Conditions: Sleep Apnea, Obstructive Pulmonary Disease, Chronic Obstructive Respiration Disorders
Keywords: E2006 Lemborexant Peripheral Oxygen Saturation Apnea Hypopnea Index
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 63
Healthy volunteers: no

Brief summary:
The primary purpose of the study is to determine whether lemborexant increases the apnea hypopnea index (AHI) on Day 8 of treatment in adult and elderly participants (adults greater than or equal to \[\>=\] 45 to less than \[\<\] 65 years; elderly \>=65 to 90 years) with moderate to severe obstructive sleep apnea (OSA) compared with placebo, and using pulse oximetry determine whether lemborexant decreases the peripheral oxygen saturation (SpO2) during total sleep time (TST) on Day 8 of treatment in adult and elderly participants (adults \>=45 to \<65 years; elderly \>=65 to 90 years) with moderate to severe chronic obstructive pulmonary disease (COPD) compared with placebo.

Detailed description:

Arms:
arm 1: Participants with 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 will be maintained between the 2 treatment periods. arm 2: Participants with 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 will be maintained between the 2 treatment periods. arm 3: Participants with COPD 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 will be maintained between the 2 treatment periods. arm 4: Participants with COPD 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 will be maintained between the 2 treatment periods.

Interventions: intervention 1: Placebo intervention 2: Lemborexant 10 mg intervention 3: Placebo intervention 4: Lemborexant 10 mg
Intervention descriptions: intervention 1: OSA: Lemborexant-matched oral placebo will be administered at bedtime in the clinic (within 5 minutes before lights off) or at home when not in the clinic. intervention 2: OSA: 10 mg oral lemborexant will be administered at bedtime in the clinic (within 5 minutes before lights off) or at home when not in the clinic. intervention 3: COPD: Lemborexant-matched oral placebo will be administered at bedtime in the clinic (within 5 minutes before lights off) or at home when not in the clinic. intervention 4: COPD: 10 mg oral lemborexant will be administered at bedtime in the clinic (within 5 minutes before lights off) or at home when not in the clinic.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol
Incorporating Amendment 01
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REVISION HISTORY
Revisions to Version 1.0 
  New version/date:  Version 2.0/13 Jul 2020 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised treatments in Treatment 
Period 2 for appropriate representation 
of crossover design and included 
footnotes to maintain consistency with 
the schedule of assessment table, 
Figure 1 
To clarify that patients will 
crossover to the alternative 
treatment
Figure 1
Revised the duration of study period 
from 5 to 9 months
Correction
Section 2 Synopsis-Study 
Period and Phase of 
Development
Deleted footnote citation “n” for 
polysomnography (PSG) from 
Visit 2A in the schedule of assessment 
table
Deleted footnote citation “n” in the 
rows for “Administer study drug in 
clinic” in the schedule of assessment 
table
To clarify that the PSG is 
performed during the Screening 
period for both obstructive sleep 
apnea (OSA) and obstructive 
pulmonary disease (COPD)
cohorts
To correct erroneously placed 
superscript
Table 4
Added footnotes “q” and “r” to PSG 
for Baseline Period 1 and Baseline 
Period 2, respectively, in the schedule 
of assessment table
To clarify that PSG will occur after 
randomization and study drug 
administration during Baseline 
period 1, and after study drug 
administration during Baseline 
Period 2
Table 4
Marked ‘inclusion/exclusion’ criteria 
and oxygen saturation assessments for 
Baseline Period 2
To clarify that inclusion/exclusion 
criteria will be reevaluated during 
Baseline Period 2
Section 2 Synopsis-Study 
Design
Table 4
Section 9.1.2
Mentioned that the oxygen saturation 
as measured by a pulse oximeter will 
also be recorded at Visit 3A and 
Visit 6A in addition to Visit 1
To confirm that the subject 
continues to meet oxygen 
saturation criteria requirements
Table 4
Exclusion criterion added to chronic 
obstructive pulmonary disease
(COPD) cohort as follows: recent 
changes to COPD medications or 
recent acute exacerbation of COPD 
(ie, needing hospitalization or 
treatment with oral corticosteroids 
and/or antibiotics) within 3 months of 
enrollment
To clarify that COPD patients 
should be on a stable COPD 
treatment regimen and have stable 
disease prior to study enrollment
Section 2 Synopsis-Exclusion 
Criteria (COPD Cohort)
Section 9.3.2


