Conditions: Obstructive Sleep Apnea Healthy Subjects
Keywords: Elderly Healthy Subjects Adult Healthy Subjects Lemborexant Respiratory Safety Peripheral Oxygen Saturation Total Sleep Time
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 146
Healthy volunteers: yes

Brief summary:
This study will be conducted to determine whether lemborexant as compared to placebo decreases the peripheral oxygen saturation during total sleep time in healthy adult and elderly participants after a single dose of treatment and to determine whether it increases the apnea-hypopnea index after single and multiple doses of treatment in adult and elderly participants with mild obstructive sleep apnea (OSA).

Detailed description:
Healthy Volunteer (HV) Cohort:

The HV Cohort comprises a randomized, double-blind, placebo-controlled, 3-period crossover study. Eligible healthy adult and elderly participants will be randomized to treatment sequence A, B, or C, each consisting of 3 Treatment Periods, each of one night's duration, in which participants will receive a single dose of lemborexant 10 milligrams (mg), or lemborexant 25 mg, or placebo. Treatment Periods will be separated by a washout interval of at least 14 days. A sufficient number of participants will be randomized to ensure that 8 evaluable adult participants (\<65 years) and 4 evaluable elderly participants (≥65 years) complete the study.

OSA Cohort:

The OSA Cohort comprises a multiple-dose, randomized, double-blind, placebo-controlled, 2-period crossover study. Adult and elderly participants with mild OSA will be randomized to treatment sequence D or E, each consisting of 2 Treatment Periods, each of 8 nights' duration, in which participants will receive lemborexant 10 mg or placebo. The Treatment Periods will be separated by a washout interval of at least 14 days. A sufficient number of participants will be randomized to ensure that 20 evaluable adult participants (\<65 years) and 10 evaluable elderly participants (≥65 years) complete the study.

Arms:
arm 1: Eligible healthy adult and elderly participants will receive lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period. arm 2: Eligible healthy adult and elderly participants will receive lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 2, and then lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period. arm 3: Eligible healthy adult and elderly participants will receive lemborexant 25 mg (2 lemborexant 10 mg tablet and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 1, followed by lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period. arm 4: Eligible adult and elderly participants with mild OSA will receive one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period. arm 5: Eligible adult and elderly participants with mild OSA will receive one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period.

Interventions: intervention 1: Placebo intervention 2: Lemborexant 10 mg intervention 3: Lemborexant 25 mg intervention 4: Placebo intervention 5: Lemborexant 10 mg
Intervention descriptions: intervention 1: HV: Lemborexant-matched oral placebo will be administered at bedtime in the clinic (within 5 minutes of lights off). intervention 2: HV: 10 mg oral lemborexant will be administered at bedtime in the clinic (within 5 minutes of lights off). intervention 3: HV: 25 mg oral lemborexant will be administered at bedtime in the clinic (within 5 minutes of lights off). intervention 4: OSA: Lemborexant-matched oral placebo will be administered at bedtime in the clinic (within 5 minutes of lights off) in the evening of Days 1 and 8. On Days 2 to 7, participants will take study drug at home, immediately (within 5 minutes) of the time they intend to try to sleep. intervention 5: OSA: 10 mg oral lemborexant will be administered at bedtime in the clinic (within 5 minutes of lights off) in the evening of Days 1 and 8. On Days 2 to 7, participants will take study drug at home, immediately (within 5 minutes) of the time they intend to try to sleep.

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol
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Revision History 
Previous Version:  v1.0
Current Version:  v2.0
Date of Latest Revision: 12 Mar 2018 (revised per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Updated text in synopsis to align with 
text in the body of the protocol
Correction
Synopsis:

Sites

Primary Objective

Study Design

Exclusion Criteria
Corrected typo
Correction
Section 8.1.2
Revised word for specificity
Correction
Section 8.2.1
Section 9.1.1.2.1
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2006-A001-102
Study Protocol 
Title:
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study 
to Evaluate the Respiratory Safety of Lemborexant in Adult and 
Elderly Healthy Subjects and Adult and Elderly Subjects with Mild 
Obstructive Sleep Apnea
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Investigational 
Product Name:
E2006/Lemborexant
Indication:
Not Applicable
Phase:
1
Approval Date:
V1.0
11 Dec 2017 (original protocol)
V2.0
12 Mar 2018 (revised per Amendment 01)
GCP Statement:
This study is to be performed in full compliance with International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Respiratory 
Safety of Lemborexant in Adult and Elderly Healthy Subjects and Adult and Elderly Subjects with 
Mild Obstructive Sleep Apnea
Investigator(s)
TBD
Sites
Approximately 10 investigational sites in the US (revised per Amendment 01)
Study Period and Phase of Development
Phase 1
First Subject Screened to Last Subject Out: Approximately 5 months
Objectives
Primary Objective (Healthy Volunteer [HV] Cohort)
To determine whether lemborexant decreases the peripheral oxygen saturation (SpO2) during total 
sleep time (TST) in healthy adult and elderly subjects after a single dose of treatment compared with 
placebo
Primary Objective (Obstructive Sleep Apnea [OSA] Cohort) (revised per Amendment 01)
To determine whether lemborexant increases the AHI after multiple doses of treatment in adult and 
elderly subjects with mild OSA compared with placebo
Secondary Objectives (HV Cohort)
1.
Determine whether lemborexant increases the apnea-hypopnea index (AHI) after a single
dose of treatment compared with placebo 
2.
Determine whether lemborexant decreases SpO2 during TST below defined thresholds after a 
single dose of treatment compared with placebo
3.
Evaluate safety and tolerability of lemborexant
Secondary Objectives (OSA Cohort)
1.
Determine whether lemborexant increases the AHI after the first dose of treatment compared 
with placebo
2.
Determine whether lemborexant decreases the mean SpO2 during TST after the first and after
multiple doses of treatment compared with placebo (revised per Amenement 01)
3.
Determine whether lemborexant decreases SpO2 during TST below defined thresholds after 
the first and after multiple doses of treatment compared with placebo (revised per 
Amendment 01)
4.
Evaluate safety and tolerability of lemborexant 
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Exploratory Objectives (HV and OSA Cohorts)
Explore the effects of lemborexant compared with placebo after a single dose in HV Cohort and after 
the first and multiple doses in the OSA Cohort on the following: 
1.
The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, and 
wake
2.
AHI during REM and NREM sleep 
3.
AHI separately for adult and elderly subjects
4.
The mean SpO2 during TST separately for adult and elderly subjects
In addition, explore the following for both HV and OSA Cohorts:
1.
Plasma concentrations of lemborexant and metabolites M4, M9, and M10
2.
Exposure-response 
(E-R) 
relationships 
between 
lemborexant 
concentrations 
and 
pharmacodynamic (PD) variables, including but not limited to respiratory safety variables 
(AHI, mean SpO2 during TST, proportion of TST during which the SpO2 is decreased below 
defined thresholds)
Study Design (revised per Amendment 01)
E2006-A001-102 is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, 
crossover study in adult and elderly healthy subjects and in adult and elderly subjects with mild 
obstructive sleep apnea (OSA).  
Study 102 will consist of 2 cohorts: healthy subjects and subjects with mild OSA. The design of the 
study is based on the studies conducted with suvorexant in healthy volunteers and subjects with OSA.
HV Cohort
The HV Cohort comprises a randomized, double-blind, placebo-controlled, 3-period crossover study.
Eligible healthy adult and elderly subjects will be randomized to treatment sequence A, B or C, each 
consisting of 3 Treatment Periods, each of one night’s duration, in which subjects will receive a 
single dose of lemborexant 10 mg, or lemborexant 25 mg, or placebo; Treatment Periods will be 
separated by a washout interval of at least 14 days.
A sufficient number of subjects will be 
randomized to ensure that 8 evaluable adult subjects (<65 years) and 4 evaluable elderly subjects 
(≥65 years) complete the study.
Treatment 
Sequence
Treatment Periods in the HV Cohort
1 (one night)
2 (one night)
3 (one night)
A
lemborexant-matched 
placebo
lemborexant 10 mg
lemborexant 25 mg
B
lemborexant 10 mg
lemborexant 25 mg
lemborexant-matched 
placebo
C
lemborexant 25 mg
lemborexant-matched 
placebo
lemborexant 10 mg
OSA Cohort 
The OSA Cohort comprises a randomized, double-blind, placebo-controlled, 2-period crossover 
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study. 
Adult and elderly subjects with mild OSA will be randomized to treatment sequences D or E, each 
consisting of 2 Treatment Periods, each of 8 nights’ duration, in which subjects will receive
lemborexant 10 mg or placebo. The Treatment Periods will be separated by a washout interval of at 
least 14 days. A sufficient number of subjects will be randomized to ensure that 20 evaluable adult 
subjects (<65 years) and 10 evaluable elderly subjects (≥65 years) complete the study.
Treatment 
Sequence
Treatment Periods in the OSA Cohort
1 (eight nights)
2 (eight nights)
D
lemborexant-matched placebo
lemborexant 10 mg
E
lemborexant 10 mg
lemborexant-matched placebo
Phases of the Study (HV and OSA Cohorts)
For both the HV and OSA cohorts, there will be 2 phases, Prerandomization and Randomization. 
The Prerandomization Phase for both cohorts will consist of the Screening Period (up to 21 days) and 
a Baseline Period (≤1day prior to randomization). 
For the HV Cohort, the Randomization Phase will comprise 3 Treatment Periods, each of 1-day 
duration, separated by a washout interval of at least 14 days, followed by a 14-day Follow-Up Period.
For the OSA Cohort, the Randomization Phase will comprise 2 Treatment Periods, each of 8 days 
duration, separated by a washout interval of at least 14 days, and a Follow-Up Period of 14 days.  
For both cohorts, an End of Study (EOS) Visit will occur at least 14 days after the final dose of study 
medication.
Prerandomization Phase - HV and OSA Cohorts
Screening Period
At the Screening Period, informed consent will be obtained after the study has been fully explained to 
the subject and before the conduct of any screening procedures or assessments.  All subjects will 
undergo routine safety assessments, including 12-lead electrocardiograms (ECG), physical 
examination, vital signs, weight, height, hematology, blood clinical chemistry analysis, urinalysis,
viral serology, reporting of adverse events (AEs), and assessment of suicidality.  (revised per 
Amendment 01)
A medical, psychiatric, and sleep history interview will be conducted; medical history will include 
history of falls. Female subjects of childbearing potential will undergo a serum pregnancy test.  
Subjects will be instructed on study restrictions pertaining to prohibited medications, drugs, alcohol, 
and caffeine. A urine drug test and breath alcohol test will be administered.
After at least 6 days (to allow subjects the opportunity to complete the sleep diary for at least 5 
consecutive nights), subjects will return to the clinic for the second Screening Visit (Visit 2) to 
undergo polysomnography (PSG). On this and all other 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, scheduled assessments (including a urine drug test and breath alcohol test), as described 
in the Schedule of Assessments/Procedures, and preparations (eg, placement of the electrode montage 
and pulse oximeter). (revised per Amendment 01)
Subjects who continue to meet the eligibility criteria will remain overnight in the sleep laboratory. 
The median habitual bedtime (MHB) will be calculated from the most recent 5 days of the subject’s 
sleep diary, and used to determine bedtime (“lights off”). The PSG recording will begin at lights off 
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and will continue for 8 hours (until lights on).  The end of the 8-hour PSG recording will be defined 
as waketime (“lights on”). Subjects may leave the clinic after the investigator determines that it is 
safe for them to do so. 
The PSG recording will be reviewed for exclusion criteria related to obstructive sleep apnea (for the 
HV Cohort) and to moderate or severe obstructive sleep apnea (for the OSA Cohort), periodic limb 
movement disorder (PLMD), and parasomnias. The pulse oximetry recording will be reviewed for 
exclusion criteria related to oxygen desaturation.  Subjects who continue to meet the eligibility 
criteria will enter the Baseline Period.
Baseline Period
For both cohorts, the Baseline day is also Day 1 of the Treatment Period. At the Baseline Period,
subjects will be admitted to the clinic, and blood and urine samples will be collected for routine 
safety assessments. An ECG and urine drug test and breath alcohol test will be performed, and vital 
signs will be assessed. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered. 
Females of childbearing potential will undergo a urine pregnancy test. 
Randomization Phase – HV Cohort
Treatment Period
For the HV Cohort, subjects who continue to meet the eligibility criteria will be randomized to 
treatment sequence A, B or C consisting of 3 Treatment Periods, 1-night duration each.  
Randomization will be stratified by age (to be specified in the Statistical Analysis Plan [SAP]).  
Within each age stratum, subjects will be randomized to 1 of the 3 treatment sequences. Each 
treatment sequence will be a different ordering of treatment administration.  The study treatments will 
be lemborexant 10 mg, lemborexant 25 mg, and placebo.  
At Treatment Period 1, subjects will enter the sleep laboratory and remain there overnight, where 
bedtime (lights off) will occur at the MHB determined at Screening Visit 2.  Female subjects of 
childbearing potential will have a urine pregnancy test, and all subjects will have a urine drug test and 
breath alcohol test upon entry to the sleep laboratory. Subjects will be administered their assigned 
dose of study drug immediately (within 5 minutes) before lights off. The PSG recording will begin at 
lights off and will continue for 8 hours (until lights on). The following morning, a blood sample for 
pharmacokinetic (PK) assessment will be collected and vital signs assessed, as indicated in the 
Schedule of Procedures/Assessments.  Subjects may leave the clinic after the investigator determines 
that it is safe for them to do so.  
Treatment Period 1 will be followed by Treatment Periods 2 and 3, with each treatment separated 
from the next by a washout of at least 14 days.  Each period will follow the same procedures and 
assessments as Treatment Period 1.
Follow-Up Period
Following Treatment Period 3, a 14-day Follow-Up Period will begin immediately.  Subjects will not 
receive any treatment during the Follow-Up and will return to the clinic after at least 14 days
following the treatment period for an EOS Visit at which safety will be assessed, including AEs, 12-
lead ECG, vital signs, weight, clinical hematology and blood chemistry laboratory evaluations, urine 
pregnancy test, urinalysis, and suicidality assessed by the C-SSRS. If subjects discontinue 
prematurely, they will undergo an Early Termination (ET) Visit and will be followed for at least 14 
days, after which, an EOS visit should be scheduled.
Randomization Phase - OSA Cohort
Treatment Period
Subjects who continue to meet the eligibility criteria after the Baseline Visit will be randomized to 
treatment sequences D or E consisting of 2 Treatment Periods, 8 nights duration each.  
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Randomization will be stratified by age. Within each age stratum, subjects will be randomized to 
1 of the 2 treatment sequences in a 1:1 ratio. Subjects will then enter Treatment Period 1. Treatments 
administered will be lemborexant 10 mg followed by placebo or placebo followed by lemborexant 10 
mg, with the treatment periods separated by a washout interval of at least 14 days. 
Subjects will remain overnight in the sleep laboratory. Bedtime (lights off) will be the MHB that was 
determined at Screening Visit 2. Subjects will receive study drug immediately (within 5 minutes) 
before lights off. The PSG recording will begin at lights off and will continue for 8 hours (until lights 
on). The following morning, a blood sample for PK assessment will be collected and vital signs 
assessed, as indicated in the Schedule of Procedures/Assessments. A single PK sample will be 
collected predose in Period 2 and within 1 hour of awakening in both Periods.
Subjects will be 
provided with study drug to be administered for 6 consecutive nights at home, and will be instructed 
to take the medication immediately (within 5 minutes) before bedtime. If SpO2 <80% for ≥20% of 
TST during the first night of treatment, the subject must be discontinued. Subjects may leave the 
clinic after the investigator determines that it is safe for them to do so. Subjects will be instructed to 
promptly contact the investigator in case of any new complaints or exacerbation of current symptoms. 
On Day 5 (with a window of ±2 days), the site will telephone the subject to assess AEs and record 
concomitant medications. If any AE is clinically significant and requires follow-up, an Unscheduled 
Visit should be arranged as soon as possible.
After 6 consecutive nights of administering study drug at home, subjects will return to the clinic to
remain overnight in the sleep laboratory for a PSG assessment. Subjects will undergo measurement 
of vital signs, urine pregnancy test for female subjects of childbearing potential, and urine drug and 
breath alcohol tests prior to the start of the PSG. Study drug will be administered immediately prior 
to the MHB (ie, within 5 minutes). In addition a blood sample for pre-dose (trough) PK will be taken 
within 1 hour before dosing. The following morning, a PK blood sample will be collected.  Subjects 
will be instructed on study restrictions related to prohibited medications/drugs, alcohol and caffeine, 
and the prohibitions regarding the use of continuous positive airway pressure (CPAP) device or 
dental appliance. Subjects may leave the clinic after the investigator determines that it is safe for 
them to do so. 
After Treatment Period 1, there will be a washout interval of at least 14 days. After the washout 
interval, subjects will return to the clinic for Treatment Period 2, which will follow the same schedule 
and procedures as did Treatment Period 1. 
Follow-Up Period
When the subject is discharged from the clinic after Treatment Period 2, the Follow-Up Period will 
begin. The Follow-Up Period will have a duration of at least 14 days, during which the subjects will 
not receive any study treatment. At the end of the Follow-Up Period, subjects will return to the clinic 
for an EOS visit at which safety will be assessed including adverse events, 12-lead ECGs, vital signs, 
weight, clinical hematology and blood chemistry labs, urine pregnancy test, and suicidality assessed 
by the C-SSRS. If subjects discontinue prematurely, they will undergo an ET Visit and will then be 
followed for at least 14 days, after which, an EOS visit should be scheduled. 
Adjudication Committee 
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure. A set of preferred terms 
constituting a customized Medical Dictionary for Regulatory Activities (MedDRA) query for 
cataplexy or seizure will be used to identify events for adjudication (including cataplexy, muscle 
fatigue, muscular weakness, muscle tone disorder, hypotonia, drop attacks, slurred speech, diplopia, 
falls, convulsions [standardized MedDRA query (SMQ) narrow and broad], atypical migraine, loss of 
consciousness, decreased consciousness, myoclonus, syncope, transient global amnesia, lipothymia, 
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[faintness] and transient ischemic attack). To assist in the preparation of narratives about such events 
and to support the committee’s adjudication process, investigators and site staff will be instructed to 
query subjects who report any of the above events for supplemental information using a questionnaire 
for events potentially related to cataplexy and the serious adverse event (SAE) form for any of the 
above events considered serious.
Number of Subjects
HV Cohort: A sufficient number of subjects will be screened in order to ensure that a total of 12 
evaluable subjects complete the study (8 evaluable adult subjects [<65 years] and 4 evaluable elderly 
subjects [≥65 years]). Discontinued subjects may be replaced to ensure 8 adult subjects and 4 elderly 
subjects complete all 3 Treatment Periods.
OSA Cohort: A sufficient number of subjects will be screened in order to ensure that a total of 30 
evaluable subjects complete the study (20 evaluable adult subjects [<65 years] and 10 evaluable 
elderly subjects [≥65 years]). Discontinued subjects may be replaced to ensure 20 adults and 10 
elderly subjects complete both Treatment Periods.
Inclusion Criteria (HV and OSA Cohorts)
1.
Male or female, age ≥18 years and ≤90 years at the time of informed consent
2.
Voluntary agreement and ability to provide written informed consent 
3.
Reports habitually sleeping for at least 5.5 hours per night 
4.
Agrees to stay in bed for 7 hours per night for the duration of treatment.
5.
Reports habitual bedtime between 21:00 and 01:00 
6.
SpO2 ≥94% assessed as part of vital signs at Screening Visit 1
Additional Inclusion Criteria (HV Cohort)
7.
Body mass index (BMI) <32 kg/m2
8.
On Screening PSG (Screening Visit 2) AHI <5 
Additional Inclusion Criteria (OSA Cohort)
9.
BMI <40 kg/m2
10. Obstructive sleep apnea, diagnosed according to the criteria of the International Classification of 
Sleep Disorders, version 3 (ICSD-3) 
11. On Screening PSG: AHI >5 to <15 (mild severity)
Exclusion Criteria (HV and OSA Cohorts)
1.
A current diagnosis of restless legs syndrome, PLMD, circadian rhythm sleep disorder, or 
narcolepsy
2.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator 
indicate the need for referral for a diagnostic evaluation for the presence of narcolepsy
3.
A history of a parasomnia or parasomnia observed on the Screening PSG that in the investigator’s 
opinion makes the subject unsuitable for the study
4.
Periodic Limb Movement with Arousal Index (PLMAI) as measured on the Screening PSG: 
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
Age 18 to <65 years: PLMAI ≥10

