most wake-
promoting neurotransmitters via 2 G protein coupled receptors, the OX1R and OX2R.  
Antagonists that block both OX1R and OX2R receptor are called dual orexin receptor 
antagonists (DORA). DORAs provide an alternative approach to treat insomnia disorder 
with better benefit/risk balance than those of other currently available medications.  The only 
approved DORA is suvorexant, which was approved in US and Japan but not in China.
7.1.2
Lemborexant (E2006)
7.1.2.1
Mechanism of Action
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.
Orexin neuropeptides (orexin A and orexin B) have been recognized as critical upstream 
controllers of most wake-promoting neurotransmitters via two G protein coupled receptors, 
the orexin-1 receptor and the orexin-2 receptor.  Small-molecule antagonists of orexin 
receptors, such as suvorexant, have recently emerged as a new class of chemical compounds 
that represents a novel alternative approach to treat insomnia disorder.

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7.1.2.2
Clinical Experience With Lemborexant
7.1.2.2.1
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-A001-005 (Study 005):  relative bioavailability study of capsules vs tablet 
formulations.  This study demonstrated that the capsules and tablets provided similar 
exposure (maximum observed concentration [Cmax] and area under the concentration-time 
curve [AUC]), thus allowing the tablet formulation to be used in future clinical trials.
E2006-A001-007 (Study 007):  human mass balance absorption, distribution, metabolism, 
and excretion study to characterize the route and extent of excretion of lemborexant. This 
study demonstrated that elimination takes place by fecal (57%) and urinary excretion (29%) 
based on total recovery (86.5%) of radioactivity following a single dose of radiolabeled 
lemborexant. In addition, there were no human-specific metabolites and the only major 
(12%) metabolite was M10.  The blood-to-plasma ratio was approximately 0.65.
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)
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

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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. Drug-PBO differences in SDLP >2.4 cm are considered to reflect clinically 
meaningful driving impairment. Lemborexant 2.5, 5 and 10 mg 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. The upper bound of the 95 percent confidence intervals for the mean 
changes in SDLP were all below 2.4 cm for all three doses of lemborexant on Days 2 and 9, 
indicating that there was not clinically meaningful driving impairment. The upper bound of 
the 95 percent confidence intervals for the mean changes in SDLP for zopiclone was >2.4 cm 
on Days 2 and 9, demonstrating assay sensitivity.
E2006-A001-107 (Study 107):  This Phase 1 study was conducted to evaluate the effects of 
the 5 and 10 mg doses on next-morning residual sleepiness in subjects with insomnia 
disorder.  The study design was randomized, double-blind, and PBO-controlled with a 3-way 
crossover.  Next morning residual sleepiness was measured on a modified multiple sleep 
onset latency test (M-MSLT).  An active comparator, flurazepam 30 mg, was included to 
confirm assay sensitivity.  Results showed that for neither 5 mg nor 10 mg was the lower 
bound of the 95% confidence interval (CI) of the treatment difference in change from 
baseline of average sleep onset latency on the M-MSLT more than 6 minutes, which was the 
prespecified criterion defining clinically meaningful next-morning residual sleepiness.  That 
is, neither dose level of lemborexant resulted in a clinically meaningful reduction in average 
time to sleep onset in the morning hours, supporting the safety of these doses and their use in 
Phase 3 studies.
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, lemborexant 5 mg
(LEM5), lemborexant 10 mg (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, 

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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.
7.1.2.2.2
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 SE was achieved without unacceptable 
next-day residual sleepiness as evaluated by the Karolinska Sleepiness Scale (KSS).
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 LPS and 
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.
7.1.2.2.3
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 sSOL 
sSE, sWASO, and sTST, over the first 7 nights and the last 7 nights of treatment.

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E2006-G000-303 (Study 303):  Study 303 was a 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. Subjects 
were administered PBO or one of two treatment regimens (LEM5, 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 
maintenance variables after 6 months of treatment. (revised per Amendment 01)
Based on these data, a New Drug Application (NDA) for lemborexant was submitted to the 
US Food and Drug Administration (FDA) for the treatment of insomnia disorder in 
December 2018 and accepted for review in February 2019.  Subsequently, NDA for 
lemborexant was submitted to the Japan Pharmaceuticals and Medical Devices Agency
(PMDA) for the treatment of insomnia disorder in March 2019 and to Health Canada in 
August 2019.  The data demonstrated efficacy of lemborexant 10 mg on objective and 
subjective measures of sleep onset and sleep maintenance.  (revised per Amendment 01)
7.2
Study Rationale
Clinical studies of lemborexant has been conducted or are in the process of conducting with 
16 Phase 1/Pharmacology studies and a Phase 2 dose range-finding study in insomnia 
disorder, sequentially confirming the safety and efficacy of lemborexant in healthy 
volunteers, patients with insomnia as well as some requisite special populations (Section 
7.1.2.2.1).  Lemborexant clinical development program included two multinational Phase 3 
studies, Studies 303 and 304, which have been conducted overseas (Section 7.1.2.2.3).  Study 
304 demonstrated that short-term (1 month) treatment of lemborexant is effective on 
objective sleep latency and sleep maintenance assessed by PSG. Study 303 was designed to 
provide evidence of long-term efficacy of lemborexant on subjective sleep latency and sleep 
maintenance assessed by sleep diary.
In the original protocol (Version 1.0; 02 Aug 2018) of this Study 311, submitted with the 
Clinical Trial Authorisation (CTA), all sleep parameters were subjectively assessed by sleep 
diary, with no objective assessments by PSG.  The CTA for the lemborexant program in 
China was filed with the Center for Drug Evaluation (CDE) in September 2018, and was 
approved in January 2019. The CDE recommended that Study 311 use the same primary and 
key secondary endpoints as the global Phase 3 study (Study 304), that are objectively
assessment by PSG.  (revised per Amendment 01)
As per CDE recommendation, Study 311 will be a multicenter, randomized, double-blind, 
PBO-controlled, parallel-group study of the efficacy and safety of 1 dose level of 
lemborexant (10 mg) for 30 nights in Chinese subjects with insomnia. Similar to Study 304, 
all subjects will be assessed for objective sleep measures using PSG in order to demonstrate 
the statistical difference between LEM10 and PBO in LPS after 1 month of treatment.  

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Patient-reported (subjective) sleep measures will also be assessed using a sleep diary.
(revised per Amendment 01)
The treatment period is 1 month. This treatment period meets the recommendation from the 
Guideline for the diagnosis and treatment of adult insomnia in China, which recommend 
treatment evaluation for 4 weeks. This short-term study should be sufficient for the China 
NDA because long-term data will be provided by Study 303.
Subjects will be Chinese male or female, age 18 years or older in order to evaluate patients of 
a broad age-range. There is no need to specify the number of elderly subjects in Study 311 as 
there are sufficient data on elderly patients from Study 303 and Study 304.
Subjects will be randomized to LEM10 or PBO treatment in an approximate 1:1 ratio.  For 
the development of sleep-promoting drugs, because it is not able to exclude PBO effect in 
active drugs, a PBO-controlled trial is required for assay of efficacy and safety.  (revised per 
Amendment 01)
8
STUDY OBJECTIVES
8.1
Primary Objective (revised per Amendment 01)
To confirm using PSG that lemborexant LEM10 is superior to PBO on objective sleep onset 
as assessed by LPS during the last 2 nights of 1 month of treatment in subjects with insomnia 
disorder
8.2
Secondary Objectives (revised per Amendment 04)
The secondary objectives are:
•
To evaluate LEM10 compared to PBO on sleep efficiency as assessed by SE 
during the last 2 nights of treatment
•
To evaluate LEM10 compared to PBO on sleep on sleep maintenance as assessed 
by WASO during the last 2 nights of treatment
•
To evaluate LEM10 compared to PBO on sleep maintenance as assessed by 
sSOL, sSE, sWASO over the last 7 nights of 1 month of treatment
•
To evaluate the efficacy of LEM10 compared to PBO on sleep (LPS, WASO, SE) 
as measured by PSG during the first 2 nights of treatment
•
To evaluate the safety and tolerability of lemborexant
•
To evaluate the effect of lemborexant compared to PBO on insomnia severity and 
daytime functioning, as assessed by the Insomnia Severity Index (ISI) 
•
To evaluate rebound insomnia following completion of treatment with 
lemborexant