Age ≥65 years: PLMAI >15
5.
Females who are breastfeeding or pregnant. For females of childbearing potential, the serum 
beta-human chorionic gonadotropin (ß-hCG) pregnancy test must be negative at Visit 1 and the 
urine pregnancy test must be negative at Screening Visit 2 and Baseline. An additional 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the first dose of study drug.  
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.
NOTES: 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).
It is permissible that if a highly effective method of contraception is not appropriate or acceptable 
to the subject, the subject must agree to use a medically acceptable method of contraception, ie, 
double-barrier methods of contraception such as condom plus diaphragm or cervical/vault cap 
with spermicide.
6.
History of or suspected drug or alcohol use disorder within approximately 2 previous years
7.
A positive drug test at Screening or Baseline, or unwilling to refrain from use of recreational 
drugs during the study
8.
Reports habitually consuming more than 14 drinks containing alcohol per week (females) or 
more than 21 drinks containing alcohol per week (males), and unwilling to forego alcohol during 
the days prior to PSG recordings and to limit alcohol intake to no more than 2 alcohol-containing 
drinks per day (females) or 3 alcohol-containing drinks per day (males) on all non-PSG days for 
the duration of his/her participation in the study (NB: alcohol will not be permitted in the sleep 
laboratory). 
9.
Reports habitual caffeine use that is excessive in the opinion of the investigator. 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.  (revised per Amendment 01)
10. Known to be human immunodeficiency virus (HIV) positive
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11. Active viral hepatitis (B or C) as demonstrated by positive viral serology at Screening
12. A prolonged QT/QTc interval (QTcF >450 ms) as demonstrated by a repeated ECG at Screening 
(repeated if initial ECG indicates a QTcF interval >450 ms) (revised per Amendment 01)
13. Comorbid nocturia resulting in the need to get out of bed to use the bathroom more than 3 times 
during the night
14. Any history of medical or psychiatric condition that in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments
15. Any suicidal ideation with intent to act with or without a plan, current or within 6 months before 
the C-SSRS administration during the Screening (e.g. answering “Yes” to questions 4 or 5 on the 
Suicidal Ideation section of the C-SSRS)  (revised per Amendment 01)
16. Any suicidal behavior (per the Suicidal Behavior section of the C-SSRS) within 10 years of 
Screening  (revised per Amendment 01)
17. Scheduled for surgery during the study that requires general anesthesia or administration of 
prohibited medications
18. Used any prohibited prescription or over-the-counter medications within 1 week or 5 half-lives, 
whichever is longer, before the Screening PSG
19. Hypersensitivity to lemborexant or excipients
20. Currently enrolled in another interventional clinical trial or used any investigational drug or 
device within 30 days or 5 times the half-life, whichever is longer preceding informed consent
21. Previously participated in other clinical trial of lemborexant
22. Is unable to avoid working a night shift within 2 weeks before the Screening PSG, or between the 
Screening PSG and end of study
23. Has travelled across 3 or more time zones in the week prior to Screening, or plans to travel across 
3 or more time zones during the study
24. Clinically significant findings based on vital signs, physical examination, ECG, or clinical 
laboratory tests (revised per Amendment 01)
Additional Exclusion Criteria (HV Cohort)
25. Any valid event of SpO2 <90% during the Screening PSG 
26. Current evidence of a clinically significant, active respiratory disorder. This includes 
bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease, or any other 
pulmonary disorder identified by review of medical history, physical examination, and which in 
the opinion of the investigator, could compromise the subject’s safety or interfere with study 
assessments. 
27. Presence of significant illness (including insomnia) that requires treatment or may influence the 
study assessments (e.g. psychiatric disorders, disorders of the gastrointestinal tract, liver, kidney, 
respiratory system, endocrine system, hematological system, neurological system, cardiovascular 
system, or a congenital abnormality), malignancy within the past 5 years (other than adequately 
treated basal cell carcinoma or in situ carcinoma of the cervix), or chronic pain that in the opinion 
of the investigator could interfere with the study assessments. Subjects for whom a sedating drug 
would be contraindicated for safety reasons because of the subject’s occupation or activities are 
also excluded.
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Additional Exclusion Criteria (OSA Cohort)
28. SpO2 <80% for ≥ 5% of TST during the Screening PSG 
29. Uses or plans to use  CPAP device or dental appliance within 2 weeks of the Screening PSG 
(Screening Visit 2) or during the study 
30. Current evidence of a clinically significant, active respiratory disorder other than OSA. This 
includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any other 
pulmonary disorder identified by review of medical history, physical examination, and which in 
the opinion of the investigator, could compromise the subject’s safety or interfere with study 
assessments. 
31. Current evidence of other clinically significant disease (e.g. psychiatric disorders, disorders of the 
gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, 
neurological system, cardiovascular system, or a congenital abnormality), malignancy within the 
past 5 years (other than adequately treated basal cell carcinoma or in situ carcinoma of the 
cervix), or chronic pain that in the opinion of the investigator could affect the subject’s safety or 
interfere with the study assessments. Subjects for whom a sedating drug would be contraindicated 
for safety reasons because of the subject’s occupation or activities are also excluded. Subjects 
with insomnia disorder, who complain of difficulties with sleep onset and/or sleep maintenance, 
are eligible provided that they meet this criterion. Note that medications to treat insomnia are 
prohibited; see the appendices of the protocol.
Study Treatments
HV Cohort: lemborexant 10-mg film-coated tablets, lemborexant 25-mg dose consisting of 2 tablets 
of lemborexant 10 mg and 1 tablet of lemborexant 5 mg, lemborexant-matched placebo tablets. To 
maintain the blind, additional placebo tablets will be added in order to have in total 3 tablets 
administered during each Treatment Phase.
Study drug will be administered at bedtime in the clinic (within 5 minutes of lights off) in the evening 
of Day 1. Treatments will be administered orally with 240 mL (8 fluid ounces) of water.
OSA Cohort: lemborexant 10-mg film-coated tablets, lemborexant-matched placebo tablets
Study drug will be administered at bedtime in the clinic (within 5 minutes of lights off) in the evening 
of Days 1 and 8. On Days 2 to 7, subjects will take study drug at home, immediately (within 5 
minutes) of the time they intend to try to sleep. Treatments will be administered orally with 240 mL 
(8 fluid ounces) of water.
Duration of Treatment
HV Cohort: A maximum of 3 days, comprising 3 Treatment Periods, each with a duration of 1 day
OSA Cohort: A maximum of 16 days, comprising 2 Treatment Periods, each with a duration of 8 
days.
Concomitant Drug/Therapy (HV and OSA Cohorts)
OSA subjects will be required to abstain from using a CPAP device or dental appliance for at least 
2 weeks before the Screening PSG, and throughout the study (until after the EOS Visit). 
Subjects must abstain from the use of recreational drugs throughout the study. No alcohol will be 
permitted in the clinic.
Prohibited medications (see appendices of the protocol) should not be used during the study. A 
subject must not have used any prohibited prescription or over-the-counter medications within 1 
week or 5 half-lives, whichever is longer, before Screening Visit 2. 
Prohibited medications include strong cytochrome P450 (CYP3A) inhibitors and all CYP3A inducers
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as listed in the appendices to the protocol. Prohibited medications also include any pharmacological 
treatment for insomnia disorder, including any medications (hypnotics or medications with known 
sedating effects) that are used for the purpose of inducing sleep or for treating OSA. These 
prohibitions apply even if the entire class to which that medication belongs is not prohibited 
(eg, anticonvulsants). 
If a medication is not specified as prohibited but is in the same class as a medication that is listed in 
appendices of the protocol, and if the investigator is uncertain whether the medication has known 
sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy, 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 strong 
CYP3A inhibitors and all CYP3A inducers will not be permitted at any time for any duration during 
the study as listed in appendices to the protocol.
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Assessments
Screening Assessments 
Sleep Diary
A paper Sleep Diary will be completed within an hour of morning wake time on each morning of the 
Screening Period until the Screening PSG. This Sleep Diary will yield information on the MHB that 
will be used to determine eligibility, and to determine bedtime (lights off) in the clinic. 
Efficacy Assessments
Not applicable. 
Pharmacokinetic Assessments
A single blood sample for plasma concentrations of lemborexant and its metabolites M4, M9, and 
M10 will be taken at predefined visits (see Schedule of Procedures/Assessments). The exact time and 
date of the most recent dose administered before each sample will be documented.
Safety Assessments
Safety assessments will include monitoring and recording all AEs; laboratory evaluation for 
hematology, blood chemistry, and urinalysis; 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.
C-SSRS
Suicidality will be assessed using the C-SSRS. The C-SSRS assesses an individual’s degree of 
suicidality, including suicidal ideation and suicidal behavior.
Pharmacodynamic Assessments
PSG
Each PSG recording will include an electrode montage with electroencephalography (EEG), 
electromyography (EMG), electrooculography (EOG), and ECG channels. In addition, the montage 
will include channels for recording respiratory variables including pulse oximetry. In addition, the 
Screening PSG will include channels for assessment of symptoms of periodic limb movement 
disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard criteria. At 
Screening Visit 2, the PSG will be used to calculate AHI and PLMAI for evaluation of eligibility 
criteria. Subsequent PSGs will be used to determine:

AHI: the number of apneas and hypopneas divided by the TST (in minutes) and multiplied by 
60 (min / hour) (ie, the average number of apneas and hypopneas per hour of sleep), as 
defined by the American Academy of Sleep Medicine (respiratory safety/PD assessment)

SpO2 level

REM/NREM stages (minutes and proportion from TST and time in bed)
Transmissive pulse oximetry is a noninvasive method for monitoring peripheral oxygen saturation 
(SpO2). A sensor device is placed on a thin part of the subject’s body; in the present study, this will 
be a fingertip. The device passes two wavelengths of light through the body part to a photodetector. 
This measures the changing absorbance at each of the wavelengths, allowing determination of the 
absorbance caused by the pulsing arterial blood alone, excluding venous blood, skin, bone, muscle 
and fat. The reading of oxygen saturation by pulse oximetry is not necessarily identical to the reading 
of arterial oxygen saturation (SaO2) from (invasive) analysis of arterial blood gas, but the two are 
sufficiently correlated that pulse oximetry is valuable for measuring oxygen saturation in a clinical 
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setting, including in clinical trials.
Bioanalytical Methods
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10) will be measured using 
validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay methods.
Statistical Methods
Details of statistical methods and analyses will be specified in the Statistical Analysis Plan (SAP).
The following endpoints will compare lemborexant treatments with placebo:
Primary Endpoint (HV Cohort)
The mean SpO2 during TST on Day 1 of treatment 
Secondary Endpoints (HV Cohort)
1.
The AHI on Day 1 of treatment
2.
The percentage of TST during which SpO2 is <90%, <85% and <80% on Day 1 of treatment
3.
The proportion of subjects with at least one incident of SpO2 <90% for at least 30 seconds
during TST on Day 1 of treatment
Primary Endpoint (OSA Cohort)
The AHI on Day 8 of treatment
Secondary Endpoints (OSA Cohorts)
1.
The AHI on Day 1 of treatment
2.
The mean SpO2 during TST on Day 1 and Day 8 of treatment 
3.
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and Day 
8 of treatment
4.
The proportion of subjects with at least one incident of SpO2 <90% for at least 30 seconds 
during TST on Day 1 and Day 8 of treatment.
Exploratory Endpoints (HV and OSA Cohorts)
1.
The mean SpO2 during REM sleep, NREM and wake 
2.
The AHI during REM and NREM sleep
3.
The AHI separately for adult and elderly subjects at all days assessed
4.
The mean SpO2 during TST separately for adult and elderly subjects at all days assessed
Pharmacokinetic Endpoint (HV and OSA Cohorts)
Lemborexant and metabolites M4, M9 and M10 plasma concentrations 
Pharmacokinetic/Pharmacodynamic (Exposure-Response) Endpoint (HV and OSA Cohorts)
Correlations between plasma concentrations of lemborexant and select pharmacodynamic variables 
including AHI, mean SpO2 during TST, and proportion of TST in which SpO2 is <90%, <85% and 
<80% at all days assessed.
Analysis Sets
Safety Analysis Set: Group of subjects who received study drug and have at least one postdose safety 
assessment.
Pharmacodynamic Analysis Set: The PD Analysis Set is the group of subjects who received at least 1 
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dose of study drug in all Treatment Periods and who had sufficient PD data to derive at least 1 
primary PD parameter. 
Pharmacokinetic Analysis Set: Group of subjects who have at least 1 quantifiable plasma 
concentration after dosing with lemborexant.
Efficacy Analyses
Not applicable
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual lemborexant and M4, M9 and M10 plasma 
concentration listings. The PK Analysis Set will be used for summaries of lemborexant and M4, M9 
and M10 plasma concentrations.
Pharmacodynamic Analyses
The following analyses will be performed on the PD Analysis Set for each cohort.
Analysis for the Primary Endpoint
HV Cohort: Mean SpO2 during TST will be analyzed using a mixed effect model . The model will 
include fixed effects for sequence, period, and treatment, and a random effect for subject within 
sequence. The following will be presented: least squares (LS) means, difference in LS mean of 
lemborexant 10 mg and lemborexant 25 mg compared to placebo, a two-sided 90% CI (equivalent to 
a one-sided lower 95% CI) for the true mean difference (lemborexant − placebo) in SpO2 and p-value. 
If the lower bound of the one-sided 95% CI of the treatment difference of SpO2 is less than -5, this 
will provide evidence that the given dose of lemborexant does not result in a clinically significant 
decrease in SpO2 compared to placebo.
OSA Cohort: AHI will be analyzed using a mixed effect model. The model will include fixed effects 
for sequence, period, and treatment, and a random effect for subject within sequence. The following 
will be presented: LS means, difference in LS mean of lemborexant 10 mg compared to placebo, a 
two-sided 90% CI (equivalent to a one-sided upper 95% CI) for the true mean difference 
(lemborexant − placebo) in AHI and p-value. If the upper bound of the one-sided 95% CI of the 
treatment difference of AHI is less than 5, this will provide evidence that the given dose of 
lemborexant does not result in a clinically significant increase in AHI with mild OSA compared with 
placebo.
A sensitivity analysis may also be performed on the primary endpoint where outliers are excluded. 
Other sensitivity analyses may be explored. 
Plots of AHI and SpO2 treatment difference data (both individual and LS Mean) will be used to 
explore the results.
Analysis for the Secondary Endpoints
The continuous secondary endpoints will be analyzed using the same model as the primary endpoint. 
Treatment comparison will be performed using contrasts.  
The proportion of subjects with SpO2 <90% will be summarized using descriptive statistics. All 
analyses will be performed separately for each cohort.
Analysis for the Exploratory Endpoints
Summaries and plots of all endpoints may be produced for appropriate subgroups (eg age group, sex, 
BMI, race).
Subgroup analyses will also be performed as appropriate on primary and all secondary endpoints. All 
analyses will be performed separately for each cohort.
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Pharmacokinetic/Pharmacodynamic (Exposure-Response) Analyses
The exposure-response (E-R) relationship between plasma concentrations of lemborexant after PSG, 
and selected PD parameters including but not limited to the respiratory safety variables (including 
AHI, mean SpO2 during TST, and [proportion]of TST in which SpO2 is <90%, <85%, and <80%) will 
be explored graphically. Any emergent relationship may be followed using population model-based 
analysis. The potential effect of covariates (eg, age) on the E-R relationship may be explored. The PK 
Analysis Set will be used for these assessments. All analyses will be performed separately for each 
cohort.
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set. The incidence of AEs, out-of-
normal-range markedly abnormal laboratory variables, out-of-range vital signs, and suicidality 
variables (C-SSRS) will be summarized using descriptive statistics.  All analyses will be performed 
separately for each cohort.
Interim Analyses
No interim analysis is planned.
Sample Size Rationale
HV Cohort:
A mean difference of 5 percentage points between treatments in SpO2 is considered to be clinically 
meaningful in a study of the respiratory safety of suvorexant in healthy adult volunteers (Uemura, et 
al., 2015). From that source, the within-subject variance is assumed to be 0.315%. With a total of 12 
subjects (4 elderly and 8 adults) completing the study and assuming that the true difference between 
treatments is -1.0, there is 99% power that the lower bound of the 90% confidence interval for the 
difference in SpO2 (lemborexant - placebo) would be greater than -5. Although the estimate of 
within-subject variability is based on a study of adult healthy volunteers, the addition of elderly 
subjects is expected to have a minimal effect on the combined variability and thus a minimal effect 
on the power. 
OSA Cohort: A mean difference between treatments in AHI > 5 is considered clinically meaningful 
in studies of the respiratory safety of sleep agents in OSA (Sun, et el., 2016). The within-subject 
variance is assumed to be 25.34 for AHI for adult subjects (Sun, et al, 2016) and 30.41 for AHI for 
elderly subjects (where the elderly within-subject variance is estimated from adult data + 20%,
Mitterling, et al, 2015; Lee, et al, 2016). Assuming the true difference in AHI (lemborexant –
placebo) on Day 8 is as high as 1.5, a total of 30 subjects completing the study (20 adult, 10 elderly), 
provides 82% power that the upper bound of the 90% CI for the treatment difference in AHI 
(lemborexant − placebo) on Day 8 would be < 5. 
Sample Size Estimates
Description
Combined 
within-subject 
variance of AHI
Adult
N
Elderly
N
Total
N
Total 
Power
(%)
80% overall power with 
20 adult subjects
26.96
20
10
30
82
85% overall power with 
20 adult subjects
27.38
20
14
34
86
80% overall power with 
20 elderly subjects
28.54
12
20
32
82
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85% overall power with 
20 elderly subjects
28.16
16
20
36
86
Equal number of 
subjects
27.875
20
20
40
90
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................24
5
ETHICS............................................................................................................................26
5.1
Institutional Review Boards/Independent Ethics Committees ..............................26
5.2
Ethical Conduct of the Study.................................................................................26
5.3
Subject Information and Informed Consent...........................................................27
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................28
7
INTRODUCTION ...........................................................................................................29
7.1
Lemborexant ..........................................................................................................30
7.1.1
Lemborexant and Respiratory Function.......................................................30
7.1.2
Mechanism of Action...................................................................................31
7.1.3
Clinical Experience With Lemborexant.......................................................31
7.1.3.1
Phase 1 .................................................................................................31
7.1.3.2
Phase 2 .................................................................................................33
7.2
Study Rationale......................................................................................................33
8
STUDY OBJECTIVES....................................................................................................36
8.1
Primary Objectives.................................................................................................36
8.1.1
HV................................................................................................................36
8.1.2
OSA..............................................................................................................36
8.2
Secondary Objectives.............................................................................................36
8.2.1
HV................................................................................................................36
8.2.2
OSA..............................................................................................................36
8.3
Exploratory Objectives (HV and OSA Cohorts) ...................................................37
9
INVESTIGATIONAL PLAN..........................................................................................37
9.1
Overall Study Design and Plan..............................................................................37
9.1.1
Healthy Volunteer Cohort............................................................................37
9.1.1.1
Prerandomization Phase (HV Cohort) .................................................38
9.1.1.1.1
Screening Period (HV Cohort).......................................................38
9.1.1.1.2
Baseline Period (HV Cohort).........................................................39
9.1.1.2
Randomization Phase (HV Cohort) .....................................................39
9.1.1.2.1
Treatment Periods (HV Cohort).....................................................40
9.1.1.2.2
Follow-Up Period (HV Cohort).....................................................40
9.1.2
Obstructive Sleep Apnea (OSA Cohort)......................................................41
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9.1.2.1
Prerandomization Phase (OSA Cohort)...............................................44
9.1.2.1.1
Screening Period  (OSA Cohort) ...................................................44
9.1.2.1.2
Baseline Period (OSA Cohort).......................................................45
9.1.2.2
Randomization Phase (OSA Cohort)...................................................45
9.1.2.2.1
Treatment Periods (OSA Cohort) ..................................................45
9.1.2.2.2
Follow-Up Period (OSA Cohort)...................................................46
9.2
Discussion of Study Design, Including Choice of Control Groups.......................47
9.2.1
Study Design (HV Cohort) ..........................................................................47
9.2.2
Study Design (OSA Cohort)........................................................................47
9.2.3
Randomization.............................................................................................48
9.2.3.1
HV Cohort............................................................................................48
9.2.3.2
OSA Cohort .........................................................................................48
9.2.4
Adjudication Committee (HV and OSA Cohorts).......................................48
9.3
Selection of Study Population................................................................................49
9.3.1
Inclusion Criteria (HV and OSA Cohorts)...................................................49
9.3.2
Additional Inclusion Criteria (HV Cohort)..................................................49
9.3.3
Additional Inclusion Criteria (OSA Cohort)................................................49
9.3.4
Exclusion Criteria (HV and OSA Cohorts) .................................................50
9.3.5
Additional Exclusion Criteria (HV Cohort).................................................52
9.3.6
Additional Exclusion Criteria (OSA Cohort) ..............................................52
9.4
Treatments..............................................................................................................53
9.4.1
Treatments Administered.............................................................................53
9.4.1.1
Identity of Investigational Products.....................................................54
9.4.1.2
Chemical Name, Structural Formula of lemobrexant..........................54
9.4.2
Comparator Drug .........................................................................................55
9.4.2.1
Labeling for Study Drug......................................................................55
9.4.2.2
Storage Conditions...............................................................................55
9.4.3
Method of Assigning Subjects to Treatment Sequences..............................55
9.4.4
Selection of Doses in the Study...................................................................55
9.4.5
Selection and Timing of Dose for Each Subject..........................................56
9.4.6
Blinding........................................................................................................56
9.4.7
Prior and Concomitant Therapy...................................................................56
9.4.8
Prohibitions and Restrictions during Study Period......................................57
9.4.8.1
Food and Water....................................................................................57
9.4.8.2
Beverage and Other Restrictions .........................................................57
9.4.8.3
Physical Activity Restrictions..............................................................57
9.4.9
Treatment Compliance.................................................................................57
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9.4.10
Drug Supplies and Accountability...............................................................57
9.5
Study Assessments.................................................................................................59
9.5.1
Assessments.................................................................................................59
9.5.1.1
Demography.........................................................................................59
9.5.1.2
Baseline Assessments ..........................................................................59
9.5.1.2.1
Medical History .............................................................................59
9.5.1.2.2
Sleep Diary.....................................................................................59
9.5.1.3
Efficacy Assessments...........................................................................60
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................60
9.5.1.4.1
Pharmacokinetic Assessments .......................................................60
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................60
9.5.1.5
Safety Assessments..............................................................................61
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...61
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................63
9.5.1.5.3
Laboratory Measurements .............................................................64
9.5.1.5.4
Vital Signs and Weight Measurements..........................................65
9.5.1.5.5
Physical Examinations...................................................................65
9.5.1.5.6
Electrocardiograms ........................................................................65
9.5.1.5.7
Other Safety Assessments..............................................................66
9.5.1.6
Other Assessments...............................................................................66
9.5.1.6.1
Viral Tests......................................................................................66
9.5.1.6.2
Pregnancy Test...............................................................................66
9.5.1.6.3
Urine Drug Test .............................................................................66
9.5.1.6.4
Breath Alcohol Test .......................................................................66
9.5.2
Schedule of Procedures/Assessments ..........................................................66
9.5.2.1
Schedules of Procedures and Assessments for the HV and OSA 
Cohorts.................................................................................................66
9.5.2.2
Description of Procedures/Assessments Schedule...............................74
9.5.2.3
Total Volume of Blood Sampling........................................................74
HV Cohort 74
OSA Cohort.......................................................................................................74
9.5.3
Appropriateness of Measurements...............................................................75
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................75
9.5.4.1
Reporting of Serious Adverse Events..................................................75
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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................76
9.5.4.3
Reporting of Events Association with Special Situations....................76
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................76
9.5.4.3.2
Reporting of Study-Specific Events...............................................77
9.5.4.4
Expedited Reporting ............................................................................77
9.5.4.5
Breaking the Blind...............................................................................77
9.5.4.6
Regulatory Reporting of Adverse Events ............................................77
9.5.5
Completion/Discontinuation of Subjects.....................................................77
9.5.6
Abuse or Diversion of Study Drug ..............................................................78
9.5.7
Confirmation of Medical Care by Another Physician .................................78
9.6
Data Quality Assurance .........................................................................................78
9.6.1
Data Collection ............................................................................................78
9.6.2
Clinical Data Management ..........................................................................79
9.7
Statistical Methods.................................................................................................79
9.7.1
Statistical and Analytical Plans....................................................................79
9.7.1.1
Study Endpoints...................................................................................79
9.7.1.1.1
Primary Endpoint (HV Cohort) .....................................................79
9.7.1.1.2
Secondary Endpoints (HV Cohort)................................................79
9.7.1.1.3
Primary Endpoint (OSA Cohort) ...................................................80
9.7.1.1.4
Secondary Endpoints (OSA Cohort)..............................................80
9.7.1.1.5
Exploratory Endpoints (HV and OSA Cohorts) ............................80
9.7.1.1.6
Pharmacokinetic Endpoint (HV and OSA Cohorts)......................80
9.7.1.1.7
Pharmacokinetic/Pharmacodynamic (Exposure-Response) 
Endpoint (HV and OSA Cohorts)..................................................80
9.7.1.2
Definitions of Analysis Sets.................................................................80
9.7.1.3
Subject Disposition..............................................................................81
9.7.1.4
Demographic and Other Baseline Characteristics ...............................81
9.7.1.5
Prior and Concomitant Therapy...........................................................81
9.7.1.6
Efficacy Analyses ................................................................................81
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................82
9.7.1.7.1
Pharmacokinetic Analyses.............................................................82
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................82
9.7.1.8
Safety Analyses....................................................................................83
9.7.1.8.1
Extent of Exposure.........................................................................83
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9.7.1.8.2
Adverse Events ..............................................................................83
9.7.1.8.3
Laboratory Values..........................................................................85
9.7.1.8.4
Vital Signs......................................................................................85
9.7.1.8.5
Other Safety Analyses....................................................................85
9.7.1.9
Other Analyses.....................................................................................85
9.7.2
Determination of Sample Size .....................................................................85
9.7.3
Interim Analysis...........................................................................................86
9.7.4
Other Statistical/Analytical Issues ...............................................................86
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................86
10
REFERENCE LIST .........................................................................................................87
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......90
11.1
Changes to the Protocol .........................................................................................90
11.2
Adherence to the Protocol......................................................................................90
11.3
Monitoring Procedures...........................................................................................90
11.4
Recording of Data..................................................................................................91
11.5
Identification of Source Data.................................................................................91
11.6
Retention of Records..............................................................................................91
11.7
Auditing Procedures and Inspection......................................................................92
11.8
Handling of Study Drug.........................................................................................92
11.9
Publication of Results ............................................................................................92
11.10 Disclosure and Confidentiality ..............................................................................93
11.11 Discontinuation of Study .......................................................................................93
11.12 Subject Insurance and Indemnity...........................................................................93
12
APPENDICES .................................................................................................................94
LIST OF IN-TEXT TABLES
Table 1
AHI and Oxygen Saturation During Sleep by Decade of Life (Healthy 
Sleepers).....................................................................................................30
Table 2
Treatments Administered (HV Cohort) .....................................................53
Table 3
Treatments Administered (OSA Cohort)...................................................54
Table 4
List of Laboratory Tests.............................................................................64
Table 5
Schedule of Assessments and Procedures for the HV Cohort in Study 
E2006-A001-102........................................................................................67
Table 6
Schedule of Procedures and Assessments for OSA Cohort in Study 
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Table 7
Summary of Blood Sample Volumes (HV Cohort)...................................74
Table 8
Summary of Blood Sample Volumes (OSA Cohort).................................74
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LIST OF IN-TEXT FIGURES
Figure 1
Study Design for HV Cohort .....................................................................42
Figure 2
Study Design for OSA Cohort...................................................................43
LIST OF APPENDICES
Appendix 1
Sponsor's Grading for Laboratory Values .................................................95
Appendix 2
List of Prohibited Medications...................................................................97
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Acronym
Term
-hCG
beta human-chorionic gonadotropin
AD-D
Alzheimer’s Disease Dementia
AE
Adverse Event
AHI
apnea-hypopnea index
ANOVA
analysis of variance
ATC
anatomical therapeutic chemical
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to 
infinity
BMI
body mass index
BP
blood pressure
C-SSRS
Columbia – Suicide Severity Rating Scale
CFR
code of federal regulations
CI
confidence interval
CLIA
clinical laboratory improvement amendments
CPAP
continuous positive airway pressure
CRA
clinical research associate
CSR
clinical study report
CT
computed tomography
CV
curriculum vitae
CYP3A
cytochrome P450
ECG
electrocardiogram
EEG
electroencephalogram
EMG
electromyography
EOG
electrooculography
EOS
end-of-study
ET
early termination
FDA
Food and Drug Administration
HIV
human immunodeficiency virus
HV
healthy volunteers
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICSD
International Classification of Sleep Disorders
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Acronym
Term
IEC
internal ethics committee
IRB
Institutional Review Board
ISWRD
Irregular Sleep-Wake Rhythm Disorder
IUS
intrauterine hormone releasing system
KSS
Karolinska Sleepiness Scale
LC-MS/MS
liquid chromatography with-tandem mass spectrometry
LLT
lower level term
LS
least-squares
MedDRA
Medical Dictionary for Regulatory Activities
MHB
median habitual bedtime
M-MSLT
modified multiple sleep onset latency test