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•
To evaluate morning residual sleepiness during treatment and following 
completion of treatment with lemborexant
8.3
Exploratory Objectives (revised per Amendment 01)
The exploratory objectives are:
•
To explore the effects of LEM10 and PBO on subjective quality of sleep
•
To evaluate the effects of LEM10 and PBO on sleep architecture
•
To explore the effects of LEM10 and PBO on Beck Depression Inventory-II
(BDI-II) and Beck Anxiety Inventory (BAI)
•
To summarize plasma concentrations of lemborexant and its metabolites M4, M9,
and M10
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E2006-J086-311 is a multicenter, randomized, double-blind, PBO-controlled, parallel-group 
study of LEM10 for 30 nights in Chinese subjects (age 18 years or older, only in Taiwan age 
20 years and older) who have insomnia disorder.  (revised per Amendment 03)
The study will have 2 phases: the Prerandomization Phase and the 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 14-day Follow-Up Period before an End of Study (EOS) Visit.
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will 
undergo routine safety assessments at specified visits, including questioning regarding 
adverse events (AEs), 12-lead ECGs, vital signs, weight, height (once at Visit 1), clinical 
hematology and chemistry analysis and urinalysis.  At each visit from Screening to the EOS 
Visit, subjects will also undergo a urine drug screen.
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 89 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 54 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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Figure 1
Schematic Diagram of E2006-J086-311 Study Design
PSG = polysomnography, R = randomization.
a:  The first dose of active study drug will be administered at Visit 5b.  The last dose of active study drug will be administered at Visit 8a.
Phase:
Period:
Start between 
Day –35 and 
Day –19
Baseline
R
Lemborexant 10 mg
(LEM10)
Start between Day –10
and Day –4, end on 
Day –8 and Day –2
Placebo (PBO)
No Study Drug
Placebo (PBO)
Day 44
Visit 5a
Day 1
Visit 1
1 month (30 nights)
14 days but 
not >18 days
No Study Drug
PSG
Visit 2a/2b
Visit 4b
/Baseline
PSG
Visit 3a/3b
PSG
Visit 4a/4b
PSG
Visit 5b/5c
Day 1/2
PSG
Visit 6a/6b
Day 2/3
PSG
Visit 7a/7b
Day 29/30
PSG
Visit 8a/8b
Day 30/31
Visit 2b
Visit 8b
Day 31
Prerandomization
Follow-Up
Treatment a
Randomization
Screening
Run-in
No Study Drug

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9.1.1
Prerandomization Phase
9.1.1.1
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At 
the first 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 will be conducted, and will include confirmation that 
the subject meets diagnostic criteria for insomnia disorder, and further, that the subject 
complains of difficulties with sleep onset, sleep maintenance and/or early morning 
awakening.  Screening assessments will include the ISI, as well as the BDI-II and BAI, 
STOPBang and International Restless Legs Scale (IRLS), collectively called the Sleep 
Disorders Screening Battery (SDSB).
All eligible subjects will be provided with an electronic device on which they will complete 
the sleep diary.  Subjects will be trained in the use of this device.  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.  The sleep diary entries will be reviewed by site staff 
at least weekly throughout the study to ensure subject compliance with completion of the 
sleep diary and to ensure that study restrictions are met pertaining to duration of time spent in 
bed.  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, provided 
that the sleep diary entries indicate continued eligibility with regard to sleep timing, duration 
of time spent in bed, and frequency of nights with symptoms of insomnia, subjects will 
undergo the second Screening Visit (Visit 2a). (Subjects who are not eligible based on sleep 
diary entries will return to the clinic for debriefing purposes and to return study equipment.)  
This visit must occur between Day –18 and Day –12.  On this and all nights on which PSG is 
recorded, subjects will arrive at the clinic in the evening with sufficient time before bedtime 
to complete check-in procedures, any scheduled assessments, and preparations (eg, electrode 
montage placement) for the PSG recordings.  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).  The PSG will be reviewed for inclusion criteria related to the presence of 
insomnia and absence of symptoms of sleep apnea and/or 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. (revised per Amendment 01)
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 

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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.
When subjects have completed the sleep diary on at least 7 consecutive mornings during the 
Run-in Period, the diary will be reviewed for continued eligibility.  Subjects who are still 
eligible will return to the clinic for the first of 2 consecutive nights on which PSG will be 
recorded.  The first of these 2 nights must be between Day –10 and Day –4.  In the evening, 
before the PSG recording, the safety assessments will be conducted.  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 second Screening Visit.  Subjects will 
undergo an 8-hour PSG.  The next morning, subjects will complete the sleep diary.  The PSG 
recording will be reviewed for continued eligibility and subjects may then leave the clinic 
only after the investigator determines that it is safe for them to do so.  Subjects will return to 
the clinic that evening.  Study personnel will administer study drug to subjects approximately 
5 minutes before the scheduled bedtime.  A PSG will be recorded overnight.  The following 
morning subjects will complete the sleep diary.  The PSG recording will be reviewed for 
continued eligibility, and both PSGs during the Run-in Period will also serve as the baseline 
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 and they will continue to 
complete the sleep diary each morning within 1 hour after morning wake time.  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. Urine drug test will be performed as described in 
Section 9.5.2. (revised per Amendment 01)
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, and the ISI will be administered. Blood and urine samples 
will be collected for routine safety assessments, an ECG will be performed, and vital signs 
and weight will be assessed. In addition, subjects should undergo a urine drug test.  Subjects 
who complete the Baseline Period and continue to meet the eligibility criteria will be 
randomized, and will begin the Treatment Period. (revised per Amendment 01)
9.1.2
Randomization Phase
9.1.2.1
Treatment Period
The Treatment Period will begin on Day 1 and will continue until Day 31.  Subjects will be 
randomized in a double-blind manner, to receive LEM10, or PBO. (revised per Amendment 
01)
On the evening of Day1, approximately 5 minutes before the subject’s MHB, study drug will 
be administered and an 8-hour overnight PSG will be initiated.  At completion of the PSG 

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recording the following morning (Day 2), subjects will complete the sleep diary.  They may 
leave the clinic after the investigator determines that is safe for them to do so.  On the 
evening of Day 2, subjects will return to the clinic.  A PK blood sample will be collected 
predose and study drug will be administered approximately 5 minutes before the subject’s 
MHB, followed by an overnight PSG.  On the morning of Day 3, a PK sample will be 
obtained and subjects will complete the sleep diary.  Subjects may then leave the clinic after 
the investigator determines that it is safe for them to do so.  Study drug will be dispensed and 
subjects will be provided with instructions to continue completing the sleep diary each 
morning within 1 hour of waketime and taking study drug daily at home according to the 
same schedule and with the same instructions as during the Run-in Period.  On Day 29, 
subjects will return to the clinic.  Study drug will be administered approximately 5 minutes 
before the subject’s MHB, followed immediately by a PSG.  Urine drug test will be 
performed as described in Section 9.5.2.  On the morning of Day 30, subjects will complete 
the sleep diary, and may leave the clinic after the investigator determines that it is safe for 
them to do so.  On the evening of Day 30, subjects will return to the clinic.  A PK blood 
sample will be collected predose and study drug will be administered approximately 5 
minutes before the subject’s MHB, followed by a PSG.  On the morning of Day 31, a PK 
sample will be obtained.  Subjects will complete the sleep diary.  Then the ISI, BDI-II and 
BAI will be administered.  Blood and urine samples will be collected for routine safety 
assessments.  An ECG will be performed, and vital signs and weight will be assessed.  Then, 
after the investigator determines that it is safe for them to do so, subjects will be discharged 
from the clinic.  (revised per Amendment 01)
9.1.2.2
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 but will continue to complete the 
sleep diary each morning until the end of study (EOS) Visit.
At least 14 days but no more than 18 days after completion of the Treatment Period subjects 
will return to the clinic for the EOS Visit.  At the EOS Visit, in addition to standard safety 
assessments, a urine drug test will be conducted, and sleep diaries will be collected.  After 
the End of Study Visit, subjects’ participation in the study will be finished.
9.1.2.3
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 an 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 beginning from the time the subject signs the study ICF through the last 
visit.  All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  In addition, subjects who withdraw due to an AE should undergo a 
urine drug test.

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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.
The Run-in Period will also help to identify and exclude subjects who are not compliant with 
the sleep diary instructions, duration of time spent in bed, or restrictions on alcohol use.  In 
this regard, it is necessary for the subjects to be taking PBO and to obtain sleep diary data for 
a minimum of 1 week to adequately evaluate whether there is a PBO response.  These sleep 
diary data recordings will be used to further screen for eligibility, and will serve as baseline 
values for those subjects who continue to randomization.  After this minimum 7 nights of
treatment, eligible subjects will have PSG recordings on 2 consecutive nights. These
recordings will be used to further screen for eligibility, and will serve as baseline values for
those subjects who continue to randomization. (revised per Amendment 01)
9.2.3
Study Duration
In Study 304, the efficacy endpoints, change from baseline for mean LPS, SE, and WASO on 
Days 29/30, was statistically significantly superior for 10 mg of lemborexant compared to 
PBO (P<0.05).  Also, the change from baseline for mean sSOL, sSE, sWASO, and sTST
over the first 7 nights and last 7 nights of the Treatment Period were statistically significant 
for 10 mg of lemborexant compared to PBO (P<0.05).  Study 304 included 30 days of active 
treatment.  Based on the results of Study 304, it was expected that there would not be a loss 
of efficacy of lemborexant between 1 week and 4 weeks of treatment. In Study 303, efficacy 
as determined by sleep diary data showed sustained efficacy through Month 6.
9.3
Selection of Study Population
For overall subjects, approximately a total of 700 subjects will be screened to provide 
approximately 188 overall randomized subjects. Subjects will be randomized to one of the 
following treatment arms: LEM10, PBO, in an approximate 1:1 ratio.  (revised per 
Amendment 01)  
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.

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9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Chinese male or female, age 18 years or older, at the time of informed consent (in Taiwan 
only subjects with age 20 years or older are eligible) (revised per Amendment 03)
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition  (DSM-5) 
criteria for Insomnia Disorder, as follows:
-
Complains of dissatisfaction with nighttime sleep, in the form of 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
-
Associated with complaint of daytime impairment
3.
At Screening:  History of sSOL ≥30 minutes on at least 3 nights per week in the previous 
4 weeks AND/OR sWASO ≥60 minutes on at least 3 nights per week in the previous 4 
weeks 
4.
At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, 
between 7 and 9 hours 
5.
At second Screening Visit (Visit 2a) and Run-in Visit (Visit 3a): Sleep diary confirms 
regular bedtime, defined as the time the subject attempts to sleep, between 21:00 and 
01:00 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 10:00 on at least 5 of the final 7 
nights (revised per Amendment 01)
6.
At Screening and Baseline: ISI score ≥15 (revised per Amendment 01)
7.
Confirmation of current insomnia symptoms, as determined from responses on the sleep 
diary on the 7 most recent mornings before the first PSG during Screening Period (Visit 
2a) and Run-in visit (Visit 3a), such that sSOL ≥30 minutes on at least 3 of the 7 nights 
and/or sWASO ≥60 minutes on at least 3 of the 7 nights (revised per Amendment 01)
8.
At the second Screening Visit (Visit 2a) and the Run-in visit (Visit 3a): 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 Visit, such that there are no more than 2 nights 
with time spent in bed duration <7 hours or >10 hours (revised per Amendment 01)
9.
During the Run-in Period, objective (PSG) evidence of insomnia as follows:
a.
LPS average ≥30 minutes on the 2 consecutive baseline PSGs, with neither night <20
minutes and/or
b.
WASO average ≥60 minutes on the two consecutive baseline PSGs, with neither 
night <45 minutes
(revised per Amendment 01)
10. Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night

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11. Willing not to start a behavioral or other treatment program for the treatment of insomnia 
during the subject’s participation in the study
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 [β-hCG] test). A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 
hours before the first 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 be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and 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.

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5.
Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening
6.
Any suicidal behavior in the past 10 years
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. (revised per Amendment 02) Subjects for whom a sedating drug would be 
contraindicated for safety reasons because of the subject’s occupation or activities are also 
excluded  
8.
Hypersensitivity to lemborexant or to their excipients
9.
Scheduled for surgery during the study
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
•
International Restless Legs Scale score ≥16
14. Apnea-Hypopnea Index >15 or Periodic Limb Movement with Arousal Index >15 as 
measured on the PSG at the second Screening Visit (revised per Amendment 01)
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 18 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

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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. Excluding 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 first dose of study medication (Run-
in Period). (A list of prohibited concomitant medications is presented in Appendix 3 of 
protocol)
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 first 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 (revised per Amendment 01)
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 more than 3 time zones during 
the study (China mainland will be considered as 1 time zone) (revised per Amendment 01)
28. A positive drug test at Screening, Run-in, or Baseline, or unwilling to refrain from use of 
recreational drugs during the study
29. 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
30. Previously participated in any clinical trial of lemborexant

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9.4
Treatments
9.4.1
Treatments Administered
Test drug
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.
(revised per Amendment 01)
Run-In Period
All subjects will receive 1 lemborexant-matched PBO 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 (in Randomization Phase)
All subjects will receive 1 tablets as described below, according to the treatment arm to 
which the subject has been randomized: (revised per Amendment 01)
•
LEM10:  1 lemborexant 10 mg tablet
•
PBO:  1 placebo tablet matched to lemborexant 10 mg
9.4.2
Identity of Investigational Products
The sponsor will provide lemborexant tablets in strengths of 10 mg and lemborexant-
matched PBO, identical in appearance.  Tablets will be packaged in blister cards in a double-
blind manner. (revised per Amendment 03)
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. (revised per Amendment 01)
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

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9.4.2.2
Comparator Drug
PBO to match lemborexant as described in Section 9.4.2 will be used as a comparator drug in 
the study.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
The following information has to be provided:
•
For clinical study use only
•
Name of the sponsor
•
Chemical name/drug identifier
•
Lot number/batch number
•
Storage condition expiration date
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 designee 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
At Treatment Day 1, subjects will be randomized, in a double-blind manner, to receive 
LEM10 or PBO in a 1:1 ratio.  (revised per Amendment 01)  Randomization will be stratified 
by site and age group (<65 years old; ≥65 years old).  Randomization to study treatments will 
be 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.
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 study procedures 
the morning of Day 1), the investigator or designee will call the IxRS to register the subject 
information.  At Randomization (morning of Day 1), the IxRS will assign each subject a 
unique 6-digit randomization number.

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9.4.4
Selection of Doses in the Study (revised per Amendment 01)
Study 311 design includes only LEM10 because 1) LEM10 were statistically significantly 
effective on both sleep onset and maintenance compared to PBO in Studies 303 and 304, and 
2) LEM10 had a larger effect size for LPS than that of LEM5 in Studies 304 and Study 201.  
Data on efficacy and safety of LEM5 will be extrapolated from data in the overseas studies 
that included population PK analyses and the Chinese PK parameters in E2006-J086-014 
(Study 014).  Taken together with the efficacy and safety results for LEM10 in the Phase 1, 
2, and 3 studies, only 10 mg dose level were selected for the current study.  (revised per 
Amendment 01)
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 
conduct and interpretation of the study, including investigators, site personnel, and sponsor 
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 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 on the date of informed consent, will be recorded on the Prior and Concomitant 
Medication electronic case report form (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 

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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 
medication (Run-in Period).  (revised per Amendment 01)
Prohibited medications include moderate and strong CYP3A inhibitors and all CYP3A 
inducers. (revised per Amendment 01) 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).
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 will not be 
permitted at any time for any duration of use during the study.  (revised per Amendment 01)
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.  (revised 
per Amendment 01)

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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.  A drink will be 
defined as 285 mL of beer, 150 mL of wine, or 25 mL of liquor.  Subjects must not consume 
any alcohol on days when they are scheduled for a PSG recording. (revised per Amendment 
01)
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.  Tablets will be counted separately for tablets that are matched to 
lemborexant.
When subjects arrive for Baseline, 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.
9.4.9
Drug Supplies and Accountability
The investigator will maintain accurate records of the receipt of all study medication.  In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each patient in the study.  Reasons for deviation from the expected 
dispensing regimen must also be recorded.  Throughout the duration of the study, study 
medication will be reconciled on a periodic basis by the CRAs.  The investigator agrees to 
provide sufficient access to study medication as required for the reconciliation process to be 
completed in a timely fashion.
At completion of the study, all study medication will be reconciled by the CRO monitor and 
then returned at the direction of CRO to either CRO or a third party contractor to be retained 
or destroyed according to applicable local regulations.  Prior to any action being taken with 
study medication after the study is completed the investigator will contact CRO for approval 
of such action.