NREM
non-rapid eye movement
OSA
obstructive sleep apnea
OTC
over-the-counter
PD
pharmacodynamic
PK
pharmacokinetic
PLMAI
Periodic Limb Movement with Arousal Index
PLMD
Periodic Limb Movement Disorder
PSG
polysomnography
PT
Prerferred Term
QTcF
QT interval corrected for heart rate using Fridericia’s formula
REM
rapid eye movement
SAE
serious adverse event
SaO2
peripheral oxygen saturation
SAP
statistical analysis plan
SDLP
standard deviation of lateral position
SMQ
Standardized MedDRA Query
SOC
System Organ Class
SOP
standard operating procedure
TBD
to be decided
TEAE
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory values
TST
total sleep time
WHO
World Hhealth Organization
WHO DD
World Health Organization Drug Dictionary
ZOP
zopiclone
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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) constituted and functioning 
in accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E6 (Good Clinical Practice), 
Section 3, and any local regulations (eg, Federal Regulations, Title 21 CFR Part 56, for US 
studies) Any protocol amendment or revision to the ICF will be resubmitted to the IRB for 
review and approval, except for changes involving only logistical or administrative aspects of 
the study (eg, change in clinical research associate[s], change of telephone number[s]).  
Documentation of IRB 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 chairman must be sent to the principal 
investigator (PI) 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 decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB to the sponsor.
Study progress is to be reported to IRB annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, 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 of any reportable adverse events (AEs) per ICH guidelines and local IRB 
standards of practice.  Upon completion of the study, the investigator will provide the IRB 
with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB and US Food and Drug 
Administration (FDA) within 90 days.  The end of the study will be the date of the last study 
visit for the last subject in the study.  The sponsor should also provide the IRB with a 
summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB and FDA within 15 calendar days, and a detailed written explanation of the reasons for 
the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with SOPs 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 2013
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•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator/desinee must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations (eg, Federal Regulations, Title 21 CFR 
Part 50).  Each subject must sign an approved ICF before study participation.  The form must 
be signed and dated by the appropriate parties.  The original, signed ICF for each subject will 
be verified by the sponsor and kept on file according to local procedures at the site.  
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 10 investigational sites in the United States.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in the Investigator Study File provided to each site.
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7
INTRODUCTION
Lemborexant (E2006) is a novel competitive dual orexin receptor antagonist that is under 
development for both insomnia disorder and irregular sleep-wake rhythm disorder (ISWRD).
Obstructive sleep apnea (OSA) is a common sleep disorder, characterized by intermittent
cessation of airflow because of partial or complete occlusion of the upper airway during 
sleep. Repetitive collapse of the airway leads to sleep fragmentation, hypoxemia, 
hypercapnia, marked swings in intrathoracic pressure, and increased sympathetic activity.
Clinically, OSA is defined by excessive daytime sleepiness, loud snoring, witnessed apneas, 
or awakenings due to gasping or choking, in addition to at least 5 obstructive respiratory 
events per hour (Epstein, et al., 2009). The frequency of apneas and hypopneic episodes per 
hour of sleep is reported as an AHI; this evaluation requires overnight polysomnography 
(PSG). The International Classification of Sleep Disorders (ICSD) (American Academy of 
Sleep Medicine, 2014) defines the severity of OSA according to the AHI: an AHI >5 to <15 
is classed as mild, AHI >15 to <30 as moderate, and AHI >30 as severe.
As a result of daytime sleepiness, patients with OSA are at increased risk of traffic accidents 
(Teran-Santos, et al., 1999). Further, OSA is associated with an increased incidence of 
hypertension, diabetes, cardiovascular and cerebrovascular disease (Bassetti, et al., 1996; 
Bassetti and Aldrich, 1999; Nieto, et al., 2000; Nieto, et al, 2009). Ventilation with 
continuous positive airway pressure (CPAP) is the gold-standard therapy. However, long-
term compliance can be poor, with noncompliance rates as high as 50% by 1 year 
(Collen, et al., 2009). 
Widely quoted figures for overall prevalence of OSA are 2% to 4% in the general adult 
population (Young, et al., 1993). However, the available estimates are likely to be lower than 
the true burden, because OSA is insidious, under-recognized and often undiagnosed 
(Young, et al., 1997). Particularly relevant to the lemborexant program in insomnia disorder 
is that OSA commonly coexists with insomnia; as many as 50% of subjects referred to a 
sleep clinic for sleep apnea have insomnia symptoms (Krakow, et al., 2001). Also highly 
relevant to the lemborexant programs in insomnia disorder is the fact that the prevalence of 
both OSA and insomnia increases with increasing age. Regarding insomnia, epidemiologic 
surveys reveal that more than 50% of adults over the age of 65 years have some form of 
chronic sleep-related complaints (Foley, et al., 1995), which often manifest as complaints of 
difficulty in falling asleep, and night-time awakenings (Ford and Kamerow, 1989). 
Regarding OSA, in a probability sample from two Pennsylvania counties, OSA prevalence 
was shown to increase progressively with age: in men, OSA (AHI>10) was present in 3.2%, 
11.3%, and 18.1% of the 20- to 44-year, 45- to 64-year, and 61- to 100-year age groups, 
respectively (Bixler, et al., 1998; 2001). Further, and highly relevant to the lemborexant 
program in ISWRD, not only does Alzheimer Disease-Dementia (AD-D) tend to be a disease 
of old age, but signs and symptoms of sleep apnea are more common in patients with AD-D 
than in non-demented controls (Tractenberg, et al., 2005; 2006). 
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Even in healthy individuals, respiratory parameters during sleep tend to change with 
advancing decade of life, and to show deterioration after the age of 50 years; functioning 
continues to decline with age. For example, a recent study was conducted in 100 healthy 
sleepers age 19 to 77 years who had no diagnosis or suspicion of a sleep-related breathing 
disorder. Mean and minimal oxygen saturation decreased steadily after the age of 50 years, 
while mean AHI increased with each decade and showed a marked increase after the age 
of 60 years (Table 1; Mitterling, et al., 2015).
Table 1
AHI and Oxygen Saturation During Sleep by Decade of Life 
(Healthy Sleepers)
Respiratory 
parameter
Decade of life
P-value
< 30 years
31–40 years
41–50 years
51–60 years
> 60 years
n
20
21
15
15
24
AHI (median and
range) 
0.5 
(0.0–8.8)
1.0 
(0.0–22.5)
1.9 
(0.0–18.4)
2.6 
(0.0–22.6)
6.6 
(0.6–25.0)
< 0.001
Mean oxygen 
saturation%
95.2 
(93.0–97.5)
95.5 
(92.5–98.0)
95.0
(90.0–98.0)
93.8 
(91.0–96.3)
93.5 
(89.3–96.6)
0.001
Minimal oxygen 
saturation%
90.0 
(84.0–95.0)
91.0 
(86.0–95.0)
89.5 
(81.0–94.0)
88.0 
(78.0–93.0)
87.0 
(80.0–98.0)
0.014
Data are shown as median and range. 
AHI = apnea-hypopnea index.
Data from Mitterling, et al., 2015.
Given the changes in respiratory function with age even in healthy individuals, the increasing 
prevalence of both insomnia and OSA with age, and the coexistence of the 2 conditions in 
many patients, it is important to examine the safety in OSA of agents that are under 
development for sleep disorders.
7.1
Lemborexant
7.1.1
Lemborexant and Respiratory Function
In the multiple ascending dose (MAD) study (E2006-A001-002; Study 002), which recruited 
adults and elderly subjects, a continuous finger pulse oximetry channel ran for 12.5 hours 
each night of 14 nights of dosing. The peripheral oxygen saturation (SpO2) signal would 
alarm if SpO2 dropped below 92%. There was no PSG. The alarm signalled for 3 subjects, 2 
of whom received lemborexant 25 mg while the other received placebo. All 3 subjects 
experienced desaturations below 80%, the level that is considered clinically significant 
hypoxia. No subject experienced hypoxia during screening or pre-dose on study nights. 
The subject dosed with placebo was a 69-year-old Japanese male. On Days 3, 4, 7 and 9 he 
experienced episodes of desaturation that triggered the alarm. On each of these days his SpO2
dipped below 80%, each episode lasting between a few seconds and 2 minutes. His lowest 
value for SpO2 was 77% (for a few seconds). There was no consistent pattern regarding the 
timing of these events during the night.
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The first subject dosed with lemborexant 25 mg with an event was a 76-year-old white male. 
On Days 1, 2, 3, 4, 5, 6, 8, 9 and 10, he experienced desaturations that triggered the alarm. 
On Days 1, 2, 3, 4 and 10, his SpO2 dipped below 80% for a few seconds, usually returning 
to the mid-80% for several minutes before the event resolved. His lowest value for SpO2 was 
75% (for a few seconds). There was no consistent pattern regarding the timing of these 
events during the night.
The second subject dosed with lemborexant 25 mg with an event was a 66-year-old white 
male. On Day 6, his SpO2 fell to 76% for about a minute before rising to 82% for a few 
minutes, after which the event resolved. On Day 13 he experienced “hypoxemia” for a few 
seconds (no quantitative data are available).
7.1.2
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.
7.1.3
Clinical Experience With Lemborexant
7.1.3.1
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 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 
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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 AUC from zero time zero to infinity 
(AUC[0-inf]) was increased by 18% following consumption of a high fat meal.
E2006-E044-106 (Study 106) was a randomized, double-blind, placebo-controlled, 4-way 
incomplete block crossover study in healthy volunteers to evaluate on-road driving safety. 
The primary objective was to demonstrate that lemborexant 2.5, 5, and 10 mg compared to 
placebo does not impair driving as assessed by standard deviation of lateral position (SDLP) 
during an on-road driving test in the morning following a single dose (Day 2) and multiple 
doses (Day 9) of lemborexant administered at bedtime. An active comparator, zopiclone 
7.5 mg (ZOP) was included for assay sensitivity. All subjects received placebo and ZOP, and 
2 of the 3 lemborexant doses. A total of 48 subjects were randomized and completed all 4 
treatment periods; no subject discontinued from the study. No drives were stopped or never 
started while subjects were taking lemborexant; 3 drives from 2 subjects were stopped when 
subjects were taking ZOP. The primary objective was met, ie, for drives on both Day 2 and 
Day 9, for all lemborexant doses, the upper bound of the 95% CI for SDLP treatment 
difference from placebo did not exceed the prespecified clinically meaningful threshold of 
2.4 cm. Symmetry analyses were not statistically significant for any lemborexant dose at 
either Day 2 or Day 9, indicating that the frequency of subjects with SDLP treatment 
difference from placebo ≥2.4 cm (impaired) was similar to the frequency of subjects with 
SDLP treatment difference from placebo ≤-2.4 cm (improved). Assay sensitivity was 
demonstrated: for ZOP, the upper bound of the 95% CI of SDLP treatment difference from 
placebo exceeded 2.4 cm (Days 2 and 9), and the symmetry analyses for ZOP were 
statistically significant (Days 2 and 9).
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 placebo-controlled with a 3-
way crossover.  Next-morning residual sleepiness was measured on a modified multiple sleep 
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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 E2006 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.
7.1.3.2
Phase 2
A dose-finding study (E2006-G000-201; Study 201) was conducted in subjects who had 
insomnia disorder, with the primary objectives of identifying doses that resulted in efficacy 
but did not result in significant next-day residual sleepiness.  The doses evaluated were 
1, 2.5, 5, 10, 15, and 25 mg, administered once daily for 15 days.  The study was stopped 
early for efficacy after the prespecified success criterion for sleep efficiency (SE) was 
achieved without unacceptable next-day residual sleepiness as evaluated by the Karolinska 
Sleepiness 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 latency to 
persistent sleep and wake after sleep onset.  These changes were largely maintained over 15 
days of treatment with lemborexant as compared with placebo.  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 placebo.  At the highest doses of 15 and 25 mg, the 
increase in KSS from baseline was statistically significantly different from placebo 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 one- to two-fold accumulation of lemborexant 
in plasma over the 15-day Treatment Period across the dose range, next-day sleepiness did 
not increase from the beginning to the end of treatment.
7.2
Study Rationale
Sedative hypnotics represent the main pharmacologic therapy for insomnia. Benzodiazepines 
used as sedative hypnotics (eg, triazolam, flurazepam) bind to the benzodiazepine receptor at 
the gamma-amino butyric acid-A (GABA-A) complex; concerns have been raised that this 
mechanism of action might be associated with depression of central respiratory drive, 
blunting of the arousal response to hypoxia, and decreases in muscle tone in the upper 
airways (Guilleminault, 1990; Berry, et al., 1995; George, 2000), thereby exacerbating the 
symptoms of OSA. Limited data are available regarding the use of the newer 
nonbenzodiazepine receptor agonists (the “z-drugs”: zolpidem, zaleplon, zopiclone, and 
eszopiclone) in patients with OSA. The US label for Ambien® (zolpidem) includes a statement 
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that Ambien® should be “used with caution in patients with sleep apnea syndrome.” 
Regarding eszopiclone (Lunesta®), some researchers have reported an improvement in some 
aspects of respiration in patients with OSA (Eckert, et al., 2011). However, the US label for 
Lunesta, though not specifically mentioning OSA, includes a statement that caution is 
advised if Lunesta is prescribed to patients with compromised respiratory function. 
Effects of suvorexant (Belsomra®) on respiratory function have been studied in healthy
subjects (Uemura, et al., 2015). The primary assessment was of mean changes in oxygen 
saturation measured by pulse oximetry (SpO2) while secondary endpoints included the mean 
change from baseline in AHI. Single doses of suvorexant (40 mg and 150 mg) did not 
produce a clinically significant reduction of mean SpO2 during total sleep time (TST) in 
healthy subjects, compared with placebo. And there was no significant difference identified 
between suvorexant and placebo for mean change from baseline in AHI.
Both ramelteon (Rozarem®) and suvorexant (Belsomra®) have been tested in subjects with 
OSA. Single doses of ramelteon (16 mg; twice the recommended dose in insomnia) were 
compared with placebo in a 2-period crossover design in 26 non-elderly subjects with mild or 
moderate OSA (Kryger, et al., 2007). The effects on respiration were assessed by mean 
changes in AHI and in SpO2. Ramelteon did not worsen OSA. However, the fact that only 
single doses were tested is reflected in the language of the US label: “There is no available 
information on the respiratory effects of multiple doses of Rozerem in patients with sleep 
apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be 
definitively known from this study.” The only study of ramelteon in elderly subjects with 
OSA 
was 
a 
pilot 
study 
that 
primarily 
assessed 
the 
effects 
on 
insomnia 
(Gooneratne, et al., 2010). This report concluded that further research would be warranted in 
examining the role of ramelteon in older adults with insomnia symptoms and sleep apnea.
Merck conducted a 2-period-crossover study to assess the effects on respiration of suvorexant 
40 mg (when dosed to steady state) compared with placebo in 26 non-elderly subjects with 
mild or moderate OSA (Sun, et al., 2016). As with ramelteon, the primary assessment was of 
mean changes in the AHI while secondary endpoints included oxygen saturation measured by 
pulse oximetry (SpO2). Although 40 mg suvorexant is twice the maximum recommended 
dose in the US, at the time the study was initiated, Merck had intended that 40 mg be 
approved as the maximum dose. The study met its primary objective (see also below; 
Justification of the Sample Size). However, there were 8 (of a total of 25) evaluable subjects 
whose AHI at the end of the treatment period with suvorexant was ≥ 5 higher (worse) than 
the corresponding value after placebo. Five of these 8 subjects had a similar treatment 
difference in AHI on the first night of dosing. There was also wide variability in the data. 
The US label includes the following language: “There was wide inter- and intra-individual 
variability such that clinically meaningful respiratory effects of Belsomra in obstructive sleep 
apnea cannot be excluded.” Suvorexant has not been studied in OSA in subjects older than 64 
years.
The prevalence of sleep-related difficulties, including insomnia and OSA, increases with age. 
Given the increased prevalence of OSA, insomnia and AD-D with age, it is important that 
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lemborexant be studied in both adult and elderly patients with OSA. Study 102 is designed to 
assess the effects of lemborexant in subjects with mild OSA, and will recruit adult and 
elderly subjects up to the age of 90 years. 
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8
STUDY OBJECTIVES
8.1
Primary Objectives
8.1.1
HV
The primary objective of the study for the healthy volunteers (HV) cohort is to determine
whether lemborexant decreases the peripheral oxygen saturation (SpO2) during total sleep 
time (TST) in healthy adults and elderly subjects after a single dose of treatment compared 
with placebo.
8.1.2
OSA
The primary objective of the study for the OSA cohort is to determine using PSG, whether 
lemborexant increases the AHI after multiple doses of treatment in adult and elderly subjects 
with mild OSA compared with placebo.
8.2
Secondary Objectives
8.2.1
HV
The secondary objectives of the study for the HV cohort are:
1.
Determine whether lemborexant increases the apnea-hypopnea index (AHI) after a 
single dose of treatment compared with placebo 
2.
Determine whether lemborexant decreases
SpO2 during TST below defined 
thresholds after a single dose of treatment compared with placebo (revised per 
Amendment 01)
3.
Evaluate safety and tolerability of lemborexant 
8.2.2
OSA
The secondary objectives of the study for the OSA cohort are:
1.
Determine whether lemborexant increases the AHI after the first dose of treatment 
compared with placebo
2.
Determine whether lemborexant decreases the mean SpO2 during TST after the first 
and after multiple doses of treatment compared with placebo
3.
Determine whether lemborexant decreases
SpO2 during TST below defined 
thresholds after the first and after multiple doses of treatment compared with placebo
4.
Evaluate safety and tolerability of lemborexant 
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8.3
Exploratory Objectives (HV and OSA Cohorts)
Explore the effects of lemborexant compared with placebo after a single dose in HV Cohort 
and after the first and multiple doses in the OSA Cohort on the following: 
1. The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, 
and wake
2.
AHI during REM and NREM sleep 
3.
AHI separately for adult and elderly subjects
4.
The mean SpO2 during TST separately for adult and elderly subjects
In addition, explore the following for both HV and OSA Cohorts:
1.
Plasma concentrations of lemborexant and metabolites M4, M9 and M10
2.
Exposure-response (E-R) relationships between lemborexant concentrations and 
pharmacodynamic (PD) variables, including but not limited to respiratory safety 
variables (AHI, mean SpO2 during TST, proportion of TST during which the SpO2 is 
decreased below defined thresholds)
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E2006-A001-102 is a multicenter, multiple dose, randomized, double-blind, placebo-
controlled, crossover study in adult and elderly healthy subjects and adult and elderly 
subjects with mild Obstructive Sleep Apnea. 
Study 102 will consist of 2 cohorts: healthy subjects and subjects with mild OSA. The design 
of the study is based on the studies conducted with suvorexant in healthy volunteers and 
subjects with OSA.
9.1.1
Healthy Volunteer Cohort
In the HV Cohort, this will be a single dose, randomized, double-blind, placebo-controlled,
3-period crossover study, with the primary endpoint of mean SpO2 during total sleep time.  
There will be 2 phases, Prerandomization and Randomization. The Prerandomization Phase 
will last up to 21 days and will consist of the Screening Period and Baseline Period. The 
Baseline Period will last less than 1 day, and is on the same day as the Treatment Period 1, 
Study Day 1.
Eligible healthy adult and elderly subjects will be randomized to treatment sequence A, B or 
C (see Table 2), each consisting of 3 Treatment Periods, each of one night’s duration, in 
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which subjects will receive a single dose of lemborexant 10 mg, or lemborexant 25 mg, or 
placebo; Treatment Periods will be separated by a washout interval of at least 14 days.  When 
the subject is discharged from the clinic after Treatment Period 3, the Follow-Up Period will 
begin. The Follow-Up Period will have a duration of at least 14 days, during which the 
subjects will not receive any treatment.  At the end of the Follow-up Period, there will be an 
End of Study (EOS) Visit. If subjects discontinue prematurely, they will undergo an Early 
Termination (ET) Visit and will then be followed for at least 14 days, after which, an EOS 
visit should be scheduled. A sufficient number of subjects will be randomized to ensure that 
8 evaluable adult subjects (<65 years) and 4 evaluable elderly subjects (≥65 years) complete 
the study. An evaluable subject is defined as having SpO2 readable for >90% of PSG 
recording for every Treatment Period.
9.1.1.1
Prerandomization Phase (HV Cohort)
The Prerandomization Phase will last up to 21 days and will consist of a Screening Period 
and a Baseline Period.
At specified visits throughout the Prerandomization Phase and the Randomization Phase, all 
subjects will undergo routine safety assessments, including 12-lead electrocardiograms 
(ECG), physical examination, vital signs, weight, height, hematology, blood clinical 
chemistry analysis, urinalysis, reporting of AEs, and assessment of suicidality. At each clinic 
visit, subjects will also undergo a urine drug test and breath alcohol test.
9.1.1.1.1
SCREENING PERIOD (HV COHORT)
The Screening Period will begin no more than 21 days before the subject is randomized. At 
the first Screening Visit, informed consent will be obtained after the study has been fully 
explained to the subject and before the conduct of any screening procedures or assessments. 
A medical, psychiatric, and sleep history interview will be conducted. The medical history 
will include history of falls. Additional eligibility criteria will be assessed, and safety 
assessments will be conducted, as indicated in the Schedule of Procedures/Assessments; 
these will include the Columbia – Suicide Severity Rating Scale (C-SSRS). Female subjects 
of childbearing potential will undergo a serum pregnancy test. Subjects will undergo the 
following assessments during screening: demography, physical examination, viral serology, 
serum pregnancy test, urine drug test, breath alcohol test, height, weight, clinical labs, vital 
signs, ECG and concomitant medications.
Subjects will also be instructed regarding study restrictions pertaining to prohibited 
medications/drugs, alcohol and caffeine.  
After at least 6 days (to allow subjects the opportunity to complete the sleep diary for at least 
5 consecutive nights), subjects will return to the clinic for the second Screening Visit (Visit
2) to undergo polysomnography (PSG). On this and all other 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, scheduled assessments (including a urine drug test and 
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breath alcohol test) as described in the Schedule of Assessments/Procedures, and 
preparations (eg, placement of the electrode montage and pulse oximeter). 
Subjects who continue to meet the eligibility criteria will remain overnight in the sleep 
laboratory. The median habitual bedtime (MHB) will be calculated from the most recent 5 
days of the subject’s sleep diary. This will be used to determine bedtime (“lights off”) The 
PSG recording will begin at lights off and will continue for 8 hours (until lights on).  The end 
of the 8-hour PSG recording will be defined as waketime (“lights on”). Subjects may leave 
the clinic after the investigator determines that it is safe for them to do so. 
The PSG will be reviewed for exclusion criteria related to OSA. 
The pulse oximetry recording will be reviewed for exclusion criteria related to oxygen 
desaturation. Subjects who continue to meet the eligibility criteria will enter the 
Randomization Phase.
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  Screening period assessments and timing thereof are shown in Section 9.5.1.6.4.
9.1.1.1.2
BASELINE PERIOD (HV COHORT)
The purpose of the Baseline Period is to confirm protocol eligibility and to obtain baseline 
data for assessment.  Subjects who complete the Baseline Period and meet the criteria for 
inclusion/exclusion (Section 9.3) will begin the Randomization Phase.  Baseline assessments 
and timing thereof are shown in Section 9.5.1.6.4. 
A baseline period of <1 day duration will start after the Screening PSG have been reviewed 
for eligibility. Subjects will be admitted to the clinic. Blood and urine samples will be 
collected for routine safety assessment. An ECG, urine drug test, and breath alcohol test will 
be performed, and vital signs will be assessed. The Columbia-Suicide Severity Rating Scale 
(C-SSRS) will be administered. Females of childbearing potential will undergo a urine 
pregnancy test. 
9.1.1.2
Randomization Phase (HV Cohort)
Subjects who continue to meet the eligibility criteria will be randomized to treatment 
sequence A, B or C consisting of 3 Treatment Periods, 1-night duration each: lemborexant 
10 mg, lemborexant 25 mg, or placebo; Treatment Periods will be separated by a washout
interval of at least 14 days. Randomization will be stratified by age (<65 years vs. ≥ 65
years).  Within each age stratum, subjects will be randomized to 1 of the 3 treatment 
sequences. Subjects will then enter Treatment Period 1.  Procedures and assessments to be 
conducted during the Randomization Phase are detailed in Table 5.
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9.1.1.2.1
TREATMENT PERIODS (HV COHORT)
Treatment Period 1
Subjects will remain overnight in the sleep laboratory. A serum pregnancy test will be 
performed at Screening Visit 1 for women of childbearing potential; a urine pregnancy test
will be performed at all other time points specified in the Schedule of Assessments and 
Procedures. A urine drug screen and a breath alcohol test will be perfomed at Screening 
Visits 1 and 2, and at the time points specified in the Schedule of Assessments and 
Procedures.  Bedtime (lights off) will be at the median habitual bedtime (MHB) that was 
used at the second Screening Visit (Visit 2). Subjects will receive study drug immediately 
(within 5 minutes) before lights off. The PSG recording will begin at lights off and will 
continue for 8 hours (until lights on). Subjects will also be instructed on study restrictions 