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9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic 
information will include date of birth (or age), sex, and race/ethnicity. (revised per 
Amendment 04)
9.5.1.2
Screening and Baseline Assessments
9.5.1.2.1
MEDICAL 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.  The physical examination will 
include a brief neurological examination to assess possible impairment in major functions (ie, 
motor, cerebellar, sensory, major pathological reflexes). The neurological examination must 
be conducted by a clinician whose clinical experience ensures that an adequate assessment of 
domains underlying the exclusion criteria can be performed.
Physical examinations (full or brief) will be performed as described in Section 9.5.1.5.5.
9.5.1.2.2
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.
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)

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•
IRLS (International Restless Legs Scale):  a subjective scale comprising ten 
questions, which measures severity of symptoms of restless legs syndrome (Abetz 
et al., 2006)
9.5.1.2.3
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.
9.5.1.2.4
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).
9.5.1.3
Efficacy Assessments
9.5.1.3.1
POLYSOMNOGRAPHY (PSG) (REVISED PER AMENDMENT 01)
Each PSG recording will include an electrode montage with electroencephalography (EEG), 
electromyography (EMG), electrooculography, and ECG channels, for scoring of sleep 
parameters and sleep architecture via standard sleep scoring criteria.  In addition, the first 
PSG will include channels for assessment of symptoms of sleep apnea and periodic limb 
movement disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard 
criteria.  The PSG at the second Screening Visit will be used only to calculate the Apnea-
Hypopnea Index and the Periodic Limb Movements with Arousal Index for evaluation of 
eligibility criteria; sleep parameters and sleep architecture will not be evaluated from this 
PSG.  The 2 PSGs obtained during the Run-in Period will be used to a) determine eligibility 
and b) derive baseline PSG parameters for those subjects who are randomized.
All PSG parameters will be obtained separately for each PSG recording and averaged across 
the pairs of consecutive PSG nights.
The following parameters will be derived from all PSGs:
•
LPS:  minutes from lights off to the first epoch of 20 consecutive epochs of non-
wakefulness
•
SE:  proportion of time spent asleep per time in bed (TIB), calculated as total 
sleep time (TST)/interval from lights off until lights on
•
WASO:  minutes of wake from the onset of persistent sleep until lights on
•
TST:  minutes of sleep from sleep onset until terminal awakening
•
Mean duration of long awakenings (DurLongAw):  average duration of all long 
awakenings (with long awakening defined as 10 or more consecutive epochs [ie, 5 

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minutes or longer] scored as wake or N1, initiated with at least one epoch of 
wake, after onset of persistent sleep, and including any terminal awakening)
Additional sleep architecture parameters will be also calculated from each PSG, 
including:
•
Sleep onset latency: minutes from lights off to the first epoch of any stage of sleep 
(N1, N2, N3, rapid eye movement [REM])
•
Number of awakenings after persistent sleep, with an awakening defined as at 
least 2 consecutive epochs of wakefulness; an awakening could not be interrupted 
by stage N1, but must have been interrupted by stage N2, N3, or REM
•
Number of long awakenings (with long awakening defined as 10 or more 
consecutive epochs [ie, 5 minutes or longer] scored as wake or N1, initiated with 
at least 1 epoch of wake, after onset of persistent sleep, and including any 
terminal awakening)
•
Percentage of stage wake and sleep stages per TIB: wake, non-REM (NREM) 
sleep (stages N1, N2, N3 separately and combined), REM sleep
•
Minutes of sleep stages per TIB: wake, NREM sleep (stages N1, N2, N3), REM 
sleep
•
Percentage of sleep stages per TST: NREM sleep (stages N1, N2, N3 separately 
and combined), REM sleep
•
Minutes of sleep stages per TST: NREM sleep (stages N1, N2, N3), REM sleep
•
REM episode frequency and duration
•
Mean REM/NREM cycle duration
•
REM latency: minutes from first epoch of sleep (N1, N2, or N3) to first epoch of 
REM
Each of these PSG-derived variables, with the exceptions of SE, REM episode frequency and 
duration, mean REM/NREM cycle duration, and REM latency, were also calculated by hour 
and by half of the 8-hour time interval in bed.
9.5.1.3.2
ELECTRONIC SLEEP DIARY
The sleep diary will be completed within an hour of morning waketime on each morning of 
the study from Screening through the end of the study.  Sleep diary entries may be 
maintained in paper format as a backup to the electronic sleep diary, if necessary.  This sleep 
diary will yield several self-reported measures of sleep that will be used to determine 
eligibility, as well as to assess efficacy and safety.  In addition, the sleep diary will include 
questions that relate to morning sleepiness.
Subjects must comply with requirements for completion of the sleep diary.  Failure to 
comply will require discussion with the Medical Monitor and may result in discontinuation 
of the subject from the study.

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Sleep Parameters
•
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
•
sTST:  derived minutes of sleep from sleep onset until the time the subject 
stopped trying to sleep for the night
•
sSE:  proportion of sTST per subjective time spent in bed, calculated as the 
interval from the time the subject reported attempting to sleep until the time the 
subject stopped trying to sleep for the night, and time spent asleep derived from 
subjective time spent in bed minus sWASO
Sleep architecture parameters will be calculated as described above under assessments.
(revised per Amendment 01)
Quality of Sleep and Morning Sleepiness
The sleep diary will be used to assess the subject’s global perception of quality of sleep on 
the previous night with the following question:  “How would you rate the quality of your 
sleep last night?” Subjects will rate the quality of their sleep on a scale from 1 to 9, with 1 
being extremely poor and 9 being extremely good.
The sleep diary will be used to assess subjective ratings of morning sleepiness with the 
following question:  “How sleepy/alert do you feel this morning?” Subjects will rate their 
sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely sleepy and 9 being 
extremely alert.
9.5.1.3.3
INSOMNIA SEVERITY INDEX
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.
9.5.1.3.4
BECK DEPRESSION INVENTORY-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 (Arnau et al., 2001).  Scores on the BDI-II range from 0 to 63, with higher scores 
indicating higher levels of depressive symptoms.  Subjects with BDI-II scores >19 will be 
excluded from participation.

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9.5.1.3.5
BECK ANXIETY INVENTORY
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 
(Carney et al., 2011).  Scores on the BAI range from 0 to 63, with higher scores indicating 
higher levels of anxiety symptoms.  Subjects with scores on the BAI >15 will be excluded 
from participation.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
A single blood sample (4 mL per blood draw) for plasma concentrations of lemborexant and 
its metabolites M4, M9, and M10 will be taken at predefined visits.  The time and date of the 
2 most recent lemborexant doses administered before each sample will be documented.  The 
handling and shipment of blood samples will be described in a manual to be provided to the 
study sites.  Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10)
will be measured using validated liquid chromatography-tandem mass spectrometry assay
methods.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER
ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic 
measurement of vital signs, weight and ECGs; and the performance of physical 
examinations.  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.  
(revised per Amendment 01)
9.5.1.5.1
ADVERSE EVENTS
An adverse event (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 drugs 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:  

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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 non-protocol-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 observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit.  Serious AEs (SAEs) will be collected for 
28 days after the last dose.
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 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.
Abnormal ECG (QTc) 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 (>450 ms) and there is an increase of more than 60 ms (>60 ms) from baseline.  Any 
ECG abnormality that the investigator considers as an AE should be reported as such.
AEs in clinical investigation subjects include any change in the subject’s condition.  This 
includes symptoms, physical findings, or clinical syndromes.  All AEs encountered during 
the clinical study will be reported on the eCRF.
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 eCRF.  The definitions are as follows:

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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 9.5.1.5.2 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 eCRF in response to 
the following question:
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.
9.5.1.5.2
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)

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•
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 eCRF 
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 post 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 place before study entry
9.5.1.5.3
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 2. Subjects 
should be in a seated or supine position during blood collection.
Viral testing for hepatitis B and C will be conducted from a blood sample obtained at 
Screening. The specific test for hepatitis B is the surface antigen panel (HBsAg) with 
confirmation as needed.  The specific tests for hepatitis C are the hepatitis C virus (HCV) 
antibody immunoglobulin G (IgG), with confirmation as needed using the HCV score.   

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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 
abuse: eg, cocaine, cannabinoids, phencyclidine, opioids (as a group), benzodiazepines, 
barbiturates, and amphetamines.
Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Blood Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function parameters
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.
Serum pregnancy tests and urine drug tests will be collected for screening purposes.  A 
dipstick will be used for urine pregnancy testing and urine drug testing, to be performed at 
time points shown in the Schedule of Procedures/Assessments (Table 3).  The total blood 
volume to be drawn for laboratory measures in the study (Table 2) will be indicated on the 
ICF.
Table 2
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments (revised per Amendment 03)
Volume per Sample 
Collection
(mL)
Collection Time points
Total Volume
Collected 
(mL)
Clinical laboratory testsa
7
Screening
Day 1
Day 31
End of Study
28
Pregnancy testing b
N/A 
Screening
N/A 
Viral tests
8.5
Screening
8.5
Pharmacokinetic samplinga
4
Day 2, Day 3
Day 30, Day 31
16

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Table 2
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments (revised per Amendment 03)
Total
52.5 mL
a:
Clinical laboratory tests and/or pharmacokinetic sampling will also be conducted at ET visits, and may also 
be obtained at unscheduled visits at the discretion of the investigator. 
b:
Included in the clinical laboratory test volume
Clinical laboratory tests during the study will be performed by a central laboratory.  All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  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. Only when there is an unavoidable reason that the central laboratory 
cannot be used (eg, lockdown by coronavirus disease pandemic), the clinical laboratory tests 
can be performed by the local laboratory instead of the central laboratory. For consistency 
for a given subject, if the local laboratory had been used at baseline, it should be used 
continuously even if the central laboratory can be used later on.  (revised per Amendment 05)
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the eCRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event 
eCRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], and body temperature [in centigrade] will be 
obtained at the visits designated on 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.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations (full or brief) will be performed as designated on the Schedule of 
Procedures/Assessments (Table 3).  At Screening and at the EOS/ET visit, a full physical 
examination will be conducted, including evaluation of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, skin.  The full physical examination 
will include a brief neurological examination to assess possible impairment in major 

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functions (ie, motor, cerebellar, sensory, major pathological reflexes).  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region 
and at the discretion of the investigator.  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 examinations, including the brief 
neurological examinations, will be included in the source documentation at the site.  Only 
changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the AE eCRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
ECGs will be obtained as designated on the Schedule of Procedures/Assessments (Table 3).
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events eCRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Reporting of Serious Adverse Events [Section 9.5.4.1]).
9.5.1.5.7
OTHER SAFETY 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 this study.

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Table 3
Schedule of Procedures / Assessments in Study E2006-J086-311 (revised per Amendment 01 and 
02)
Phase
Prerandomization
Randomization
Period
Screening
Run-in
BL
Treatmenta
Follow-Up
ETb
UNS
Visit
1
2a
2b
3a
3b
4ac
4b
5a
5b
5c
6ad
6b
7a
7b
8ae
8b
EOSf
Target Study Day
–35
to
–19
–18
to
–12
–17
to
–11
–10 
to
–4
–9
to
–3
–9
to
–3
–8
to
–2
1
1
2
2
3
29
–2/+5
30
–2/+5
30
–2/+5
31
–2/+5
44
Procedures/   
Assessments
Informed consent 
X
Demographics
X
Inclusion/exclusion 
criteriag
Height
X
Weight
X
X
X
X
X
Clinical laboratory 
testsh
X
X
X
X
X
X
Serology (Hepatitis B 
and C)i
X
Serum pregnancy test
(β-hCG) j
X
Urine pregnancy testj
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
Sleep, medical, and 
psychiatric history
X
ISI 
X
X
X
SDSBl
X
Physical examm
X
X
X
X
X
X

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Table 3
Schedule of Procedures / Assessments in Study E2006-J086-311 (revised per Amendment 01 and 
02)
Phase
Prerandomization
Randomization
Period
Screening
Run-in
BL
Treatmenta
Follow-Up
ETb
UNS
Visit
1
2a
2b
3a
3b
4ac
4b
5a
5b
5c
6ad
6b
7a
7b
8ae
8b
EOSf
Target Study Day
–35
to
–19
–18
to
–12
–17
to
–11
–10 
to
–4
–9
to
–3
–9
to
–3
–8
to
–2
1
1
2
2
3
29
–2/+5
30
–2/+5
30
–2/+5
31
–2/+5
44
Procedures/   
Assessments
Prior / concomitant 
medications
Beck Depression 
Inventory II 
X
X
Beck Anxiety Inventory
X
X
Urine drug test
X
X
X
X
X
X
X
X
X
X
X
Sleep diaryn
PK blood samplingo
X
X
X
X
X
Polysomnographyp
X
X
X
X
X
X
X
Randomization
X
Dispense study drugq
X
X
Study drug at bedtimer
Retrieve unused study 
drug
X
X
Check study drug 
compliances
X
X
X
Admission to clinic
X
X
X
X
Discharge from clinic
X
X
X
X
Discharge from study
X
X
Adverse eventst

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BL = baseline, ECG = electrocardiogram, EMG = electromyography, EOS = end of study; ET = early termination, ISI = Insomnia Severity Index, PK = 
pharmacokinetic, PSG = polysomnography, SDSB = Sleep Disorders Screening Battery, UN = unscheduled visit.
a:
AE, concomitant therapy will be confirmed by telephone on Day 14 (±2).  Diary entries will be reviewed by site staff at least weekly throughout the study to 
ensure subject compliance with completion of the sleep diary, drug compliance and to ensure that study restrictions are met pertaining to duration of time spent 
in bed.  Subjects will also be reminded of study restrictions pertaining to timing of meals and caffeine/alcohol use.
b:
Subjects who discontinue the study early for any reason after Randomization at Visit 5 should complete this visit.
c:
Must be consecutive with Visit 3a.
d:
Must be consecutive with Visit 5b.
e:
Must be consecutive with Visit 7a.
f:
Must occur 14 – 18 days after Visit 8.
g:
Inclusion and exclusion criteria to be evaluated at visits other than or in addition to Visit 1 are listed in Appendix 2.
h:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
i:
Viral screening for hepatitis B (HBsAg) and hepatitis C (HCV antibody IgG) will be conducted. 
j:
Female subjects of child-bearing potential only.
k:
The ECG should be repeated if an abnormality is observed. If subject has a normal ECG baseline reading, but during any visit thereafter the QT is measured 
as >450 ms, 3 consecutive ECGs separated by 5 to 10 minutes will be performed to confirm the abnormality.
l:
The Sleep Disorders Screening Battery includes: STOPBang, International Restless Legs Scale.
m:
Full physical examination (including a brief neurological exam) will be carried out at Screening and EOS and ET (if applicable).  Brief physical examinations 
will be carried out at other visits.
n:
Should be completed, within 1 hour of morning waketime, on every day of the study from Screening until the end of the study, and reviewed for eligibility 
before initiating any study assessments at Visit 2 and Visit 3.
o:
One PK blood sample (approximately 4 mL) will be obtained at the following timepoints: within 2 hours predose Day 2 and Day 30; within 1 hour after 
morning waketime on Day 3 and Day 31.
p:
PSG recordings will include a standard montage on all PSG nights.  Diagnostic channels (respiratory effort, airflow, leg EMG) will be added to the standard 
montage on the PSG at Visit 2.  All PSG visits will require an overnight stay in the clinic.  At least 2 nights must intervene between the second BL PSG (Visit 
4b) and BL (Visit 5a).  
q:
On Visit 5b, 6a, 7a, 8a, study drug will be administered to the subject by clinical staff. The study drug will be dispensed to subjects on Visit 6b, on days that 
the subjects are not admitted to the clinic subjects will self-administer study drug.
r:
First dose of study drug is taken by the subject on the first night at home after Visit 2b.  On the days that subjects are admitted to the clinic, study drug will be 
administered to the subject by clinical staff.  The first dose of active study drug will be administered at Visit 5b.  The last dose of active study drug will be 
administered at Visit 8a.  On days that the subjects are not admitted to the clinic subjects will self-administer study drug.  All study drug administration must 
be approximately 5 minutes of bedtime (defined as the time the subject attempts to sleep). 
s:
Subjects will be questioned about study drug compliance upon check-in at Visits 3a, 5a, and 7a.  Tablet counts for study drug compliance will be done after 
end of Run-in Period and end of Treatment Period.
t:
At each visit, subjects will be asked whether they have had a fall since the previous visit.