related to prohibited medications/drugs, caffeine and alcohol. The following morning, a PK 
blood sample will be collected and vital signs assessed, as indicated in the Schedule of 
Procedures/Assessments. Subjects may leave the clinic after the investigator determines that 
it is safe for them to do so. 
After Treatment Period 1, there will be a washout interval of at least 14 days.
Treatment Period 2
After the washout interval, subjects will return to the clinic for Treatment Period 2, which 
will follow the same schedule and procedures as in Treatment Period 1 (including urine 
pregnancy test for female subjects of childbearing potential, urine drug test, and breath 
alcohol test).  In addition, a blood sample for predose (trough) PK will be taken within 1 hour 
before dosing on the PSG night.
After Treatment Period 2, there will be a washout interval of at least 14 days.
Treatment Period 3
After the washout interval, subjects will return to the clinic for Treatment Period 3, which 
will follow the same schedule and procedures as did Treatment Period 1. 
When the subject is discharged from the clinic after Treatment Period 3, the Follow-Up 
Period will begin immediately. The Follow-Up Period will have a duration of at least 14 
days, during which the subjects will not receive any treatment.  (revised per Amendment 01)
9.1.1.2.2
FOLLOW-UP PERIOD (HV COHORT)
At the end of the Follow-Up Period, subjects will return to the clinic for an EOS visit at 
which safety will be assessed including adverse events, 12-lead ECG, vital signs, weight, 
clinical labs as indicated in Table 5, and suicidality assessed by the C-SSRS. If subjects 
discontinue prematurely, they will undergo an ET Visit and will then be followed for at least 
14 days, after which, an EOS visit should be scheduled.
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The Treatment Phase assessments and timing thereof are shown in Section 9.5.1.6.4.
9.1.2
Obstructive Sleep Apnea (OSA Cohort)
In the OSA Cohort, this will be a randomized, double-blind, placebo-controlled, 2-period 
crossover study.  Lemborexant will be compared with placebo, using for the primary 
endpoint the AHI on the last night of dosing (both treatment periods), and with secondary 
endpoints that assess oxygen saturation as SpO2.  As with the HV cohort, there will be 2 
phases, Prerandomization and Randomization. The Prerandomization Phase will last up to 
21 days and will consist of the Screening Period and Baseline Period. The Baseline Period 
will last less than 1 day, and is on the same day as the Treatment Period 1, Study Day 1.
At Baseline, subjects will undergo a screening PSG to confirm the diagnosis and severity of 
OSA.  At specified visits throughout the Prerandomization Phase and the Randomization 
Phase, all subjects will undergo routine safety and pharmacodynamics assessments.  Adult 
and elderly subjects with mild OSA will be randomized to treatment sequences D or E (see
Table 3) each consisting of 2 Treatment Periods, each of 8 nights’ duration, in which subjects 
will receive lemborexant 10 mg or placebo; the Treatment Periods will be separated by a 
washout interval of at least 14 days days. When the subject is discharged from the clinic 
after Treatment Period 2, the Follow-Up Period will begin. The Follow-Up Period will have a 
duration of at least 14 days, during which the subjects will not receive any treatment. At the 
end of the Follow-Up Period, subjects will return to the clinic for an EOS visit.  If subjects 
discontinue prematurely, they will undergo an Early Termination (ET) Visit and will then be 
followed for at least 14 days, after which, an EOS visit should be scheduled.  A sufficient 
number of subjects will be randomized to ensure that 20 evaluable adult subjects (<65 years) 
and 10 evaluable elderly subjects (≥65 years) complete the study. An evaluable subject is 
defined as having AHI validly calculated from PSG recoding for every Treatment Period.
No interim analysis is planned.
The EOS will be the date of the last study visit for the last subject.
An overview of the study design for the HV cohort and OSA cohort is presented in Figure 1
and Figure 2, respectively.
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Figure 1
Study Design for HV Cohort
EOS = End of Study, ET = Early Termination Visit, S = Sleep Laboratory, R = randomization.
a. Sequence A = placebo (Period 1), lemborexant 10 mg (Period 2), and lemborexant 25 mg (Period 3)
Sequence B = lemborexant 10 mg (Period 1), lemborexant 25 mg (Period 2), and placebo (Period 3)
Sequence C = lemborexant 25 mg (Period 1), placebo (Period 2), and lemborexant 10 mg (Period 1)
Visit:
Screening
Baseline
Phase:
Period:
Study Day:
Washout
Washout
Prerandomization
1
3A
6 EOS/ET
3B
Follow-up
assessment
Randomization
-21 
to -
8
1
2
16
Sequence A
a
Sequence C
a
2A
2B
-15 
to -
2
-14 to 
-1
4A
4B
5A
5B
17
31
32
S
S
46
Treatment
Period 3
Sequence B
a
Treatment
Period 2
Treatment
Period 1
S
S
S
R
Lemborexant-
matched placebo
Lemborexant-
matched placebo
Lemborexant-
matched placebo
Lemborexant 
10 mg
Lemborexant 
10 mg
Lemborexant 
10 mg
Lemborexant 
25 mg
Lemborexant 
25 mg
Lemborexant 
25 mg
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Figure 2
Study Design for OSA Cohort
EOS = End of Study, S = Sleep Laboratory, R = randomization
Sequence D = Placebo (Period 1), Lemborexant 10 mg (Period 2); Sequence E = Lemborexant 10 mg (Period 1), Placebo (Period 2).
Placebo
Visit:
Screening
Baseline
Treatment
Period 1
Phase:
Period:
Study Day:
Washout
Treatment
Period 2
Prerandomization
Follow-up
assessment
Randomization
-21 
to -8
1
2
5
9
Placebo
Lemborexant 
10 mg
Lemborexant
10 mg
Sequence D
Sequence E
2A
2B
-15 
to -2
-14 to 
-1
4
5A
5B
8
6B
7
8A
8B
23
24
27
30
31
S
S
S
45
1
3A
3B
9 EOS
S
R
6A
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9.1.2.1
Prerandomization Phase (OSA Cohort)
The Prerandomization Phase for the OSA Cohort will last up to 21 days and will consist of a 
Screening Period and a Baseline Period.
At specified visits throughout the Prerandomization Phase and the Randomization Phase, all 
subjects will undergo routine safety assessments, including 12-lead electrocardiograms 
(ECG), physical examination, vital signs, weight, height, hematology, blood clinical 
chemistry analysis, urinalysis, reporting of adverse events (AEs), and assessment of 
suicidality. At each clinic visit, subjects will also undergo a urine drug test and breath alcohol
test.
9.1.2.1.1
SCREENING PERIOD (OSA COHORT)
The Screening Period will begin no more than 21 days before the subject is randomized. At 
the first Screening Visit, informed consent will be obtained after the study has been fully 
explained to the subject and before the conduct of any screening procedures or assessments. 
A medical, psychiatric, and sleep history interview will be conducted. The medical history 
will include history of falls. Additional eligibility criteria will be assessed, and safety 
assessments will be conducted, as indicated in the Schedule of Procedures/Assessments; 
these will include the Columbia – Suicide Severity Rating Scale (C-SSRS). Female subjects 
of childbearing potential will undergo a serum pregnancy test. Subjects will undergo the 
following assessments during screening: demography, physical examination, viral serology, 
serum pregnancy test, urine drug test, breath alcohol test, height, weight, clinical labs, VS, 
ECG and concomitant medications.
Subjects will also be instructed regarding study restrictions pertaining to prohibited 
medications/drugs, alcohol and caffeine.  
After at least 6 days (to allow subjects the opportunity to complete the sleep diary for at least 
5 consecutive nights), subjects will return to the clinic for the second Screening Visit (Visit 
2) to undergo polysomnography (PSG). On this and all other 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, scheduled assessments (including a urine drug test and 
breath alcohol test) as described in the Schedule of Assessments/Procedures, and 
preparations (eg, placement of the electrode montage and pulse oximeter). 
Subjects who continue to meet the eligibility criteria will remain overnight in the sleep 
laboratory. The median habitual bedtime (MHB) will be calculated from the most recent 5 
days of the subject’s sleep diary. This will be used to determine bedtime (“lights off”) The 
PSG recording will begin at lights off and will continue for 8 hours (until lights on).The end 
of the 8-hour PSG recording will be defined as waketime (“lights on”). Subjects may leave 
the clinic after the investigator determines that it is safe for them to do so. 
The PSG will be reviewed for exclusion criteria related to OSA moderate or severe OSA, 
periodic limb movement disorder, and parasomnias. 
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The pulse oximetry recording will be reviewed for exclusion criteria related to oxygen 
desaturation. Subjects who continue to meet the eligibility criteria will enter the 
Randomization Phase.
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  Screening period assessments and timing thereof are shown in Section 9.5.1.6.4.
9.1.2.1.2
BASELINE PERIOD (OSA COHORT)
The purpose of the Baseline Period is to confirm protocol eligibility and to obtain baseline 
data for assessment.  Subjects who complete the Baseline Period and meet the criteria for 
inclusion/exclusion (Section 9.3) will begin the Randomization Phase.  Baseline assessments 
and timing thereof are shown in Section 9.5.1.6.4. 
A baseline period of <1 day duration will start after the Screening PSG have been reviewed 
for eligibility. Subjects will be admitted to the clinic. Blood and urine samples will be 
collected for routine safety assessment. An ECG, urine drug test, and breath alcohol test will
be performed, and vital signs will be assessed. The Columbia-Suicide Severity Rating Scale 
(C-SSRS) will be administered. Females of childbearing potential will undergo a urine 
pregnancy test. 
9.1.2.2
Randomization Phase (OSA Cohort)
Subjects who continue to meet the eligibility criteria will be randomized in treatment 
sequences D or E consisting of 2 Treatment Periods, 8 nights duration each: lemborexant 
10 mg and placebo, with the treatments periods separated by a washout interval of at least 
14 days. Randomization will be stratified by age (<65 years vs ≥65 years). Within each age
stratum, subjects will be randomized to 1 of the 2 treatment sequences in a 1:1 ratio.
Subjects will then enter Treatment Period 1. Procedures and assessments to be conducted 
during the Randomization Phase are detailed in Table 6.
9.1.2.2.1
TREATMENT PERIODS (OSA COHORT)
Subjects who continue to meet the eligibility criteria will be randomized in treatment 
sequences D or E consisting of 2 Treatment Periods, 8 nights duration each: lemborexant 
10 mg and placebo, with the treatments periods separated by a washout interval of at least 
14 days. Randomization will be stratified by age (<65 years vs ≥65 years). Within each age
stratum, subjects will be randomized to 1 of the 2 treatment sequences in a 1:1 ratio.
Treatment Period 1
Subjects will remain overnight in the sleep laboratory. Subjects will undergo the following 
procedures at the Screening Visits 1 and 2 and on Day 1: urine pregnancy test for female 
subjects of childbearing potential, and for all subjects, a urine drug test and breath alcohol
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test).  Bedtime (lights off) will be at the MHB that was used at the second Screening Visit 
(Visit 2). Subjects will receive study drug immediately (within 5 minutes) before lights off. 
The PSG recording will begin at lights off and will continue for 8 hours (until lights on). The
following morning, a PK blood sample will be collected and vital signs assessed, as indicated 
in the Schedule of Procedures/Assessments. Subjects will be provided with study drug to be 
administered for 6 consecutive nights at home, and will be instructed to take the medication 
immediately (within 5 minutes) of bedtime. Subjects will also be instructed on study 
restrictions related to prohibited medications/drugs, caffeine and alcohol, and the prohibitions 
regarding the use of CPAP device or dental appliance. If SpO2 <80% for ≥ 20% of TST 
during the first night of treatment, the subject must be early terminated. Subjects may leave 
the clinic after the investigator determines that it is safe for them to do so. Subjects will be 
instructed to promptly contact investigator in case of any new complaints or exacerbation of 
current symptoms.
On Day 5 (with a window of ±2 days), the site will telephone the subject to assess AEs and 
record concomitant medications. If any AE is suspected as significant and requires a clinic
visit, an Unscheduled Visit should be conducted as soon as possible.  
After 6 consecutive nights of administering study drug at home, subjects will return to the 
clinic and will remain overnight in the sleep laboratory. Subjects will undergo the same 
procedures as on Day 1 (including urine pregnancy test for female subjects of childbearing 
potential, a urine drug test, and an breath alcohol test), in addition to which, a blood sample
for pre-dose (trough) PK will be taken within 1 hour before dosing. The following morning, a 
PK blood sample will be collected. Routine safety assessments will also conducted, as 
indicated in the Schedule of Procedures/Assessments. Subjects will be instructed on study 
restrictions related to prohibited medications/drugs, alcohol and caffeine, and the prohibitions 
regarding the use of CPAP device or dental appliance. Subjects may leave the clinic after the 
investigator determines that it is safe for them to do so. 
After Treatment Period 1, there will be a washout interval of at least 14 days.
Treatment Period 2
After the washout interval, subjects will return to the clinic for Treatment Period 2, which 
will follow the same schedule and procedures as did Treatment Period 1. 
When the subject is discharged from the clinic after Treatment Period 2, the Follow-Up 
Period will begin. The Follow-Up Period will have a duration of at least 14 days, during 
which the subjects will not receive any treatment.
9.1.2.2.2
FOLLOW-UP PERIOD (OSA COHORT)
At the end of the Follow-Up Period, subjects will return to the clinic for an EOS visit at 
which safety will be assessed including adverse events, 12-lead ECGs, vital signs, weight,
clinical hematology and blood chemistry labs, urine pregnancy test, and suicidality assessed 
by the C-SSRS. If subjects discontinue prematurely, they will undergo an Early Termination 
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(ET) Visit and will then be followed for at least 14 days, after which, an EOS visit should be
scheduled.
The Treatment Phase assessments and timing thereof are shown in Section 9.5.1.6.4
9.2
Discussion of Study Design, Including Choice of Control Groups
E2006-A001-102 (Study 102) is a randomized, double-blind, placebo-controlled, crossover 
study to evaluate the respiratory safety of lemborexant in adult and elderly healthy subjects 
and adult and elderly subjects with mild obstructive sleep apnea.
9.2.1
Study Design (HV Cohort)
In the HV Cohort, this will be a randomized, double-blind, placebo-controlled, 3-period 
crossover study. 
Eligible healthy adult and elderly subjects will be randomized to treatment sequence A, B or 
C, each consisting of 3 Treatment Periods, each of one night’s duration, in which subjects 
will receive a single dose of lemborexant 10 mg, or lemborexant 25 mg, or placebo; 
Treatment Periods will be separated by a washout interval of at least 14 days. A sufficient
number of subjects will be randomized to ensure that 8 evaluable adult subjects (<65 years) 
and 4 evaluable elderly subjects (≥65 years) complete the study.
Table 1
Study Design (HV Cohort)
Treatment 
Sequence
Treatment Periods in the HV Cohort
1 (one night)
2 (one night)
3 (one night)
A
lemborexant-matched 
placebo
lemborexant 10 mg
lemborexant 25 mg
B
lemborexant 10 mg
lemborexant 25 mg
lemborexant-
matched placebo
C
lemborexant 25 mg
lemborexant-matched 
placebo
lemborexant 10 mg
9.2.2
Study Design (OSA Cohort)
In the OSA Cohort, this will be a randomized, double-blind, placebo-controlled, 2-period 
crossover study. 
Adult and elderly subjects with mild OSA will be randomized to treatment sequences D or E, 
each consisting of 2 Treatment Periods, each of 8 nights’ duration, in which subjects will 
receive lemborexant 10 mg or placebo; the Treatment Periods will be separated by a washout 
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interval of at least 14 days. A sufficient number of subjects will be randomized to ensure that
20 evaluable adult subjects (<65 years) and 10 evaluable elderly subjects (≥65 years) 
complete the study. 
Table 2
Study Design (OSA Cohort)
Treatment 
Sequence
Treatment Periods in OSA Cohort
1 (eight nights)
2 (eight nights)
D
lemborexant-matched placebo
lemborexant 10 mg
E
lemborexant 10 mg
lemborexant-matched placebo
9.2.3
Randomization
Randomization will be used in this study to avoid bias in the assignment of subjects to the 
order of treatment administration, to increase the likelihood that known and unknown subject 
attributes (eg, demographics and baseline characteristics) are balanced across treatments, and 
to ensure the validity of statistical comparisons across treatments.  Blinding to treatment will 
be used to reduce potential bias during data collection and evaluation of endpoints.
9.2.3.1
HV Cohort
Subjects who continue to meet the eligibility criteria will be randomized to treatment 
sequence A, B or C consisting of 3 Treatment Periods, one-night duration each: lemborexant 
10 mg, lemborexant 25 mg, or placebo; Treatment Periods will be separated by a washout 
interval of at least 14 days. Randomization will be stratified by age (<65 years vs ≥65 years).  
Subjects will then enter Treatment Period 1.
9.2.3.2
OSA Cohort
Subjects who continue to meet the eligibility criteria will be randomized to treatment 
sequences D or E consisting of 2 Treatment Periods, 8 nights duration each: lemborexant 
10 mg followed by  placebo or placebo followed by lemborexant 10 mg, with the treatments 
periods separated by a washout interval of at least 14 days. Randomization will be stratified 
by age (<65 years vs ≥65 years). Within each age stratum, subjects will be randomized to 
1 of the 2 treatment sequences in a 1:1 ratio. Subjects will then enter Treatment Period 1. 
9.2.4
Adjudication Committee (HV and OSA Cohorts)
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure. A set of 
preferred terms constituting a customized Medical Dictionary for Regulatory Activities 
(MedDRA) query for cataplexy or seizure will be used to identify events for adjudication 
(including cataplexy, muscle fatigue, muscular weakness, muscle tone disorder, hypotonia, 
drop attacks, slurred speech, diplopia, falls, convulsions [standardized MedDRA query 
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(SMQ) narrow and broad], atypical migraine, loss of consciousness, decreased 
consciousness, myoclonus, syncope, transient global amnesia, lipothymia, [faintness] and 
transient ischemic attack). To assist in the preparation of narratives about such events and to 
support the committee’s adjudication process, investigators and site staff will be instructed to 
query subjects who report any of the above events for supplemental information using a 
questionnaire for events potentially related to cataplexy.. 
9.3
Selection of Study Population
For the HV Cohort, a sufficient number of subjects will be screened in order to ensure that a 
total of 12 evaluable subjects complete the study ((8 evaluable adult subjects [<65 years] and 
4 evaluable elderly subjects [≥65 years]). Discontinued subjects may be replaced to ensure 
12 subjects complete all 3 Treatment Periods.
For the OSA Cohort, a sufficient number of subjects will be screened in order to ensure that a 
total of 30 evaluable subjects complete the study (20 evaluable adult subjects [<65 years] and 
10 evaluable elderly subjects [≥65 years]). Discontinued subjects may be replaced to ensure 
20 adults and 10 elderly subjects complete both Treatment Periods.
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.
9.3.1
Inclusion Criteria (HV and OSA Cohorts)
Subjects must meet all of the following criteria to be included in this study:
1.
Male or female, age ≥18 years and ≤90 years at the time of informed consent
2.
Voluntary agreement and ability to provide written informed consent 
3.
Reports habitually sleeping for at least 5.5 hours per night
4.
Agrees to stay in bed for 7 hours per night for the duration of treatment
5.
Reports habitual bedtime between 21:00 and 01:00
6.
SpO2 ≥94% assessed as part of vital signs at Screening Visit 1
9.3.2
Additional Inclusion Criteria (HV Cohort)
Subjects must meet the following additional criterion to be included in the HV Cohort:
7.
Body mass index (BMI) ≤32 kg/m2
8.
On Screening PSG (Screening Visit 2) AHI<5
9.3.3
Additional Inclusion Criteria (OSA Cohort)
Subjects must meet the following additional criteria to be included in the OSA Cohort:
9.
BMI ≤40 kg/m2
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10. Obstructive sleep apnea, diagnosed according to the criteria of the International 
Classification of Sleep Disorders (ICSD), version 3 (ICSD-3)
11. On Screening PSG: AHI >5 to <15 (mild severity)
9.3.4
Exclusion Criteria (HV and OSA Cohorts)
Subjects who meet any of the following criteria will be excluded from this study:
1.
A current diagnosis of restless legs syndrome, periodic limb movement disorder,
circadian rhythm sleep disorder, or narcolepsy
2.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicate the need for referral for a diagnostic evaluation for the presence 
of narcolepsy
3.
A history of a parasomnia or parasomnia observed on the Screening PSG that in the 
investigator's opinion makes the subject unsuitable for the study
4.
Periodic Limb Movement with Arousal Index (PLMAI) as measured on the Screening 
PSG: 
◦
Age 18 to <65 years: PLMAI ≥10
◦
Age ≥ 65 years: PLMAI >15
5.
Females who are breastfeeding or pregnant. For females of childbearing potential, the 
serum beta-human chorionic gonadotropin (ß-hCG) pregnancy test must be negative 
at Visit 1 and the urine pregnancy test must be negative at Screening Visit 2 and 
Baseline. An additional assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the first dose of study drug.
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.
NOTES: 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).
It is permissible that if a highly effective method of contraception is not appropriate 
or acceptable to the subject, the subject must agree to use a medically acceptable 
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method of contraception, ie, double-barrier methods of contraception such as condom 
plus diaphragm or cervical/vault cap with spermicide.
6.
History of or suspected drug or alcohol use disorder within approximately 2 previous 
years
7.
A positive urine drug test or breath alcohol test at Screening or Baseline, or unwilling 
to refrain from use of recreational drugs during the study
8.
Reports habitually consuming more than 14 drinks containing alcohol per week 
(females) or more than 21 drinks containing alcohol per week (males), and unwilling 
to forego alcohol on the days prior to PSG and to limit alcohol intake to no more than 
2 alcohol-containing drinks per day (females) or 3 alcohol-containing drinks per day 
(males) on all non-PSG days for the duration of his/her participation in the study 
(NB: alcohol will not be permitted in the sleep laboratory). 
9.
Reports habitual caffeine use that is excessive in the opinion of the investigator. 
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
10. Known to be human immunodeficiency virus (HIV) positive
11. Active viral hepatitis (B or C) as demonstrated by positive viral serology at Screening
12. A prolonged QT/QTc interval (QTcF >450 ms) as demonstrated by a repeated ECG at 
Screening (repeated if initial ECG indicates a QTcF interval >450 ms)
13. Comorbid nocturia resulting in the need to get out of bed to use the bathroom more 
than 3 times during the night
14. Any history of medical or psychiatric condition that in the opinion of the investigator 
could affect the subject’s safety or interfere with the study assessments
15. Any suicidal ideation with intent to act with or without a plan, current or within 
6 months before the C-SSRS administration during the Screening (e.g. answering 
“Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS
16. Any suicidal behavior (per the Suicidal Behavior section of the C-SSRS) within 
10 years of Screening.
17. Scheduled for surgery during the study that requires general anesthesia or 
administration of prohibited medications
18. Used any prohibited prescription or OTC medications within 1 week or 5 half-lives, 
whichever is longer, before the Screening PSG
19. Hypersensitivity to lemborexant or excipients
20. Currently enrolled in another interventional clinical trial or used any investigational 
drug or device within 30 days or 5 times the half-life, whichever is longer preceding 
informed consent
21. Previously participated in other clinical trial of lemborexant
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22. Is unable to avoid working a night shift within 2 weeks before the Screening PSG, or 
between the Screening PSG and EOS
23. Has travelled across 3 or more time zones in the week prior to Screening, or plans to 
travel across 3 or more time zones during the study
24. Clinically significant findings based on vital signs, physical examination, ECG, or 
clinical laboratory tests 
9.3.5
Additional Exclusion Criteria (HV Cohort)
25. Any valid event of SpO2 <90% during the Screening PSG 
26. Current evidence of a clinically significant, active respiratory disorder. This includes 
bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease, or any 
other pulmonary disorder identified by review of medical history, physical 
examination, and which in the opinion of the investigator, could compromise the 
subject’s safety or interfere with study assessments. 
27. Presence of significant illness (including insomnia) that requires treatment or may 
influence the study assessments (e.g. psychiatric disorders, disorders of the 
gastrointestinal tract, liver, kidney, respiratory system, endocrine system, 
hematological system, neurological system, cardiovascular system, or a congenital 
abnormality), malignancy within the past 5 years (other than adequately treated basal 
cell carcinoma or in situ carcinoma of the cervix), or chronic pain that in the opinion 
of the investigator could interfere with the study assessments. Subjects for whom a 
sedating drug would be contraindicated for safety reasons because of the subject’s 
occupation or activities are also excluded.
9.3.6
Additional Exclusion Criteria (OSA Cohort)
28. SpO2 <80% for ≥ 5% of TST during the Screening PSG 
29. Uses or plans to use of CPAP device or dental appliance within 2 weeks of the 
Screening PSG (Screening Visit 2) or during the study 
30. Current evidence of a clinically significant, active respiratory disorder other than 
OSA. This includes bronchiectasis, emphysema, asthma, chronic obstructive 
pulmonary disease or any other pulmonary disorder identified by review of medical 
history, physical examination, and which in the opinion of the investigator, could 
compromise the subject’s safety or interfere with study assessments. 
31. Current evidence of other clinically significant disease (e.g. psychiatric disorders, 
disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine 
system, hematological system, neurological system, cardiovascular system, or a 
congenital abnormality), malignancy within the past 5 years (other than adequately 
treated basal cell carcinoma or in situ carcinoma of the cervix), or chronic pain that in 
the opinion of the investigator could affect the subject’s safety or interfere with the 
study assessments. Subjects for whom a sedating drug would be contraindicated for 
safety reasons because of the subject’s occupation or activities are also excluded.
Subjects with insomnia disorder, who complain of difficulties with sleep onset and/or 
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sleep maintenance, are eligible provided that they meet this criterion. Note that 
medications to treat insomnia are prohibited; see Appendix 2 of the protocol.
9.4
Treatments
9.4.1
Treatments Administered
HV Cohort
The treatments administered in the HV Cohort will be as follows:

Lemborexant 10 mg:  one 10-mg lemborexant tablet and 2 lemborexant-matched 
placebo tablets 

Lemborexant 25 mg:  two 10-mg lemborexant tablets and one 5-mg lemborexant 
tablet 

Placebo:  3 lemborexant-matched placebo tablets.
To maintain the blind, additional placebo tablets will be added in order to have a total of 
3 tablets administered during each Treatment Period.
Study drug will be administered at bedtime in the clinic (within 5 minutes of lights off) in the 
evening of Day 1. Treatments will be administered orally with 240 mL (8 fluid ounces) of 
water.
Table 2
Treatments Administered (HV Cohort)
Treatment 
Sequence
Treatment Periods in the HV Cohort
1 (one night)
2 (one night)
3 (one night)
A
lemborexant-matched 
placebo
lemborexant 10 mg
lemborexant 25 mg
B
lemborexant 10 mg
lemborexant 25 mg
lemborexant-
matched placebo
C
lemborexant 25 mg
lemborexant-matched 
placebo
lemborexant 10 mg
OSA Cohort
The treatments administered in the OSA Cohort will be as follows:

Lemborexant 10 mg:  one 10-mg lemborexant tablet
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
Placebo:  one lemborexant-matched placebo tablet.
Study drug will be administered at bedtime in the clinic (within 5 minutes of lights off) in the 
evening of Days 1 and 8. On Days 2 to 7, subjects will take study drug at home, immediately 
(within 5 minutes) of the time they intend to try to sleep. Treatments will be administered 
orally with 240 mL (8 fluid ounces) of water.
Table 3
Treatments Administered (OSA Cohort)
Treatment 
Sequence
Treatment Periods in OSA Cohort
1 (eight nights)
2 (eight nights)
D
lemborexant-matched placebo
lemborexant 10 mg
E
lemborexant 10 mg
lemborexant-matched placebo
9.4.1.1
Identity of Investigational Products
Lemborexant and placebo will be supplied by the sponsor in labeled containers.  
Study drug must be stored as instructed on the study drug label.  Study drug must be kept in a 
secure location and carefully stored at the study site within its original container.  The 
product release certificates for lemborexant and placebo will be included in the clinical study 
report (CSR) for this protocol.
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study drug will consist of either lemborexant or placebo and will be supplied in a 
subject medication bottle. 
For the HV cohort, the medication bottle for each dose is as follows:  lemborexant 10-mg 
dose consisting of 1 film-coated tablet and 2 lemborexant-matched placebo tablets, 
lemborexant 25-mg dose consisting of 2 tablets of lemborexant 10 mg and 1 tablet of 
lemborexant 5 mg, and placebo dose consisting of 3 lemborexant-matched placebo tablets.
For the OSA Cohort, study drug will be provided as lemborexant 10-mg dose consisting of 1 
film-coated 10 mg tablet, and placebo dose consisting of 1 lemborexant-matched placebo 
tablet. For each period, the bottle will contain 9 tablets (8 tablets and 1 tablet as overage).
9.4.1.2
Chemical Name, Structural Formula of lemobrexant
•
Test drug code:  E2006
•
Generic name:  lemborexant
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•
Chemical name:  (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-
2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide
•
Molecular formula:  C22H20F2N4O2
•
Molecular weight:  410.42
9.4.2
Comparator Drug
Not applicable
9.4.2.1
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with regulations in the United States.
9.4.2.2
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 Sequences
Subjects will be assigned to treatments (or treatment sequences) 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.
9.4.4
Selection of Doses in the Study
In the HV cohort (single dose study), lemborexant 10 mg and lemborexant 25 mg have been
selected. The single dose of lemborexant 25 mg would correspond to the levels of Cmax and 
AUC achieved at the steady state after multiple doses of lemborexant 10 mg.
In the OSA cohort, the lemborexant dose of 10 mg was chosen as the maximum dose being 
studied in the insomnia Phase 3 program. 
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9.4.5
Selection and Timing of Dose for Each Subject
Subjects will remain overnight in the sleep laboratory. Bedtime (lights off) will be at the 
median bedtime (MHB) that was used at the second Screening Visit (Visit 2). Subjects will 
receive study drug immediately (within 5 minutes) before lights off. 
9.4.6
Blinding
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. The investigator is to record the date and time and the reason for breaking 
the code.
9.4.7
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent or 90 days before first dose/administration 
of study drug, if appropriate) will be recorded on the Prior & Concomitant Medication CRF 
or Non-Pharmacological Procedures CRF.  The investigator will record on the Adverse Event 
CRF any adverse event (AE) for which the concomitant medication/therapy was 
administered. 
OSA subjects will be required to abstain from using a CPAP device or dental appliance for at 
least 2 weeks before the Screening PSG, and throughout the study (until after the EOS Visit). 
Subjects must abstain from the use of recreational drugs throughout the study. No alcohol 
will be permitted in the clinic.
Prohibited medications (Appendix 2 of the protocol)] should not be used during the study. 
A subject must not have used any prohibited prescription or over-the-counter medications 
within 1 week or 5 half-lives, whichever is longer, before Screening Visit 2. 
Prohibited medications include strong CYP3A inhibitors and all CYP3A inducers as listed in
Appendix 2. 
Prohibited medications also include any pharmacological treatment for 
insomnia disorder, including any medications (hypnotics or medications with known sedating 
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effects) that are used for the purpose of inducing sleep or for treating OSA. These 
prohibitions apply even if the entire class to which that medication belongs is not prohibited 
(eg, anticonvulsants). 
If a medication is not specified as prohibited but is in the same class as a medication that is 
listed in Appendix 2 of the protocol, and if the investigator is uncertain whether the 
medication has known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy, 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 strong CYP3A inhibitors and all CYP3A inducers will not be permitted at any time 
for any duration during the study as listed in Appendix 2. 
9.4.8
Prohibitions and Restrictions during Study Period
9.4.8.1
Food and Water
Not applicable.
9.4.8.2
Beverage and Other Restrictions
Subjects must forego alcohol on day of PSG and to limit alcohol intake to no more than 2 
alcohol-containing drinks per day (females) or 3 alcohol-containing drinks per day (males) 
on all non-PSG days for the duration of his/her participation in the study.  Alcohol will not be 
permitted in the sleep laboratory. 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. Subjects must forgo grapefruit juice during the duration of the study.
9.4.8.3
Physical Activity Restrictions
Not applicable.
9.4.9
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.10
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
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•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
•
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable
•
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable
•
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV
•
A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to Good Clinical Practice (GCP) guidelines as well as local or regional 
requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 
drugs/study supplies that occurs at the site.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA, Medicine and Healthcare products Regulatory Agency).  As applicable, all unused 
study drugs and empty and partially empty containers from used study drugs are to be 
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returned to the investigator by the subject and together with unused study drugs that were 
shipped to the site but not dispensed to subjects are to be returned to the sponsor’s designated 
central or local depot(s) during the study or at the conclusion of the study, unless provision is 
made by the sponsor for destruction of study drugs and containers at the site.  Destruction at 
the site will only occur under circumstances where regulation or supply type prohibits the 
return of study drugs to the central or local depot(s).  Approval for destruction to occur at the 
site must be provided by the sponsor in advance.  Upon completion of drug accountability 
and reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed and sealed and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic 
information will include date of birth, sex, and race/ethnicity.
9.5.1.2
Baseline Assessments
Baseline assessments shall include inclusion/exclusion criteria, medical history, sleep diary, 
safety assessments (Section 9.5.1.5), PSG (with Pulse Oximetry), and C-SSRS.
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All relevant medical and surgical history must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.2.2
SLEEP DIARY
The Sleep Diary will be completed within an hour of morning waketime on each morning of 
the Screening Period until the Screening PSG. This Sleep Diary will yield information on the 
MHB that will be used to determine eligibility, and to determine bedtime (lights off) in the 
clinic. 
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9.5.1.3
Efficacy Assessments
Not applicable.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
A single blood (4 mL) sample for plasma concentrations of lemborexant and its metabolites 
M4, 
M9 
and 
M10 
will 
be 
taken 
at 
predefined 
visits 
(see 
Schedule 
of 
Procedures/Assessments). The time and date of the 2 most recent doses administered before 
each sample will be documented. PK sample collection, processing, handling and shipping 
instructions will be provided either as a stand-alone PK lab manual or as part of the central 
labs manual.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
PSG
Each PSG recording will include an electrode montage with electroencephalography (EEG), 
electromyography (EMG), electrooculography (EOG), and ECG channels. In addition, the 
montage will include channels for recording respiratory variables including pulse oximetry. 
In addition, the Screening PSG will include channels for assessment of symptoms of periodic 
limb movement disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard 
criteria. At Screening Visit 2, the PSG will be used to calculate AHI and PLMAI for 
evaluation of eligibility criteria. Subsequent PSGs will be used to determine:
•
AHI: the number of apneas and hypopneas divided by the TST (in minutes) and 
multiplied by 60 (min / hour) (ie, the average number of apneas and hypopneas per hour 
of sleep), as defined by the American Academy of Sleep Medicine (respiratory safety/PD 
assessment)
•
SpO2 level
Transmissive pulse oximetry is a noninvasive method for monitoring peripheral oxygen 
saturation (SpO2). A sensor device is placed on a thin part of the subject’s body; in the 
present study, this will be a fingertip. The device passes two wavelengths of light through the 
body part to a photodetector. This measures the changing absorbance at each of the 
wavelengths, allowing determination of the absorbance caused by the pulsing arterial blood 
alone, excluding venous blood, skin, bone, muscle and fat. The reading of oxygen saturation 
by pulse oximetry is not necessarily identical to the reading of arterial oxygen saturation 
(SaO2) from (invasive) analysis of arterial blood gas, but the two are sufficiently correlated 
that pulse oximetry is valuable for measuring oxygen saturation in a clinical setting, 
including in clinical trials.
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Further details are provided in PSG manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; monitoring 
of hematology, blood chemistry, and urinalysis; periodic measurement of vital signs and 
ECGs; and performance of physical examinations as detailed in Table 5 and Table 6. Safety 
will be assessed at every clinic visit throughout the study, including after the last dose of 
study drug, and at the EOS Visit.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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 drug(s) is 
lemborexant. 
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  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.  Subjects who fail screening primarily due 
to AE(s) must have the AE(s) leading to screen failure reported on the Screening Disposition 
CRF.  Serious AEs 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 
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laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.7 for a description of the C-SSRS).
All AEs must be followed for 28 days after the subject’s last dose, or until resolution,
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 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
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Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF 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)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care 
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•
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
If possible, a blood sample for PK analysis should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5 and Table 6) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Table 4
List of Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium, calcium
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Total protein, albumin, globulin, cholesterol, triglycerides, glucose, 
lactate dehydrogenase, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
CYP3A = cytochrome P450 Family 3A, RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the study will be performed by PPD Clinical Laboratories.  
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 may be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
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laboratory:  A central laboratory will perform tests to qualify subjects for entry into the 
study.  Laboratory certification as available will be included in the final clinical study report 
for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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 peripheral oxygen saturation (SpO2) 
[percentage]), and weight (kg) will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 5 and Table 6) by a validated method.  Blood pressure and 
pulse will be measured after the subject has been sitting for 5 minutes.  All BP measurements 
should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed prior to 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 will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 5 and Table 6).  Documentation of the physical examination 
will be included in the source documentation at the site.  Significant findings at the Screening 
Visit will be recorded on the Medical History and Current Medical Conditions CRF.  
Changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the Adverse Events CRF.
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well. A urogenital examination will only be required in the presence 
of clinical symptoms related to this region.
At each visit, subjects will be asked whether they have had a fall since the previous visit. If 
yes, supplemental information must be obtained to support a narratives for the event, per 
Section 9.2.4, Adjudication Committee.
9.5.1.5.6
ELECTROCARDIOGRAMS
Twelve-lead electrocardiograms will be obtained and reviewed locally as designated in the 
Schedule of Procedures/Assessments (Table 5 and Table 6).
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An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
Columbia-Suicide Severity Rating Scale (C-SSRS)
An assessment of suicidal ideation, suicidal thoughts and self-injurious behavior using the 
C-SSRS (Posner et al., 2011) will be performed at Screening, Baseline, and at the Follow-Up 
Visit, as designated in the Schedule of Procedures/Assessments (Table 5 and Table 6).
Qualified personnel must evaluate responses on the C-SSRS and take appropriate action as 
detailed in the training and certification process for administering the C-SSRS.
9.5.1.6
Other Assessments
9.5.1.6.1
VIRAL TESTS
A 6 mL sample of blood will be taken for hepatitis B surface antigen and hepatitis C 
antibodiesat Screening.
9.5.1.6.2
PREGNANCY TEST
A serum β-hCG test will be performed for premenopausal women and postmenopausal 
women who have been amenorrheic for less than 12 months.  Urine pregnancy tests will be 
performed for all subsequent visits.  A 6-mL sample of blood will be taken at designated time 
points as specified in the Schedule of Procedures/Assessments (Table 5 and Table 6).
9.5.1.6.3
URINE DRUG TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 5 and Table 6).  This sample will be tested for 
common drugs of use/abuse: eg, cocaine, cannabinoids, PCP, opioids (as a group), 
benzodiazepines, barbiturates, and amphetamines.
9.5.1.6.4
BREATH ALCOHOL TEST
A breath alcohol test will be obtained at designated time points as specified in the Schedule 
of Procedures/Assessments (Table 5 and Table 6).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedules of Procedures and Assessments for the HV and OSA Cohorts
HV Cohort
Table 5 presents the schedule of procedures/assessments for the HV cohort of this study.
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Table 5
Schedule of Assessments and Procedures for the HV Cohort in Study E2006-A001-102
Phase
Prerandomization
Randomization
UNb
Period
Screening
BL
Treatment 1
Treatment 2
Treatment 3
Follow-Up
Visit
1
2A
2B
3A
3B
4A
4B
5A
5B
6 EOS/ETa
Study Day
-21
to 
8
15
to 
2
14
to
1
1
2d
16c
17d
31c
32d
46c,e
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical, psychiatric, and sleep historyf
X
Physical examination
X
X
X
X
Viral serology
X
Sleep diaryg
-------------
Urine drug testh
X
X
X
X
X
X
Breath alcohol test
X
X
X
X
X
X
Height
X
Weight
X
X
X
Clinical laboratory testsi
X
X
X
X
PK blood samplingj
X
X
X
X
X
Pregnancy testk
X
X
X
X
X
X
Vital signsl
X
X
X
X
X
X
X
X
X
X
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Table 5
Schedule of Assessments and Procedures for the HV Cohort in Study E2006-A001-102
Phase
Prerandomization
Randomization
UNb
Period
Screening
BL
Treatment 1
Treatment 2
Treatment 3
Follow-Up
Visit
1
2A
2B
3A
3B
4A
4B
5A
5B
6 EOS/ETa
Study Day
-21
to 
8
15
to 
2
14
to
1
1
2d
16c
17d
31c
32d
46c,e
12-lead ECG
X
X
X
X
Randomization
X
Administer study drug in clinic m
Xl
X
X
PSG (with Pulse Oximetry) n
Xn
Xl
X
X
C-SSRS
X
X
X
+7-day window
X
X
X
Adverse eventso
---------------------------------------------------------------------------------------------------------------------------------------------

Prior and concomitant medications
---------------------------------------------------------------------------------------------------------------------------------------------