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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
Completion of sleep diaries by subjects is considered to be an appropriate method to measure 
changes in subjective sleep parameters, thereby allowing assessments of secondary efficacy 
in this study.  The advantages of the electronic sleep diary to be used in this study include 
that the questions and instructional text have been adapted from sleep diaries that were 
developed by clinicians and researchers with expertise in insomnia disorder, and have 
undergone linguistic validation and cognitive debriefing to optimize their use in this study. 
The sleep diary will include questions to assess the subject’s rating of sleep quality each 
night and sleepiness/alertness level in the morning.
The ISI has been widely used to evaluate the subjective impact of insomnia severity on 
psychosocial functioning, which is one type of daytime functioning impairment experienced 
by those with insomnia disorder.  Because the objectives of this study include assessing the 
response to lemborexant of both nighttime sleep and daytime impairment complaints, the ISI 
will be evaluated for changes from baseline.  These measures have been used in studies 
evaluating the impact of treatment for insomnia on patients’ global perceptions of sleep 
quality and quality of life.  Together these measures will provide a broad evaluation of the 
effects of lemborexant on each patient’s sleep, daytime functioning, quality of life and 
productivity.
The safety assessments performed in this study, including clinical laboratory analyses, vital 
sign parameters, electrocardiograms, and assessment of AEs are standard evaluations to 
ensure subject safety.  Additional safety related assessments include evaluation of morning 
sleepiness and rebound insomnia, which will be measured using the validated sleep diary.
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 regulatory authorities and the Sponsor or designated CRO on a 
completed SAE form by email or fax as soon as possible but no later than 24 hours from 
when the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and 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.

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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 follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the 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.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
or the responsible CRO, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy 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, an induced abortion, or a spontaneous 
abortion 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 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 1 business day 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 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.

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9.5.4.3
Reporting of Events Association 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
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 eCRF 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 eCRF.
9.5.4.3.2
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 
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 

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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
For purposes of entering subject disposition in the eCRF, a subject will be considered to have 
completed the study per protocol after the End of Study visit has been completed.  The 
subject may elect to discontinue the study at any time for any reason.  Subjects who 
discontinue study drug prematurely at any time after randomization at Visit 5 (Study 
Baseline) will be encouraged to return to the site as soon as practicable (preferably within 7 
days). (revised per Amendment 02) These subjects will be encouraged to continue to 
complete all study assessments (excepting PK samples, which will not be taken), including 
the sleep diary, and to return for all subsequent clinic visits, without the administration of 
study medication.
Subjects will undergo an ET Visit and an EOS Visit, as described in the Schedule of 
Procedures/Assessments (Table 3).
Subjects who withdraw because of an AE should also undergo a urine drug test.
If the investigator or sponsor discontinues a subject from the study prematurely, the 
investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and will provide appropriate referral for 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.  This information will be recorded in the eCRF.
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 of secondary reasons for discontinuation.  Study disposition information 
will be collected on the Subject Disposition eCRF.
A subject removed from the study for any reason will 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 9.5.1.5.1.  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.
9.6.1
Data Collection
Data required by the protocol will be collected in a validated data management system that is 
compliant with all regulatory requirements. These data include eCRFs, computer tablets and 
electronic sleep diaries. As defined by C-GCP, the eCRF 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 eCRF must follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee must sign the completed 
eCRF to attest to its accuracy, authenticity, and completeness.
Completed, original eCRFs 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 eCRF 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.  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 statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses 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.
All statistical tests will be based on the 5% level of significance (2 sided).
9.7.1.1
Study Endpoints (revised per Amendment 04)
The following endpoints will be analyzed for LEM10 compared to PBO.
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint will be change from baseline of objective LPS during the last 2 nights 
of treatment of LEM10 compared to PBO.
9.7.1.1.2
SECONDARY ENDPOINTS
•
Change from baseline of objective SE during the last 2 nights of 1 month of 
treatment of LEM10 compared to PBO
•
Change from baseline of objective WASO during the last 2 nights of 1 month of 
treatment of LEM10 compared to PBO
•
Change from baseline of sSOL during the last 7 nights of 1 month of treatment of 
LEM10 compared to PBO
•
Change from baseline of sSE during the last 7 nights of treatment of LEM10 
compared to PBO
•
Change from baseline of sWASO during the last 7 nights of treatment of LEM10 
compared to PBO
•
Change from baseline of PSG parameters (LPS, SE, WASO) over the first 2 
nights of 30 nights of LEM10 compared to PBO
•
Safety and tolerability of lemborexant
•
Change from Study Baseline in insomnia severity and daytime functioning, 
assessed as the ISI total number and total score from the 4 items related to daily 
function on the ISI after 1 month of treatment with LEM10 compared to PBO

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•
Rebound insomnia endpoints as assessed from the sleep diary during the Follow-
Up Period
•
Morning residual sleepiness during treatment and following completion of 
treatment
9.7.1.1.3
EXPLORATORY ENDPOINTS
•
Subjective quality of sleep
•
Sleep architecture
•
Effects on BDI–II and BAI
•
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
9.7.1.2
Definitions of Analysis Sets
•
The Safety Analysis Set is the group of randomized subjects who received at least 
1 dose of randomized study drug and had at least 1 postdose safety assessment.
•
The Full Analysis Set (FAS) is the group of randomized subjects who received at 
least 1 dose of randomized study drug and had at least 1 postdose efficacy 
measurement.
•
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently 
complied with the protocol.  Details of the evaluability criteria will be determined 
before database lock and treatment unblinding will be specified in the SAP.
•
The PK Analysis Set is the group of subjects who received at least 1 dose of 
randomized study drug and had at least one 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.
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.

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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
variables include age, height, weight, and body mass index (BMI); categorical variables 
include sex, age group (<65 years old; ≥65 years old), BMI group (less than 18.5, 18.5 to less 
than 25, 25 to 30, above 30), race and ethnicity.
Characteristics of insomnia at Study Baseline will be summarized using LPS, SE, WASO, 
sSOL, sSE, sWASO, sTST, and ISI.  The BDI-II and BAI scores will also be summarized at 
Study Baseline. 
The demographic data will be summarized by subgroups of age group, sex, BMI group and 
race.  The above tables will be produced for the FAS if it differs from the Safety Analysis 
Set.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11 digit code 
using the World Health Organization Drug Dictionary (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 are defined as medications that stopped before the first dose of study drug, 
where study drug includes PBO during the Run-in Period.
Concomitant medications are defined as medications that (1) started before the 1st dose of 
study drug (including the Run-in Period) and are continuing at the time of the 1st dose of 
study drug, or (2) started on or after the date of the 1st dose of study drug (including the Run-
in Period) to the last dose day plus 14 days.  All medications will be presented in subject data 
listing.
Summaries of concomitant medications will also be separately subgrouped into Safety 
Analysis Set. (revised per Amendment 01)
9.7.1.6
Efficacy Analyses
The efficacy analyses will be performed on the FAS except the per protocol analysis will be 
performed on the PP.  (revised per Amendment 01)
Definitions of Baseline
Baseline data are captured during the Run-in and Baseline Period.

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9.7.1.6.1
ANALYSIS FOR THE PRIMARY ENDPOINT (REVISED PER AMENDMENT 01)
Null Hypothesis: For objective LPS, no difference exists in the mean change from Study 
Baseline to the last 2 nights of Month 1 of treatment with LEM10 compared with PBO.
Alternative Hypothesis: For objective LPS, a difference exists in the mean change from 
Study Baseline the last 2 nights of Month 1 for LEM10 compared with PBO.
The objective LPS change from Baseline (the mean of Days 1 and 2, and the mean of Day 29 
and 30) will be analyzed using the mixed effect model repeated measurement analysis 
(MMRM) on the FAS. The model will include all data and will be adjusted for the 
corresponding baseline value (the means from the 2 PSG recordings during the Run-in 
Period), site, age group (<65 years old; ≥65 years old), treatment, time (Days 1/2, and Days 
29/30), and the interaction of treatment by time. Since LPS is known to be non-normally 
distributed, a log-transformation will be used in the analysis.  Factor “Site” will be defined in 
the SAP before database lock. An unstructured covariance matrix will be used, and if the 
model fails to converge, then an autoregressive matrix will be used. The missing values will 
be imputed using a pattern mixture model utilizing multiple imputations (MI) assuming the 
missing values are missing not at random (MNAR) utilizing the complete case missing value 
pattern (CCMV-subjects who completed primary efficacy assessments without missing 
values).  The missing values for a given visit will be imputed using all available values 
including the retrieved measurement from the post-discontinuation data. The P-value, least 
square (LS) means and the 95% confidence interval (CI) for the treatment difference will also 
be provided.
Subgroup analyses and additional sensitivity analysis will be performed as appropriate.
The following analyses will be considered as sensitivity analyses:
•
PP analysis: The same primary efficacy analyses described above will be repeated 
based on PP analysis set.
•
Completer analysis: The same primary efficacy analyses described above will be 
repeated on subjects who completed all efficacy assessments and have no missing 
values.
•
As-treated analysis: The same primary efficacy analyses (MMRM analysis with 
MI for missing value imputation) will be repeated based on the actual treatment 
the subject received regardless of randomization.
•
MMRM analysis assuming missing at random (MAR): The same primary 
endpoint analysis described above will be analyzed using MMRM assuming the 
missing values are MAR.
•
MI Imputation assuming MNAR utilizing CCMV-4: The same MMRM method 
used in the primary analysis will be applied utilizing CCMV-4 (ie, up to 4 
monotone missing patterns will be used for missing value imputation as follows)

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Study days where results are available
1
2
29
30
Pattern 1
x
x
x
x
Pattern 2
x
x
x
–
Pattern 3
x
x
–
–
Pattern 4
x
–
–
–
x: result present; – : result missing
9.7.1.6.2
SECONDARY EFFICACY ANALYSIS (REVISED PER AMENDMENT 04)
The other efficacy endpoints (change from Baseline of the following for LEM10 compared to 
PBO; mean objective SE, mean objective WASO, mean sSOL, mean sSE, and mean sWASO 
at the first 7 nights and last 7 nights of treatment; ISI total number and total score of 4 items 
of daytime functioning after 1 month of treatment) will be analyzed using the MMRM, 
assuming the missing values are missing at random (MAR).  The sSOL will be implemented 
on the log-transformation.  Subgroup analyses will be defined SAP in detail.
Rebound insomnia is defined as worsened sleep relative to Screening after study drug 
treatment is completed. Sleep diary data from the Follow-Up Period will be compared to 
sleep diary data from the Screening Period to assess whether subjects experience rebound 
insomnia. To assess rebound insomnia, both categorical analysis at the subject level and 
continuous analysis at the group mean level will be performed. For each of the first 3 nights 
and each of the 2 weeks of the Follow-Up Period the proportion of subjects whose 
corresponding value for sSOL or sWASO exceeds the corresponding Screening Period value 
by 5 minutes will be summarized by treatment group and compared to PBO. The percentage 
of ‘rebounders’ between LEM10 and PBO group will be analyzed using a chi-square test.  To 
assess statistical significance using the continuous data, the data will be analyzed using 
ANCOVA. The LS mean of each of the first 3 nights and each week of the Follow-Up 
Period will be compared to the Screening Period between LEM10 and PBO. If the lower 
bound of the 95% CI of sSOL or sWASO for each of the first 3 nights and the mean of each 
week of the Follow-Up Period exceeds the upper bound of a 95% CI for the values during the 
Screening Period in the given treatment group, it will be considered strong evidence for 
rebound insomnia. If the LS means for sSOL and sWASO for the Follow-Up Period are all 
lower than for the Screening Period, then no rebound insomnia is suggested. Otherwise, the 
degree to which the parameters worsen, and the time point(s) at which they worsen will be 
considered to evaluate whether clinically meaningful rebound insomnia is present.
To evaluate morning residual sleepiness during study treatment and following completion of 
treatment, the change from baseline of the mean of morning sleepiness item on the sleep 
diary for the first 7 mornings of the Treatment Period, the last 7 mornings of the Treatment 
Period, as well as the means of the first 7 days and second 7 days of the Follow-Up Period 
will be analyzed using MMRM assuming MAR.

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9.7.1.6.3
EXPLORATORY EFFICACY AND PHARMACODYNAMIC ANALYSES  
The change from Baseline for the mean score of the quality of sleep item on the sleep diary 
will be analyzed, to consider the subjective quality of sleep, using MMRM, assuming MAR 
for the mean of the first 7 days after 1 month of treatment.  The change from Baseline (at 
Screening) for BDI-II and BAI will be analyzed using ANCOVA including treatment and 
Baseline.  Other efficacy measures will be tabulated, and may be plotted, but will not be
statistically analyzed.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
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 
lemborexant and its metabolites M4, M9, and M10 plasma concentrations by dose and blood 
sampling point.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
There are no variables in this study that are primarily designated as PD variables.  These 
analyses are described in the Secondary Efficacy and Pharmacodynamic Analysis Section 
9.7.1.6.2 and Exploratory and Pharmacodynamic Analyses Section 9.7.1.6.3.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
Not applicable.
9.7.1.7.4
PHARMACOGENOMIC ANALYSES
Not applicable.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the relevant Safety Analysis Set. 
The incidence of AEs, out-of-normal-range laboratory safety test variables, abnormal ECG 
findings, out-of-range vital signs and weight, along with change from baseline in laboratory 
safety test variables, ECGs, and vital sign and weight measurements, will be summarized by 
treatment group using descriptive statistics.
Secondary and exploratory endpoints may be additionally presented graphically or analyzed 
by modeling methods if warranted. 
Details of all of analysis will be specified in the SAP.

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9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study
drug will be summarized descriptively.  The exposure data with LEM10 will be summarized 
for: the number (percent) of subjects who completed ≥7 days or ≥30 days.
Compliance 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 >120%.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 22.1 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 (including the Run-in Period), having been absent at pretreatment (before the Run-
in Period) 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. AEs will be 
classified as TEAEs up to 14 days after the last study treatment. (revised per Amendment 04)
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 of events as TEAEs by SOC and PT will 
also be summarized.
The number of subjects (percentage)/events with TEAEs will also be summarized by 
maximum severity (mild, moderate, or severe).
The number of subjects (percentage)/events with TEAEs will also be summarized by 
relationship to study drug (Yes [related] and No [not related]).  Treatment related TEAEs 
include those events considered by the investigator to be related to study treatment.  
The number of subjects (percentage)/events with treatment emergent SAEs will be 
summarized by MedDRA SOC and PT for each treatment group.  A subject data listing of all 
SAEs will be provided.

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The number of subjects (percentage)/events 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.
The number of subjects (percentage)/events with preferred term related to drug abuse liability 
will be summarized.  
9.7.1.8.3
LABORATORY VALUES
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  
Abnormal laboratory values will be identified as those outside (above or below) the normal 
range.  Reference (normal) ranges for laboratory parameters will be included in the CSR for 
this study.  Descriptive summary statistics (eg, mean, SD, median, minimum, maximum for 
continuous variables, and number and percentage for categorical variables) for the laboratory 
parameters and changes from Study Baseline will be evaluated by treatment group and visit.
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 will be based on 3 by 3 tables (shift tables) 
that, for a particular laboratory test, compare the Study Baseline LNH classification to the 
LNH classification by treatment group.
Clinical laboratory results post Study Baseline will be evaluated for markedly abnormal 
values.  A laboratory test will be considered markedly abnormal if the result worsens to meet 
Eisai grading criteria for laboratory values limit of Grade 2 or higher.  If the Grade 2 limit is 
missing, the Grade 1 limit will be considered.  Appendix 1 presents the Eisai grading criteria 
for laboratory values that were used to identify subjects with markedly abnormal laboratory 
values.  For the incidence of markedly abnormal laboratory values, each subject may be 
counted once in the laboratory parameter value 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, diastolic and systolic BP, pulse, 
respiration rate, temperature) and weight, and changes from Study Baseline will be presented 
by visit and treatment group.  
Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range.  Categorical analyses of 
subjects (number and percent) who fall outside the below clinically notable vital sign ranges 
(Table 4) will also be presented for change from Study Baseline (Safety Analysis Set) by 
treatment group and by time point.