Admit to clinic
X
X
X
X
Discharge from clinic
X
X
X
X
Discharge from study
X
BL = baseline; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = End of Study; ET = Early Termination; PK = 
pharmacokinetic; OSA = obstructive sleep apnea PLMD = periodic limb movement disorder; PSG = polysomnography; UN = Unscheduled Visit.
a:
Assessments as shown will be conducted at EOS visit and for subjects who discontinue the study early after Visit 3.
b:
The assessments at an Unscheduled Visit will be conducted at the Investigator’s discretion.
c:
Within a +7-day window period.
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d:
Visit must be followed by a washout interval of 14 days to 21 days in duration. 
e:
EOS visit is 14 days to 21 days after the final study dose.  Subjects who undergo an ET will be followed for at least 14 days, after which, an EOS 
visit should be scheduled.
f:
Sleep history will include: history of obstructive sleep apnea (OSA), including treatments used for OSA, history of falls, history of periodic limb movement 
disorder (PLMD), restless leg syndrome, circadian rhythm disorder and narcolepsy. 
g:
Sleep diary should be completed by the subjects within 1 hour of waketime on 5 consecutive mornings during Screening, before Screening Visit 2. Sleep 
diaries should be reviewed for eligibility before or during check-in at Screening Visit 2. The median habitual bedtime (MHB) calculated from the Sleep 
Diary during Screening will be used to schedule subjects’ PSG recordings on each night spent in the clinic.  Sleep diaries will be completed on a paper 
form.
h:
Urine drug test will be conducted using a dipstick.
i:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
j:
One blood sample (approximately 4 mL) for determination of plasma concentrations of lemborexant and metabolites M4, M9, and M10 will be obtained at 
the following time points: within 1 hour predose in the clinic (Treatment Periods 2 and 3) and within 1 hour of waking after each PSG recording (Treatment 
Periods 1, 2, and 3). The time of each PK blood draw must be recorded.
k:
Only for female subjects of childbearing potential. A serum pregnancy test will be performed at Screening Visit 1 and a urine pregnancy test at all other 
specified time points.
l:
Vital signs include systolic and diastolic blood pressure, heart rate, and respiratory rate. Oxygen saturation as measured by a pulse oximeter will be 
recorded at Screening Visit 1 only.
m: At Visit 3A, administered after all baseline assessments have been completed.
n:
PSG will include channels for assessment of symptoms of periodic limb movement disorder at Screening Visit 2A only.
o:
At each visit, subjects will be asked whether they have had a fall since the previous visit. If yes, supplemental information must be obtained to support a 
narrative for the event, per Section 9.2.4 Adjudication Committee.
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OSA Cohort
Table 6 presents the schedule of procedures/assessments for OSA cohort of the study. 
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Table 6
Schedule of Procedures and Assessments for OSA Cohort in Study E2006-A001-102
Phase
Prerandomization
Randomization
UNc
Period
Screening
BL
Treatment 1
Treatment 2
Follow-Up
Visit
1
2A
2B
3A
3B
4a
5A
5B
6A
6B
7a
8A
8B
9 EOS/ETb
Study Day
-21
to 
8
15
to 
2
14
to
1
1
2
5
8
9d
23e
24
27
30
31
45e,f
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical, psychiatric, and sleep historyg
X
Physical examination
X
X
X
X
Viral serology
X
Sleep diaryh
-------------
Urine drug testi
X
X
X
X
X
X
X
Breath alcohol test
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Clinical laboratory testsj
X
X
X
X
PK blood samplingk
X
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X
X
X
Vital signsm
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
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Table 6
Schedule of Procedures and Assessments for OSA Cohort in Study E2006-A001-102
Phase
Prerandomization
Randomization
UNc
Period
Screening
BL
Treatment 1
Treatment 2
Follow-Up
Visit
1
2A
2B
3A
3B
4a
5A
5B
6A
6B
7a
8A
8B
9 EOS/ETb
Study Day
-21
to 
8
15
to 
2
14
to
1
1
2
5
8
9d
23e
24
27
30
31
45e,f
Randomization
X
Administer study drug in clinicn
Xn
X
X
X
Study drug taken at home
---------
---------
PSG (with Pulse Oximetry)o
Xo
X
X
X
X
C-SSRS
X
X
X
+7-day window
X
X
±2-day window
X
X
Adverse eventsp
--------------------------------------------------------------------------------------------------------------------------------------------
Prior and concomitant medications
--------------------------------------------------------------------------------------------------------------------------------------------
Admit to clinic
X
X
X
X
X
Discharge from clinic
X
X
X
X
X
Discharge from study
X
AHI = apnea-hypopnea index; BL = baseline; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = End of Study; EOT = End 
of Treatment; ET = Early Termination; PK = pharmacokinetic; OSA = obstructive sleep apnea PLMD = periodic limb movement disorder; PSG = 
polysomnography; UN = Unscheduled Visit.
a:
Telephone visits. 
b:
Assessments as shown will be conducted at the EOS visit and for subjects who discontinue the study early after Visit 3.
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c:
The assessments at an Unscheduled Visit will be conducted at the Investigator’s discretion.
d:
Visit must be followed by a washout interval of 14 to 21 days in duration.
e:
Within a + 7-day window period.
f:
EOS visit is 14 days to 21 days after the final study dose.  Subjects who undergo an ET will be followed for at least 14 days, after which, an EOS visit 
should be scheduled.
g:
Sleep history will include: history of obstructive sleep apnea (OSA), including treatments used for OSA, history of falls, history of periodic limb movement 
disorder (PLMD), restless leg syndrome, circadian rhythm disorder and narcolepsy.
h:
Sleep diary should be completed by the subjects within 1 hour of waketime on 5 consecutive mornings during Screening, before Screening Visit 2. Sleep 
diaries should be reviewed for eligibility before or during check-in at Screening Visit 2. The median habitual bedtime (MHB) calculated from the Sleep 
Diary during Screening will be used to schedule subjects’ PSG recordings on each night spent in the clinic.
i:
Urine drug test will be conducted using a dipstick.
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
k:
One blood sample (approximately 4 mL) for determination of plasma concentrations of lemborexant and metabolites M4, M9, and M10 will be obtained at 
the following time points: within 1 hour predose in the clinic (before th second PSG of Treatment Period 1 and Treatment Period 2) and within 1 hour of 
waking after each PSG recording (Treatment Periods 1 and 2). The time of each PK blood draw must be recorded.
l:
Only for female subjects of childbearing potential. A serum pregnancy test will be performed at Screening Visit 1 and urine pregnancy test at all other 
specified time points.
m:
Vital signs include systolic and diastolic blood pressure, heart rate, and respiratory rate. Oxygen saturation as measured by a pulse oximeter will be 
recorded at Screening Visit 1 only.
n:
At Visit 3A, administered after all baseline assessments have been completed.
o:
Screening PSG will include channels for assessment of symptoms of periodic limb movement disorder (PLMD).
p:
At each visit, subjects will be asked whether they have had a fall since the previous visit. If yes, supplemental information must be obtained to support a 
narrative for the event, per Section 9.2.4 Adjudication Committee.
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9.5.2.2
Description of Procedures/Assessments Schedule
9.5.2.3
Total Volume of Blood Sampling
HV COHORT
Table 7 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study for the HV Cohort. Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or clinical 
symptoms necessitate testing to ensure subject safety.
Table 7
Summary of Blood Sample Volumes (HV Cohort)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Follow-Up: 1
122=24
Viral test
6
Screening: 1
61=6
PK blood sampling
4
5
45=20
Total
50
OSA COHORT
Table 8 present the number of blood samples and the total volume of blood that will be 
collected throughout the study for the OSA Cohort.  Additional samples may be taken at the 
discretion of the investigator if the results of any tests fall outside reference ranges or clinical 
symptoms necessitate testing to ensure subject safety.
Table 8
Summary of Blood Sample Volumes (OSA Cohort)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume 
Collected (mL)
Clinical laboratory tests
12
Screening:  1
Follow-Up:  1
122=24
Viral test
6
Screening:  1
61=6
PK blood sampling
4
7
47=28
Total
58
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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of respiratory 
safety and in particular, Mild Obstructive Sleep Apnea.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, ECG, and assessment of AEs, are standard evaluations to ensure 
subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, must 
be reported on a completed SAE form by email or fax as soon as possible but no later than 24 
hours from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected 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.
The detailed contact information for reporting of SAEs is provided in the Investigator 
Study File.
For urgent safety issues call: 
 (24/7 number).
For urgent safety issues, pleaseensure 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 24 hours 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 of the occurrence of the SAE, in writing, if required 
by their institution.  A copy of this communication must be forwarded to the Sponsor to be 
filed in the sponsor’s Trial Master File.
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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.
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.
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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF 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 
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
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects who discontinue the study are to complete the study’s early 
discontinuation procedures indicated in the Schedule of Procedures/Assessments (Table 5
and Table 6).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
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status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent or 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 
CRF.
A subject removed from the study for any reason will be replaced.
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 CRF.
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 on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
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Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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 WinNonlin and 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 of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
Details of statistical methods and analyses will be specified in the SAP.
The following analyses will be performed on the PD Analysis Set for each cohort:
9.7.1.1.1
PRIMARY ENDPOINT (HV COHORT)
The mean SpO2 during TST on Day 1 of treatment.
9.7.1.1.2
SECONDARY ENDPOINTS (HV COHORT)
1. The AHI on Day 1 of treatment.
2. The percentage of TST during which SpO2 is <90%, <85% and <80% on Day 1  of 
treatment
3. The proportion of subjects with at least one incident of SpO2 <90% for at least 
30 seconds during TST on Day 1 of treatment
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9.7.1.1.3
PRIMARY ENDPOINT (OSA COHORT)
The AHI on Day 8 of treatment.
9.7.1.1.4
SECONDARY ENDPOINTS (OSA COHORT)
1. The AHI on Day 1 of treatment
2. The mean SpO2 during TST on Day 1 and Day 8 of  treatment 
3. The proportion percentage of TST during which the SpO2 is <90%, <85% and <80% 
on Day 1 and Day 8 of treatment
4. The proportion of subjects with at least one incident of SpO2 <90% for at least 
30 seconds during TST on Day 1 and Day 8 of treatment.
9.7.1.1.5
EXPLORATORY ENDPOINTS (HV AND OSA COHORTS)
1. The mean SpO2 during REM sleep, NREM and wake 
2. The AHI during REM and NREM sleep
3. The AHI separately for adult and elderly subjects at all days assessed
4.
The mean SpO2 during TST separately for adult and elderly subjects at all days assessed
9.7.1.1.6
PHARMACOKINETIC ENDPOINT (HV AND OSA COHORTS)
Lemborexant and metabolites M4, M9 and M10 plasma concentrations  
9.7.1.1.7
PHARMACOKINETIC/PHARMACODYNAMIC (EXPOSURE-RESPONSE) ENDPOINT (HV
AND OSA COHORTS)
Correlations between plasma concentrations of lemborexant and select safety variables 
including AHI, mean SpO2 during TST, and proportion of TST in which SpO2 is <90%, 
<85% and <80% at all days assessed.
9.7.1.2
Definitions of Analysis Sets
Safety Analysis Set: Group of subjects who received study drug and have at least one 
postdose safety assessment.
Pharmacodynamic Analysis Set: The PD Analysis Set is the group of subjects who received 
at least 1 dose of study drug in each Treatment Period and who had sufficient PD data to 
derive at least 1 primary PD parameter. 
Pharmacokinetic Analysis Set: Group of subjects who received at least 1 dose of lemborexant 
and who had sufficient PK data to derive at least 1 PK parameter.
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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. Other reasons for study drug and study terminations will also be 
summarized. These tabulations will be produced for all randomized subjects by treatment. 
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each sequence and overall using descriptive statistics.  Continuous 
demographic and baseline variables include age height, and weight; BMI; categorical 
variables include sex, age group (<65, 65 to 74 years, 75 to 84 years, and 85 and older), BMI 
group, race, and ethnicity.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2016 or latest 
version).  The number (percentage) of subjects who took prior and concomitant medications 
will be summarized on the Safety Analysis Set by Anatomical Therapeutic Chemical (ATC) 
class, and WHO DD preferred term.  Prior medications will be defined as medications that 
stopped before the first dose of study drug.  All medications will be presented in subject data 
listings.
Prior medications are defined as medications that stopped before the first dose of study drug, 
where study drug includes placebo.
Concomitant medications are defined as medications that (1) started before the first dose of 
study drug and are continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug to the last dose day plus 14 days. All 
medications will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
Not applicable
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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 M4, M9 and M10 
plasma concentration listings. The PK Analysis Set will be used for summaries of 
lemborexant and M4, M9 and M10 plasma concentrations.
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic Analyses
The following analysis will be performed on the PD Analysis Set for each cohort.
Analysis for the Primary Endpoint
HV Cohort: Mean SpO2 during TST will be analyzed using a mixed effect model. The 
model will include fixed effects for sequence, period, and treatment, and a random effect for 
subject within sequence. The following will be presented: LS means, difference in LS mean 
of lemborexant 10 mg and lemborexant 25 mg compared to placebo, a two-sided 90% CI 
(equivalent to a one-sided lower 95% CI) for the true mean difference (lemborexant − 
placebo) in SpO2 and p-value. If the lower bound of the one-sided 95% CI of the treatment 
difference of SpO2 is less than -5, this will provide evidence that the given dose of 
lemborexant does not result in a clinically significant decrease in SpO2 compared to placebo.
OSA Cohort: AHI will be analyzed using a mixed effect model., The model will include 
fixed effects for, sequence, period, and treatment, and a random effect for subject within 
sequence. The following will be presented: LS means, difference in LS mean of lemborexant 
10 mg compared to placebo, a two-sided 90% CI (equivalent to a one-sided upper 95% CI) 
for the true mean difference (lemborexant −placebo) in AHI and p-value. If the upper bound 
of the one-sided 95% CI of the treatment difference of AHI is less than 5, this will provide 
evidence that the given dose of lemborexant does not result in a clinically significant increase 
in AHI with mild OSA compared with placebo.
A sensitivity analysis may also be performed on the primary endpoint where outliers are 
excluded. Other sensitivity analyses may be explored. 
Plots of AHI and SpO2 treatment difference data (both individual and LS Mean) will be used 
to explore the results.
Analysis for the Secondary Endpoints
The continuous secondary endpoints will be analyzed using the same model as the primary 
endpoint. Treatment comparison will be performed using contrasts.
The proportion of subjects with SpO2 <90% will be summarized using descriptive statistics.  
All analyses will be performed separately for each cohort.
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Analysis for the Exploratory Endpoints
Summaries and plots of all endpoints may be produced for appropriate subgroups 
(eg, age group, sex, BMI, race).
Subgroup analyses will also be performed as appropriate on primary and all secondary 
endpoints.  All analyses will be performed separately for each cohort.
Pharmacokinetic/Pharmacodynamic (Exposure-Response) Analyses
The exposure-response (E-R) relationship between plasma concentrations of lemborexant 
after PSG, and selected PD parameters including but not limited to the respiratory safety 
variables (including AHI, mean SpO2 during TST, and proportion of TST in which SpO2 is 
<90%, <85% and <80% will be explored graphically. Any emergent relationship may be 
followed using population model-based analysis. The potential effect of covariates (eg, age) 
on the E-R relationship may be tested. 
The PK Analysis Set will be used for these 
assessments. All analyses will be performed separately for each cohort.
Pharmacodynamic, PG, and other biomarker analyses may be performed and reported 
separately.  Details of these analyses may be described in a separate analysis plan.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, where
presented by treatment, will be summarized on an “as treated” basis using descriptive 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous
variables; n [%] for categorical variables).  Safety variables include the incidence of AEs, 
treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, and 
suicidality variables (C-SSRS).  All analyses will be performed separately for each cohort.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of subjects exposed to each treatment will be summarized descriptively by 
treatment, and a listing will also be provided.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the MedDRA.  Adverse events will be coded to the 
MedDRA (Version 20.1 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 TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 
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•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment.  The incidence of TEAEs will be reported as
the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted 
only once within a SOC and PT, even if the subject experienced more than 1 TEAE within a 
specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by cohort/dose level and 
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by system organ class (SOC) and by preferred term (PT) 
will be calculated.  Incidence (%) by causal relationship with study drug and by severity will 
also be calculated.  For clinically significant events, time of onset, and recovery will be 
reported.
Adverse events will be summarized by the following subgroups:  age, sex (male, female), 
and race (white, black, Asian, and other) if there are sufficient numbers in a category.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment.  A subject data listing of all AEs leading to death 
will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each treatment.  A subject data listing of 
all SAEs will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment. A subject data listing of 
all AEs leading to discontinuation from study drug will be provided.
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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and treatment using descriptive statistics.  
Qualitative parameters listed in Section 9.5.1.5.3 will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline to each postbaseline visit 
and to end of treatment will be reported using shift tables.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiratory rate, weight) and changes from baseline will be presented by day and time after 
dosing.
9.7.1.8.5
OTHER SAFETY ANALYSES
Not applicable.
9.7.1.9
Other Analyses
Not applicable
9.7.2
Determination of Sample Size
HV Cohort
A mean difference of 5 percentage points between treatments in SpO2 is considered to be 
clinically meaningful in a study of the respiratory safety of suvorexant in healthy adult 
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volunteers (Uemura, et al., 2015). From that source, the within-subject variance is assumed to 
be 0.315%. With a total of 12 subjects (4 elderly and 8 adults) completing the study and 
assuming that the true difference between treatments is -1.0, there is 99% power that the 
lower 
bound 
of 
the 
90% 
confidence 
interval 
for 
the 
difference 
in 
SpO2
(lemborexant - placebo) would be greater than -5. Although the estimate of within-subject 
variability is based on a study of adult healthy volunteers, the addition of elderly subjects is 
expected to have a minimal effect on the combined variability and thus a minimal effect on 
the power.
OSA Cohort
A mean difference between treatments in AHI > 5 is considered clinically meaningful in 
studies of the respiratory safety of sleep agents in OSA (Kryger, et al., 2007, 
Sun, et al., 2016). The within-subject variance is assumed to be 25.34 for AHI for adult 
subjects (Sun, et al, 2016) and 30.41 for AHI for elderly subjects (where the elderly 
within-subject variance is estimated from adult data + 20% (Mitterling, et al, 2015; Lee, et 
al., 2016). Assuming the true difference in AHI (lemborexant – placebo) on Day 8 is as high 
as 1.5, a total of 30 subjects completing the study (20 adult, 10 elderly), provides 82% power 
that the upper bound of the 90% CI for the treatment difference in AHI (lemborexant − 
placebo) on Day 8 would be < 5.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
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
American Academy of Sleep Medicine. International classification of sleep disorders, 3rd 
edition. Darien, IL: American Academy of Sleep Medicine, 2014.
Bassetti C, Aldrich MS, Chervin RD, Quint D. Sleep apnea in patients with transient 
ischemic attack and stroke: a prospective study of 59 patients. Neurology. 1996;47(5):1167-
73.
Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128 
patients. Sleep. 1999;22(2):217-23.
Berry RB, Kouchi KG, Bower JL, Light RW. Effect of upper airway anesthesia on 
obstructive sleep apnea. Am J Respir Crit Care Med. 1995;151:1857–61.
Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in 
men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;157:144–48.
Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence 
of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 
2001;163:608–13.
Collen J, Lettieri C, Kelly W, Roop S. Clinical and polysomnographic predictors of short-
term continuous positive airway pressure compliance. Chest. 2009;135(3):704-9
Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal 
threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a 
low arousal threshold. Clin Sci (Lond). 2011;120:505–14.
Epstein LJ, Kristo D, Strollo PJ, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, 
Schwab RJ, Weaver EM, Weinstein MD. Clinical Guideline for the Evaluation, Management 
and Long-term Care of Obstructive Sleep Apnea in Adults. Journal of Clinical Sleep 
Medicine. 2009;5(3):263-76.
Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep 
complaints among elderly persons: an epidemiologic study of three communities. Sleep. 
1995;18:425–32.
Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric 
disorders: an opportunity for prevention? JAMA. 1989; 262:1479–84.
George CF. Perspectives on the management of insomnia in patients with chronic respiratory 
disorders. Sleep. 2000;23(Suppl 1):S31–5
Gooneratne NS, Gehrman P, Gurubhagavatula I, Al-Shehabi E, Elisabeth Marie E, Schwab
R. Effectiveness of ramelteon for insomnia symptoms in older adults with obstructive sleep
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apnea: A randomized placebo- controlled pilot study. Journal of Clinical Sleep Medicine. 
2010;6(6):572-80.
Guilleminault C. Benzodiazepines, breathing, and sleep. Am J Med. 1990;88:25S-28S. 
Krakow B, Melendrez D, Ferreira E, et al. Prevalence of insomnia symptoms in patients with 
sleep-disordered breathing. Chest. 2001;120:1923–9.
Kryger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to 
moderate obstructive sleep apnea. Sleep Breath. 2007;11:159–164. 
Lee YJ, Kim JW, Lee Y-U-G, Jeong DU. Sleep EEG Characteristics in Young and Elderly 
Patients with Obstructive Sleep Apnea Syndrome. Investig. 2016;13(2):217-21.
Mitterling M, Högl B, Schönwald SV, Hackner H, Gabelia D, M, Birgit Frauscher B. Sleep 
and Respiration in 100 Healthy Caucasian Sleepers—A Polysomnographic Study According 
to American Academy of Sleep Medicine Standards. Sleep, 2015;38 (6):867-75.
Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-
disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep 
Heart Health Study. JAMA. 2000;283(14):1829-36.
Nieto FJ, Peppard PE, Young TB. Sleep disordered breathing and metabolic syndrome. 
WMJ. 2009;108(5):263-5.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, 
Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with adolescents 
and adults. Am J Psychiatry. 2011;168(12):1266-77.
Uemura, Naoto; McCrea, Jacqueline; Sun, Hong; Donikyan, Mardik; Zammit, Gary; Liu, 
Rong; Louridas, Bonnie; Marsilio, Sabrina; Lines, Christopher; Troyer, Matthew D.; 
Wagner, John. Effects of the orexin receptor antagonist suvorexant on respiration during 
sleep in healthy subjects. Journal Of Clinical Pharmacology; v:55 i:10 p:1093-1100; 
10/3/2015 Wiley-Blackwell. 
Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, Lines C, Wagner JA, Troyer 
MD. Effects of suvorexant, an orexin receptor antagonist, on respiration during sleep in 
patients with obstructive sleep apnea. J Clin Sleep Med. 2016;12(1):10-17.
Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea 
and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med.
1999;340(11):847-51.
Tractenberg RE, Singer CM, Kaye JA. Symptoms of sleep disturbance in persons with 
Alzheimer’s disease and normal elderly. J Sleep Res. 2005; 14:177–85
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Tractenberg RE, Singer CM, Kaye JA. Characterizing sleep problems in persons with 
Alzheimer’s disease and normal elderly. J Sleep Res. 2006; 15:97–103
Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of 
sleep apnea syndrome in middle-aged men and women. Sleep. 1997;20(9):705-6.
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-
disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-5.
C-SSRS Reference
http://www.cssrs.columbia.edu/scales_cssrs.html
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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 regulatory authorities as well as additional approval by the 
applicable IRBs.  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/or study director and the IRB 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, but the health or regulatory authority 
and IRB 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 and the Competent Authorities
detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
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•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, CT scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of 
how these images are stored, including microfiche and photographic negatives
•
Pain, 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 (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as source document.  Any correction to entries made 
on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
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documents (eg, Form FDA 1572, ICFs, and IRB correspondence).  In addition, the sponsor 
will send a list of treatment codes by study subject to the investigator after the clinical 
database for this study has been locked.  The site should plan to retain study documents, as 
directed by the sponsor, for at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 3 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.
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 ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  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 drug packaging vendor for drug destruction.  A copy of the completed drug 
disposition form will be forwarded to the sponsor.
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 and the institution/investigator.  The review is aimed at protecting the 
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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, as appropriate.
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/ 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.
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 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 and provide the 
sponsor and the IRB 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
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 – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
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
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
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
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
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 – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, 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 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
List of Prohibited 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 
•
Carbinoxamine 
•
Doxylamine 
•
Dimenhyrinate 
•
Triprolidine 
•
Bromopheniramine 
•
Chlorphemamine 
•
Hydroxazine
Antihistamines with known sedating effects
Non-sedating, eg, Loratidine is 
not prohibited
Anxiolytics with known sedating effects
•
Lorazepam 
•
Alprazolam 
•
Buspirone
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Category
Medication
Strong CYP3A inhibitors
•
Amiodarone 
•
Cimetidine 
•
Clarithromycin 
•
Diltiazem 
•
Erythromycin 
•
Fluvoxamine 
•
Grapefruit juice
•
Itraconazole 
•
Ketoconazole 
•
Mibefradil 
•
Nefazodone 
•
Troleandomycin 
•
Verapamil
CYP3A inducers
•
Carbamazepine 
•
St. John’s Wort 
•
Phenobarbital 
•
Troglitazone 
•
Phenytoin 
•
Rifabutin 
•
Rifampin
Hypnotics
Melatonin(prescribed or OTC)
Herbal preparations with sedating effects
-
MAOIs
-
Opioid Analgesics
-
Muscle relaxants (centrally-acting) with known 
sedating effects
•
GABA analogues 
•
Hydantoins 
•
Phenyltriazines
Stimulants
•
Amphetamines 
•
Modafinil 
•
Armodafinil
•
Methylfenidate
•
Theophylline
Other
•
Warfarin, heparin, ticlopidine
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Category
Medication
•
Non-stimulant diet pills
•
Systemic isoretinoin
•
Systemic glucocorticoids
•
Tryptophan
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PROTOCOL SIGNATURE PAGE
Study Protocol 
Number:
E2006-A001-102
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to 
Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly 
Healthy Subjects and Adult and Elderly Subjects with Mild 
Obstructive Sleep Apnea
Investigational 
Product Name:
E2006/Lemborexant
SIGNATURES
Authors:
 Neuroscience Business Group
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
Eisai Inc.
Date
Eisai Inc.
Date
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PPD
PPD
PPD
PPD
PPD
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-102
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study 
to Evaluate the Respiratory Safety of Lemborexant in Adult and 
Elderly Healthy Subjects and Adult and Elderly Subjects with Mild 
Obstructive Sleep Apnea
Investigational Product 
Name:
E2006/Lemborexant
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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SAP_003.pdf: 
Statistical Analysis Plan  
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2006-A001-102 
Study Protocol 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study 
to Evaluate the Respiratory Safety of Lemborexant in Adult and 
Elderly Healthy Subjects and Adult and Elderly Subjects with Mild 
Obstructive Sleep Apnea 
Date: 
05 FEB  2018 
Version: 
Final 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................5 
3.1 
Study Objectives ......................................................................................................5 
3.1.1 
Primary Objectives.........................................................................................5 
3.1.2 
Secondary Objectives.....................................................................................5 
3.1.3 
Exploratory Objectives (HV and OSA Cohorts) ...........................................6 
3.2 
Overall Study Design and Plan ................................................................................6 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................8 
5 
STATISTICAL METHODS ..............................................................................................8 
5.1 
Study Endpoints .......................................................................................................9 
5.1.1 
Primary Endpoints .........................................................................................9 
5.1.2 
Secondary Endpoints .....................................................................................9 
5.2 
Study Subjects ........................................................................................................10 
5.2.1 
Definitions of Analysis Sets.........................................................................10 
5.2.2 
Subject Disposition ......................................................................................10 
5.2.3 
Protocol Deviations ......................................................................................11 
5.2.4 
Demographic and Other Baseline Characteristics .......................................11 
5.2.5 
Prior and Concomitant Therapy ...................................................................11 
5.2.6 
Treatment Compliance .................................................................................12 
5.3 
Data Analysis General Considerations ..................................................................12 
5.3.1 
Pooling of Centers........................................................................................12 
5.3.2 
Adjustments for Covariates..........................................................................12 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................12 
5.3.4 
Examination of Subgroups ...........................................................................12 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................12 
5.3.6 
Other Considerations ...................................................................................13 
5.3.7 
Visit Window ...............................................................................................13 
5.4 
Efficacy Analyses ..................................................................................................13 
5.4.1 
Primary Pharmacodynamic  Analyses .........................................................13 
5.4.2 
Secondary Pharmacodynamic Analyses ......................................................13 
5.4.3 
Exploratory Analyses ...................................................................................14 
5.5 
Pharmacokinetic, Pharmacogenomic, and Other Biomarker Analyses .................14 
5.5.1 
Pharmacokinetic Analyses ...........................................................................14 
5.5.2 
Pharmacogenomic, and Other Biomarker Analyses ....................................14 
5.5.3 
Pharmacokinetic/Pharmacodynamic (Exposure-Response) Analysis .........14 
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5.6 
Safety Analyses ......................................................................................................14 
5.6.1 
Adverse Events ............................................................................................15 
5.6.2 
Laboratory Values ........................................................................................16 
5.6.3 
Vital Signs ....................................................................................................16 
5.6.4 
Electrocardiograms ......................................................................................17 
6 
INTERIM ANALYSES ...................................................................................................17 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................17 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................18 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................18 
10 STATISTICAL SOFTWARE ..........................................................................................18 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................18 
12 REFERENCES ................................................................................................................18 
13 APPENDICES .................................................................................................................19 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....19 
13.2 
SAS Code Example for ANOVA ..........................................................................21 
13.3 
SAS Code Example for Proc Logistic ...................................................................21 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic class 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
E2006 
lemborexant 
ECG 
electrocardiogram 
FAS 
full analysis set 
HV 
healthy volunteer 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini Mental State Examination 
OSA 
obstructive sleep apnea 
PBO 
Placebo 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PSG 
Polysomnography 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard deviation 
SI 
Système International 
SOC 
system organ class 
TEAE 
Treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
WHO 
World Health Organization 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E2006-
G000-102 (for both cohort 1 and cohort 2). Cohort 1 comprises the healthy volunteer subjects 
(HV) and cohort 2 comprises the subjects with obstructive sleep apnea (OSA). Additional 
exploratory or post-hoc analyses not identified in this SAP may be performed to facilitate 
interpretation of study results and documented in the clinical study report.  
This document is prepared on the basis of the final study protocol version 8.0 (dated 11 Dec 
2017).  The reader is referred to the study protocol, the case report form (CRF), general CRF 
completion guidelines, and various data collection instruments employed in the study for 
details of study design, conduct, and data collection.   
This SAP is to be reviewed and approved prior to study database lock.  If any updates are 
made upon blinded review of study data or for any other reasons in the course of the study, 
such modifications and rationale are likewise to be documented and approved prior to 
unblinding of study database.  
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
Primary Objective (Healthy Volunteer [HV] Cohort) 
To determine whether lemborexant decreases the peripheral oxygen saturation (SpO2) during total 
sleep time (TST) in healthy adult and elderly subjects after a single dose of treatment compared with 
placebo 
 
Primary Objective (Obstructive Sleep Apnea [OSA] Cohort)  
To determine whether lemborexant increases the AHI after multiple doses of treatment in adult and 
elderly subjects with mild OSA compared with placebo 
 
3.1.2 
Secondary Objectives 
Secondary Objectives (HV Cohort) 
1. Determine whether lemborexant increases the apnea-hypopnea index (AHI) after a single 
dose of treatment compared with placebo 
2. Determine whether lemborexant decreases SpO2 during TST velow defined thresholds after a 
single dose of treatment compared with placebo 
3. Evaluate safety and tolerability of lemborexant 
Secondary Objectives (OSA Cohort) 
1. Determine whether lemborexant increases the AHI after the first dose of treatment compared 
with placebo 
2. Determine whether lemborexant decreases the mean SpO2 during TST after the first and 
multiple doses of treatment compared with placebo 
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3. Determine whether lemborexant increases the proportion of TST during which the SpO2 is 
decreased below defined thresholds after the first and multiple doses of treatment compared 
with placebo 
4. Evaluate safety and tolerability of lemborexant  
3.1.3 
 Exploratory Objectives (HV and OSA Cohorts) 
Explore the effects of lemborexant compared with placebo after a single dose in HV Cohort and after 
the first and multiple doses in the OSA Cohort on the following:  
5. The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, and 
wake 
6. AHI during REM and NREM sleep  
7. AHI separately for adult and elderly subjects 
8. The mean SpO2 during TST separately for adult and elderly subjects 
 
In addition, explore the following for both HV and OSA Cohorts: 
1. Plasma concentrations of lemborexant and metabolites M4, M9 and M10. 
2. Exposure-response 
(E-R) 
relationships 
between 
lemborexant 
concentrations 
and 
pharmacodynamic (PD) variables, including but not limited to respiratory safety variables 
(AHI, mean SpO2 during TST, proportion of TST during which the SpO2 is decreased below 
defined thresholds) 
 
3.2 
Overall Study Design and Plan 
HV Cohort 
The HV Cohort comprises a randomized, double-blind, placebo-controlled, 3-period crossover study.  
Eligible healthy adult and elderly subjects will be randomized to treatment sequence A, B or C, each 
consisting of 3 Treatment Periods, each of one night’s duration, in which subjects will receive a 
single dose of lemborexant 10 mg, or lemborexant 25 mg, or placebo; Treatment Periods will be 
separated by a washout interval of at least 14 days.  A sufficient number of subjects will be 
randomized to ensure that 8 evaluable adult subjects (<65 years) and 4 evaluable elderly subjects (≥65 
years) complete the study. 
Treatment 
Sequence 
Treatment Periods in the HV Cohort 
1 (one night) 
2 (one night) 
3 (one night) 
A 
lemborexant-matched 
placebo 
lemborexant 10 mg 
lemborexant 25 mg 
B 
lemborexant 10 mg 
lemborexant 25 mg 
lemborexant-matched 
placebo 
C 
lemborexant 25 mg 
lemborexant-matched 
placebo 
lemborexant 10 mg 
 
 
 
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OSA Cohort  
The OSA Cohort comprises a randomized, double-blind, placebo-controlled, 2-period crossover 
study.  
Adult and elderly subjects with mild OSA will be randomized to treatment sequences D or E, each 
consisting of 2 Treatment Periods, each of 8 nights’ duration, in which subjects will receive 
lemborexant 10 mg or placebo.  The Treatment Periods will be separated by a washout interval of at 
least 14 days. A sufficient number of subjects will be randomized to ensure that 20 evaluable adult 
subjects (<65 years) and 10 evaluable elderly subjects (≥65 years) complete the study. 
 