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Table 4
Clinically Notable Vital Sign Ranges
Variable
Criterion Valuea
Change Relative to Study 
Baselinea
Clinically Notable 
Range
Heart rate
>120 bpm
Increase of 15 bpm
H
<50 bpm
Decrease of ≥15 bpm
L
Systolic BP
>180 mmHg
Increase of ≥20 mmHg
H
<90 mmHg
Decrease of ≥20 mmHg
L
Diastolic BP
>105 mmHg
Increase of ≥15 mmHg
H
<50 mmHg
Decrease of ≥15 mmHg
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 Study Baseline.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from Study Baseline (Safety Analysis 
Set) will be presented by treatment group.  Shift tables will present changes from Study 
Baseline in ECG interpretation (categorized as normal; abnormal, not clinically significant; 
and abnormal, clinically significant) by time point.
For each subject, the maximum observed QTcF, the corrected QT interval calculated using 
Bazett’s formula (QTcB), and the maximum prolongation from Study Baseline in QTcF will 
be compiled.  Categorical analyses of subjects (number and percent) with maximum 
observed QTcF values >450 ms, >480 ms, and >500 ms and maximum prolongations (from 
Study Baseline) in QTcF >30 ms and >60 ms will be presented by treatment group and by 
time point.  Categorical analyses of subjects (number and percent) with maximum observed 
PR values >220 ms, and QRS values >120 ms will be presented by treatment group and by 
time point.
9.7.1.8.6
OTHER SAFETY ANALYSES
Not applicable.
9.7.1.9
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed 
by modeling methods if warranted.  Details of all of analyses will be specified in the SAP.
9.7.2
Determination of Sample Size (revised per Amendment 01)
The sample size was considered based on LPS for each comparison between Study 201 and 
Study 304.  For LEM10 on Days 29 and 30, we assume the effect size that mean difference 
divided by common standard deviation as –0.411 under logarithm transformation.  Therefore, 
to detect a difference in LPS comparing LEM10 with PBO, at least 94 subjects per group 

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(total 188) will be needed for a 0.05 α-level, 2-sided test and more than 80% power based on 
above assumption.
9.7.3
Interim Analysis (revised per Amendment 01)
This is a fixed design.  There is no interim analysis for efficacy and no alpha spending before 
final analysis.  However a blinded sample size re-estimation through estimated standard 
deviation based on blinded data prior to the completion of enrollment, may be performed if 
there is an indication that sample size assumptions need to be changed.  This blinded sample 
size re-estimation could be performed based on signals from external studies or based on 
review of blinded data from this study prior to completion of enrollment.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.

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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.
Arnau RC, Meagher MW, Norris MP, Bramson R.  Psychometric evaluation of the Beck 
Depression Inventory-II with primary care medical patients.  Health Psychology 
2001;20(2):112-9.
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.
Carney CE, Moss TG, Harris AL, Jack D, Edinger JD, Krystal AD.  Should We Be Anxious 
When Assessing Anxiety Using the Beck Anxiety Inventory in Clinical Insomnia Patients?  J 
Psychiatr Res 2011;45(9):1243–9.
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.
Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 
2007;15:S7-10.
Soldatos CR, Allaert FS, Ohta T, Dikeos DG. How do indivisuals sleep around the world? 
Results from a single-day survey in tem countries. Sleep Medicine. 2005;6:5-13.

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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.
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 and remote 
monitoring will be conducted between onsite monitoring visits by the assigned CRA as 
described in the monitoring plan.  The investigator will allow the CRA to inspect the clinical, 
laboratory, and pharmacy facilities to assure compliance with GCP and local regulatory 
requirements.  The eCRFs 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.
Source documents include, but are not limited to the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes that have been certified for 
accuracy after production

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•
Recorded data from automated instruments such as IxRS, x-rays, and other 
imaging reports, (eg, ECGs, EEGs) regardless of how these images are stored, 
including microfiche and photographic negatives
•
Quality of life or 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
•
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
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as source document.  Any correction to entries 
made on the eCRF 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 eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents.  The 
investigator agrees to allow direct access to source documents and study facilities to sponsor 
representative(s), monitor(s) and auditor(s), and agree to inspection by regulatory authorities 
or IRB/IEC representative.
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 eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, 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. (revised per Amendment 01)

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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 the 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 C-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

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Appendix 1
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;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
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
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 2.5ULN if 
baseline was normal;
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
ALT
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
AST
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN if 
baseline was normal; 
1.0 – 1.5baseline if 
baseline was abnormal
>1.5 – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 10.0ULN if 
baseline was normal; 3.0 
– 10.0baseline if 
baseline was abnormal
>10.0ULN if 
baseline was normal; 
>10.0baseline if 
baseline was 
abnormal
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
Ionized calcium <LLN 
- 1.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
Ionized calcium <1.0 -
0.9 mmol/L; 
symptomatic
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
Ionized calcium <0.9 -
0.8 mmol/L; 
hospitalization indicated
<6.0 mg/dL
<1.5 mmol/L
Ionized calcium <0.8 
mmol/L; life-
threatening 
consequences

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Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium >ULN 
- 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium >1.5 -
1.6 mmol/L; 
symptomatic
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium >1.6 -
1.8 mmol/L; 
hospitalization indicated
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences
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 if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes
Insulin therapy initiated; 
hospitalization indicated
life-threatening 
consequences; urgent 
intervention indicated
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
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated
Oral replacement 
therapy indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L; 
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L and 
asymptomatic
<125 – 129  mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms
<120 mmol/L
life-threatening 
consequences

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Grade 1
Grade 2
Grade 3
Grade 4
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
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN without 
physiologic 
consequences 
N/A
>ULN with physiologic 
consequences 
life-threatening 
consequences
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.

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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. (revised per Amendment 01)
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, 7, 8, 9
6
Exclusion Criterion Number
1 – 30
1, 20, 21, 22, 23, 
24, 25, 27, 28
1, 9, 20, 21, 22, 27, 
28

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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
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, Claritin ™ is not 
prohibited
Anxiolytics with known sedating effects
Lorazepam 
Alprazolam 
Buspirone
Moderate CYP3A inhibitors
aprepitant
cimetidine
ciprofloxacin
clotrimazole 
crizotinib
cyclosporine 
dronedarone 
erythromycin 
fluconazole
fluvoxamine 
imatinib
tofisopam
verapamil

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Strong CYP3A inhibitors
Amiodarone 
Bocepravir
Clarithomycin 
Cobicistat
Conivaptan
Danoprevir
Fluvoxamine 
Idelalisib
Indinavir
Itraconazole 
Ketoconazole 
Lopinavir
Mibefradil 
Nefazodone 
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telapravir
Telethromycin
Tipranavir
Troleandomycin 
Voriconazole
CYP3A inducers
Carbamazepine 
St. John’s Wort 
Phenobarbital 
Troglitazone 
Phenytoin 
Rifabutin 
Rifampin
Bosentan
Efavirenz
Etravirine
Lersivirine
Modafinil
Nafcillin
Talviraline
Thioridazine

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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
–
Opioid Analgesics
–
Muscle relaxants (centrally-acting) with known 
sedating effects
GABA analogues 
Hydantoins 
Phenyltriazines
Stimulants
Amphetamines 
Modafinil 
Armodafinil
Methylfenidate
Other
Warfarin, heparin, ticlopidine
Non-stimulant diet pills
Systemic isoretinoin
Systemic glucocorticoids
Tryptophan

Cli nical St u d y Pr ot oc ol
( Per Pr ot oc ol A me n d me nt 05 )
E 2 0 0 6 -J 0 8 6-3 1 1
Eisai
FI N A L ( V 6 . 0):  2 8 J u n 2 0 2 2
C o nfi de ntial
Pa ge 8 8 of 9 0
P R O T O C O L SI G N A T U R E P A G E
St u d y Pr ot oc ol N u m ber:
E 2 0 0 6 -J 0 8 6- 3 1 1
St u d y Pr ot oc ol Title:
A M ult ice nter, Ra n d o mize d, D o u ble-Bli n d, Pl ace b o -C o nt r olle d, 
Parallel -Gr o u p, P hase 3 St u d y  of t he Efficac y a nd Saf et y of  
Le m b ore xa nt i n C hi nese S u bjects wit h I ns o m nia Dis or der
I n vesti g ati o n al Pr o d uct 
N a me:
E 2 0 0 6/le m b ore xa nt
SI G N A T U R E S
A ut h ors: (re vise d per A me n d me nt 05)
 
Ne ur ol o g y  B usi ness Gr o u p, Eisai C hi na I nc .
Date
 
 
Ne ur o l og y B usi ness Gr o u p, Eisai I nc .
Date
 
 
Me dici ne De vel o p me nt Ce nter, Eisai C o., Lt d.
Date
 
 
Me dici ne De vel o p me nt Ce nter, Eisai C o., Lt d.
Date
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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SPONSOR SIGNATURE PAGE
Study Protocol Number:
E2006-J086-311
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study of the Efficacy and Safety of 
Lemborexant in Chinese Subjects with Insomnia Disorder
Investigational Product 
Name:
E2006/lemborexant
Head, Medicine 
Development Center, 
Eisai Co., Ltd.
Signature
Date

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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-J086-311
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study of the Efficacy and Safety of 
Lemborexant in Chinese 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 China Good Clinical Practice (C-GCP), including the 
Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date