 
Treatment 
Sequence 
Treatment Periods in the OSA Cohort 
1 (eight nights) 
2 (eight nights) 
D 
lemborexant-matched placebo 
lemborexant 10 mg 
E 
lemborexant 10 mg 
lemborexant-matched placebo 
Phases of the Study (HV and OSA Cohorts) 
For both the HV and OSA cohorts, there will be 2 phases, Prerandomization and Randomization.  The 
Prerandomization Phase for both cohorts will consist of the Screening Period (up to 21 days) and a 
Baseline Period (≤1day prior to randomization).   
For the HV Cohort, the Randomization Phase will comprise 3 Treatment Periods, each of 1-day 
duration, separated by a washout interval of at least 14 days, followed by a 14-day Follow-Up Period. 
For the OSA Cohort, the Randomization Phase will comprise 2 Treatment Periods, each of 8 days 
duration, separated by a washout interval of at least 14 days, and a Follow-Up Period of 14 days.   
For both cohorts, an End of Study (EOS) Visit will occur at least 14 days after the final dose of study 
medication. 
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4 
DETERMINATION OF SAMPLE SIZE 
Sample Size Rationale 
HV Cohort: 
A mean difference of 5 percentage points between treatments in SpO2 is considered to be 
clinically meaningful in a study of the respiratory safety of suvorexant in healthy adult volunteers 
(Uemura, et al., 2015). From that source, the within-subject variance is assumed to be 0.315%. 
With a total of 12 subjects (4 elderly and 8 adults) completing the study and assuming that the 
true difference between treatments is -1.0, there is 99% power that the lower bound of the 90% 
confidence interval for the difference in SpO2 (lemborexant - placebo) would be greater than -5. 
Although the estimate of within-subject variability is based on a study of adult healthy volunteers, 
the addition of elderly subjects is expected to have a minimal effect on the combined variability 
and thus a minimal effect on the power.  
OSA Cohort: A mean difference between treatments in AHI > 5 is considered clinically 
meaningful in studies of the respiratory safety of sleep agents in OSA (Kryger, et al., 2007, Sun, 
et el., 2016). The within-subject variance is assumed to be 25.34 for AHI for adult subjects (Sun, 
et al, 2016) and 30.41 for AHI for elderly subjects (where the elderly within-subject variance is 
estimated from adult data + 20%, Mitterling, et al, 2015; Lee, et al, 2016). Assuming the true 
difference in AHI (lemborexant – placebo) on Day 8 is as high as 1.5, a total of 30 subjects 
completing the study (20 adult, 10 elderly), provides 82% power that the upper bound of the 90% 
CI for the treatment difference in AHI (lemborexant − placebo) on Day 8 would be < 5.  
Sample Size Estimates for OSA Cohort 
Description 
Combined 
within-subject 
variance of AHI 
Adult 
N 
Elderly 
N 
Total 
N 
Total 
Power 
(%) 
80% overall power with 
20 adult subjects 
26.96 
20 
10 
30 
82 
85% overall power with 
20 adult subjects 
27.38 
20 
14 
34 
86 
80% overall power with 
20 elderly subjects 
28.54 
12 
20 
32 
82 
85% overall power with 
20 elderly subjects 
28.16 
16 
20 
36 
86 
Equal number of 
subjects 
27.875 
20 
20 
40 
90 
 
5 
STATISTICAL METHODS 
All analysis will be reported separately for each cohort. All descriptive statistics for 
continuous variables will be reported using mean, standard deviation (SD), median, 
minimum and maximum.  Categorical variables will be summarized as number (percentage) 
of subjects. 
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All statistical tests will be based on the 5% level of significance (2-sided), unless otherwise 
stated.  If statistical comparisons are not defined, all pairwise comparisons will be tested. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
Primary Endpoint (HV Cohort) 
The mean SpO2 during TST on Day 1 of treatment  
 
Primary Endpoint (OSA Cohort) 
The AHI on Day 8 of treatment 
 
5.1.2 
Secondary Endpoints 
Secondary Endpoints (HV Cohort) 
1. The AHI on Day 1 of treatment 
2. The percentage of TST during which SpO2 is <90%, <85% and <80% on Day 1  of 
treatment 
3. The proportion of subjects with at least one incident of SpO2 <90% for at least 30 
seconds during TST on Day 1 of treatment 
 
Secondary Endpoints (OSA Cohorts) 
1. The AHI on Day 1 of treatment 
2. The mean SpO2 during TST on Day 1 and Day 8 of  treatment  
3. The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and 
Day 8 of treatment 
4. The proportion of subjects with at least one incident of SpO2 <90% for at least 
30 seconds during TST on Day 1 and Day 8 of treatment. 
Exploratory Endpoints (HV and OSA Cohorts) 
1. The mean SpO2 during REM sleep, NREM and wake  
2. The AHI during REM and NREM sleep 
3. The AHI separately for adult and elderly subjects at all days assessed 
4. The mean SpO2 during TST separately for adult and elderly subjects at all days assessed 
 
Pharmacokinetic Endpoint (HV and OSA Cohorts) 
Lemborexant and metabolites M4, M9 and M10 plasma concentrations  
 
Pharmacokinetic/Pharmacodynamic (Exposure-Response) Endpoint (HV and OSA Cohorts) 
Correlations between plasma concentrations of lemborexant and select pharmacodynamic variables 
including AHI, mean SpO2 during TST, and proportion of TST in which SpO2 is <90%, <85% and 
<80% at all days assessed. 
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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Analyses defined below are for each cohort separately. 
Safety Analysis Set: Group of subjects who received study drug and have at least one 
postdose safety assessment. 
Pharmacodynamic Analysis Set: The PD Analysis Set is the group of subjects who received 
at least 1 dose of study drug in each Treatment Period and who had sufficient PD data to 
derive at least 1 primary PD parameter.  
Pharmacokinetic Analysis Set: Group of subjects who received at least 1 dose of lemborexant 
and who had sufficient PK data to derive at least 1 PK parameter. 
5.2.2 
Subject Disposition 
The number of subjects screened and the number failing screening for each cohort (overall 
and by reason for failure) will be summarized. Screen failure data will be listed by cohort. 
The number of subjects randomized along with the number of subjects in each of the study 
populations will also be presented.  
All disposition tables will be presented by cohort as follows: 
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. Other reasons for study drug and study terminations will also be 
summarized. These tabulations will be produced for all randomized subjects by treatment 
sequence.  
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. Other reasons for study drug and study terminations will also be 
summarized. These tabulations will be produced for all randomized subjects by treatment 
sequence. 
The number and percentage of subjects will be summarized with the number in the FAS as 
the denominator, together with the number of subjects randomized but never dosed: 
• Randomized but never dosed (only showing number of subjects) 
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• Completed treatment 
• Prematurely discontinued treatment and the reasons for discontinuations 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuations 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing will be provided with subjects 
ordered by randomization date. 
5.2.3 
Protocol Deviations 
Protocol deviations, as specified by the monitor, will be categorized into major and minor 
deviations prior to unblinding and will be listed.  Major protocol deviations will be presented 
as a listing by cohort. 
No exploratory analyses is planned on subjects without important  protocol violations since 
this is a safety study.  
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each sequence and overall using descriptive statistics for each cohort 
separately.  Continuous demographic and baseline variables include age height, and weight; 
body mass index (BMI); categorical variables include sex, age group (<65, and  >= 65 years), 
BMI group, race, and ethnicity.   
MEDICAL HISTORY 
The number (percentage) of subjects in the Safety Analysis Set reporting a history of any 
medical condition, as recorded on the CRF, will be presented as a listing by cohort.   A 
subject data listing of medical and surgical history will be provided. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2017 or latest 
version).  The number (percentage) of subjects who took prior and concomitant medications 
will be presented as a listing by cohort. Prior medications will be defined as medications that 
stopped before the first dose of study drug.  All medications will be presented in subject data 
listings. 
Concomitant medications are defined as medications that (1) started before the first dose of 
study drug and are continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug to the last dose day plus 14 days.  All 
medications will be presented in subject data listings. 
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5.2.6 
Treatment Compliance 
Compliance for the OSA Cohort each study drug will be calculated on the basis of the 
number of tablets dispensed, lost and returned, separately for each row of tablets and overall, 
for all randomized subjects.  
Compliance = Total number of tablets dispensed - total number of tablets returned or lost    x 
100 
                       Number of tablets expected to be taken by the subject for the treatment period 
Summaries will provide descriptive summary statistics and number (percentage) of subjects 
using the categories <80%, >= 80% to <= 100%, >100% to <= 120%, and > 120% for each 
treatment group. 
Subjects in the HV Cohort will receive 1 dose of study medication per period while in clinic.  
Treatment compliance will not be calculated for this cohort.   
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
This study is a multicenter study across the United States, with approximately 10 sites. Due 
to the small sample size and the fact that this is a safety study, analysis will be based on 
pooling of data from different sites and there will be no by site analysis. 
Pooling will be performed for each cohort independently based on each cohort’s sites. 
5.3.2 
Adjustments for Covariates 
Since this is a crossover study, there will be no adjustment for covariates like age, gender 
race, …etc.  The model will include fixed effects for sequence, period, and treatment, and a random 
effect for subject within sequence. 
5.3.3 
Multiple Comparisons/Multiplicity 
No multiplicity adjustments will be made.  This is a phase I safety study.  
5.3.4 
Examination of Subgroups 
Subgroup analysis of PD endpoints will be performed  by age group (adults versus elderly) 
for the OSA Cohort. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
In general, missing values due to subject discontinuation, missed or unusable assessments 
will not be imputed. 
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Incomplete/Missing data will not be imputed, unless otherwise specified; i.e., all missing 
values will remain as missing in all statistical analyses and listings, unless otherwise 
specified.  
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
5.3.6 
Other Considerations 
Individual subject data in the database will be presented in data listings. 
5.3.7 
Visit Window 
All data will be presented using nominal visits as reported in the data. No additional 
derivation will be performed for analysis visit window. 
5.4 
Efficacy Analyses 
No efficacy data will be recorded for this study. 
5.4.1 
Primary Pharmacodynamic  Analyses 
Analysis for the Primary Endpoint 
HV Cohort: Mean SpO2 during TST will be analyzed using  a mixed effect model . The model will 
include fixed effects for sequence, period, and treatment, and a random effect for subject within 
sequence. The following will be presented: least squares (LS) means, difference in LS mean of 
lemborexant 10 mg and lemborexant 25 mg compared to placebo, a two-sided 90% CI (equivalent to 
a one-sided lower 95% CI) for the true mean difference (lemborexant − placebo) in SpO2 and p-value. 
If the lower bound of the one-sided 95% CI of the treatment difference of SpO2 is less than -5, this 
will provide evidence that the given dose of lemborexant does not result in a clinically significant 
decrease in SpO2 compared to placebo. 
OSA Cohort: AHI will be analyzed using a mixed effect model. The model will include fixed effects 
for sequence, period, and treatment, and a random effect for subject within sequence. The following 
will be presented: LS means, difference in LS mean of lemborexant 10 mg compared to placebo, a 
two-sided 90% CI (equivalent to a one-sided upper 95% CI) for the true mean difference 
(lemborexant − placebo) in AHI and p-value. If the upper bound of the one-sided 95% CI of the 
treatment difference of AHI is less than 5, this will provide evidence that the given dose of 
lemborexant does not result in a clinically significant increase in AHI with mild OSA compared with 
placebo. 
A sensitivity analysis may also be performed on the primary endpoint where outliers are excluded. 
Other sensitivity analyses may be explored.  
Plots of AHI and SpO2 treatment difference data (both individual and LS Mean) will be used to 
explore the results. 
5.4.2 
Secondary Pharmacodynamic Analyses 
Analysis for the Secondary Endpoints 
The continuous secondary endpoints for both cohorts will be analyzed using the same model as the 
primary endpoint. Treatment comparison will be performed using contrasts.   
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The proportion of subjects with SpO2 <90% will be summarized using descriptive statistics.  All 
analyses will be performed separately for each cohort. 
 
5.4.3 
Exploratory Analyses 
Summaries and plots of all endpoints may be produced for appropriate subgroups (eg  age group, sex, 
BMI, race) as deemed necessary.  
5.5 
Pharmacokinetic, 
Pharmacogenomic, 
and 
Other 
Biomarker 
Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual plasma concentration listings of 
lemborexant and its metabolites M4, M9, and M10. The PK Analysis Set will be used for 
summaries of plasma concentrations of lemborexant and its metabolites M4, M9, and M10, 
by dose.  
5.5.2 
Pharmacogenomic, and Other Biomarker Analyses 
DNA samples will be collected and stored, and may be used to examine the role of genetic 
variability in absorption, distribution, metabolism, and excretion, or development of AEs. 
Variations in lemborexant exposure or AEs may be explored by correlation of single 
nucleotide polymorphisms with PK, safety, or PD data. 
 
5.5.3 
Pharmacokinetic/Pharmacodynamic (Exposure-Response) Analysis 
The exposure-response (E-R) between plasma concentration of lemborexant after PSG, and 
selected PD parameters including but not limited to the respiratory safety variables, AHI, 
SpO2 during TST, and the proportion of TST in which SpO2 is <90%, <85%, and <80%) 
will be explored graphically.  Any emergent relationship may be followed using population 
model-based analysis.  The potential effects of covariates (eg, age) on the E-R relationship 
may be explored.  The PK analysis set will be used for these assessments.  All analyses will 
be performed separately for each cohort. 
5.6 
Safety Analyses 
Safety analyses will be performed on the Safety Analysis Set unless otherwise specified. 
Safety data, presented by treatment group, will be summarized on an “as treated” basis using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include treatment-
emergent adverse events (TEAEs), clinical laboratory parameters, vital signs and 12-lead 
ECG results.  Baseline for all safety analyses is defined as the last predose assessment prior 
to each periods’ dosing. Extent of Exposure 
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The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study 
drug will be summarized descriptively for lemborexant in the OSA Cohort.  For the HV 
Cohort extent of exposure will be summarized by the number of subjects receiving each 
treatment. 
Compliance for the OSA Cohort for lemborexant will be calculated on the basis of the 
number of tablets dispensed, lost, and returned, separately for each type (dose) of tablet.  
Summaries will provide descriptive summary statistics and number (percentage) of subjects 
below 80%, between 80% and 120%, and greater than 120%. 
5.6.1 
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 20.1 or higher) lower 
level term closest to the verbatim term. The linked MedDRA PT and primary system organ 
class (SOC) are also captured in the database.   
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or  
• Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• Worsened in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. AEs will be 
classified as TEAEs up to 14 days after the last study treatment. 
An overview of the TEAEs will be summarized by treatment group, including the number 
and percentage of subjects who experience TEAEs, treatment-related TEAEs, severe TEAEs, 
TEAEs leading to death and discontinuation from study/study drug.   
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT. A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT. The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe). The number (percentage) of non-serious TEAEs with an incidence of 
greater than 5% will be summarized. 
The number (percentage) of subjects 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.  
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The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided. 
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group. A subject data listing of all SAEs will be 
provided.   
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment. A subject data listing of all 
AEs leading to discontinuation from study drug will be provided.  
The number (percentage) of subjects with TEAEs of cataplexy that are characterized 
according to the customized MedDRA query PT as potential cataplexy-related events 
(Section 9.5.1.5 of the Protocol), or as seizure-related events will be summarized separately. 
Adjudicated events will also be presented separately.  
5.6.2 
Laboratory Values 
Clinical laboratory values will be evaluated for each laboratory parameter by subject 
separately for each cohort.  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 clinical study report 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 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 at end of study/early termination, by treatment group. 
Clinical laboratory results postbaseline 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 13.1 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. 
5.6.3 
Vital Signs 
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiration rate, temperature) and weight, and changes from Baseline will be presented by 
treatment group and day relative to dosing, separately for each cohort.  
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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 (Table 1).  Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital 
sign ranges will also be presented by treatment group and visit. 
 
Table 1 
Vital Sign Criteria 
Variable 
Criterion valuea 
Change relative to 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, bpm = beats per minute, H = high, L = low. 
a. Clinically notable means that a value must meet the criterion value and must attain the specified 
magnitude of change relative to baseline. 
5.6.4 
Electrocardiograms 
Descriptive statistics for ECG parameters and changes from Baseline will be presented 
separately for each cohort. Shift tables will present changes from Baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) by time point. 
For each subject, the maximum observed corrected QT interval calculated using Fridericia’s 
formula (QTcF), and the maximum prolongation from baseline in QTcF will be compiled.  
Categorical analyses of subjects (number and percent) with maximum observed QTcF values 
>450 msec, >480 msec, and >500 msec and maximum prolongations (from Baseline) in 
QTcF >30 msec and >60 msec will be presented by treatment group and by time point. 
Categorical analyses of subjects (number and percent) with maximum observed PR values 
>220 msec, and QRS values > 120 msec will be presented by treatment group and by time 
point. 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
Not applicable. 
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8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
No missing data will be imputed. 
9 
PROGRAMMING SPECIFICATIONS 
All analysis will be done separately for each cohort. 
All pharmacodynamic and safety data will be presented using nominal timepoint as reported 
in the data. No additional derivation will be performed for analysis visit window.  
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS v 9.3 or later. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study table, listing, and graph (TLG) shells will be provided in a separate document, 
which will show the content and format of all tables, listings, and graphs in detail. There will 
be two separate independent TLGs for the two cohorts. 
12 REFERENCES 
Kryger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to 
moderate obstructive sleep apnea. Sleep Breath. 2007;11:159–164.  
Mitterling M, Högl B, Schönwald SV, Hackner H, Gabelia D, M, Birgit Frauscher B. Sleep 
and Respiration in 100 Healthy Caucasian Sleepers—A Polysomnographic Study According 
to American Academy of Sleep Medicine Standards. Sleep, 2015;38 (6):867-75. 
Lee YJ, Kim JW, Lee Y-U-G, Jeong DU. Sleep characteristics in young and elderly patients 
with obstructive sleep apnea. Investig. 2016:13(2):217-21 
Uemura, Naoto; McCrea, Jacqueline; Sun, Hong; Donikyan, Mardik; Zammit, Gary; Liu, 
Rong; Louridas, Bonnie; Marsilio, Sabrina; Lines, Christopher; Troyer, Matthew D.; 
Wagner, John. Effects of the orexin receptor antagonist suvorexant on respiration during 
sleep in healthy subjects. Journal Of Clinical Pharmacology; v:55 i:10 p:1093-1100; 
10/3/2015 Wiley-Blackwell.  
Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, Lines C, Wagner JA, Troyer 
MD. Effects of suvorexant, an orexin receptor antagonist, on respiration during sleep in 
patients with obstructive sleep apnea. J Clin Sleep Med. 2016;12(1):10-17. 
 
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13 APPENDICES 
13.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results  
The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, 
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 – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
ALT 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
AST 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN  
>1.5 – 3.0×ULN 
>3.0 – 10.0×ULN  
>10.0×ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
Fasting glucose value: 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
consequences  
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)  
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL 
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
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 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
life-threatening 
consequences 
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 – 10 mg/dL  
≤0.59 mmol/L without 
physiologic 
consequences  
N/A 
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences  
>10 mg/dL 
>0.59 mmol/L  
life-threatening 
consequences 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 28 May 2009 (v4.03: 14 Jun, 2010). 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, , LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC =  white blood cell. 
 
 
 
 
 
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13.2 SAS Code Example for ANOVA 
 
Proc Mixed can be used to analyze the crossover design data as follows: 
 
proc mixed data=XXXX; 
class sequence patient period treatment; 
model Response= sequence patient period treatment /solution 
ddfm=satterth; 
random patient(sequence); 
lsmeans drug / pdiff cl e; 
run; 
 
 
 
13.3 SAS Code Example for Proc Logistic 
 
The following statements use the LOGISTIC procedure 
to fit a two-way logit with interaction model for the effect of Treatment and 
AgeGroup, with Age as covariate. The categorical variables Treatment and 
Sex are declared in the CLASS statement. 
 
proc logistic data=XXXX; 
class Treatment AgeGroup; 
model Binary_Response= Treatment Treatment*AgeGroup AgeGroup / expb; 
run; 
Programming Note: EXPB option displays the exponentiated values  of the parameter estimates 
^ _i in the “Analysis of Maximum Likelihood Estimates” table for the logit model. These exponentiated 
values are the estimated odds ratios for the parameters. 
 
 
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SIGNATURE PAGE 
Investigational 
Product Name: 
E2006/Lemborexant 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
 
 
 Neuroscience Business Group 
Eisai Inc. 
 
 
Date 
 
 
 
 
 
 
 
 
 
Neuroscience Business Group 
Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
 
Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
 
Eisai Inc. 
 
Date 
 
 
 
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PPD
PPD
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