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Revisions to Version 1.0 
  New version/date:  Version 2.0/13 Jul 2020 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Exclusion criteria added to obstructive 
sleep apnea (OSA) and COPD cohorts
as follows:  Exposure within the last 
14 days to an individual with 
confirmed or probable corona virus 
disease 2019 (COVID-19) or 
symptoms within the last 14 days that 
are on the most recent Centers for 
Disease Control and Prevention 
(CDC) list of COVID symptoms or 
any other reason to consider the 
subject at potential risk for an acute 
COVID-19 infection
To avoid potential risk of 
COVID-19
Section 2 Synopsis-
Additional Exclusion Criteria 
(OSA and COPD Cohorts)
Section 9.3.2
Added oxygen desaturation index 
(ODI) and absolute number of 
desaturations (with desaturation 
defined as a ≥3% reduction from 
baseline peripheral capillary oxygen 
saturation [SpO2]) to secondary
objectives and endpoints, and 
pharmacodynamic (PD) assessments
To further assess secondary 
measures of respiratory safety per 
FDA recommendation
Section 2 Synopsis-
Secondary Objectives
Section 2 Synopsis-Statistical 
Methods
Section 2 Synopsis-
Assessments
Section 8.2
Section 9.5.1.3.2
Section 9.7.1.1.2
Section 9.7.1.1.4
Deleted sensitivity analysis
Correction
Section 2 Synopsis-
Pharmacodynamic analyses
Section 9.7.1.7.2
Revised description of primary 
endpoint for OSA and COPD Cohorts
to state that the mean apnea hypopnea 
index (AHI) will be analyzed on the 
PD analysis set
To clarify what population will be 
used for the primary analysis
Section 2 Synopsis-Statistical 
methods
Section 9.7.1.7.2
Mentioned that further details of the 
analysis will be provided in the 
statistical analysis plan (SAP)
To align estimands with the 
clinical objective for each cohort
Section 2 Synopsis-Statistical 
methods
Section 9.7.1.7.2


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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2006-A001-113
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
2-Period, Crossover Study to Evaluate the Respiratory Safety of 
Lemborexant in Adult and Elderly Subjects With Moderate to 
Severe Obstructive Sleep Apnea and Adult and Elderly Subjects 
With Moderate to Severe Chronic Obstructive Pulmonary Disease
Sponsor:
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677, US
Investigational 
Product Name:
E2006/lemborexant
Indication:
Not applicable
Approval Date:
V1.0
06 Apr 2020 (original protocol)
V2.0
13 Jul 2020 (Amendment 01)
IND Number:
111871
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All 
required study documentation will be archived as required by 
regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  lemborexant
Study Protocol Title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 2-Period, Crossover Study to 
Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Subjects With Moderate to 
Severe Obstructive Sleep Apnea and Adult and Elderly Subjects With Moderate to Severe Chronic 
Obstructive Pulmonary Disease
Sites
Approximately 10 sites in the US
Study Period and Phase of Development
First Subject Screened to Last Subject Out:  Approximately 9 months (revised per Amendment 01).
Phase 1
Objectives
Obstructive Sleep Apnea Cohort:
Primary Objective
• Using polysomnography (PSG), determine whether lemborexant increases the apnea hypopnea 
index (AHI) on Day 8 of treatment in adult and elderly subjects (adults ≥45 to <65 years; 
elderly ≥65 to 90 years) with moderate to severe obstructive sleep apnea (OSA) compared 
with placebo
Secondary Objectives
• Using PSG, determine whether lemborexant increases the AHI on Day 1 of treatment 
compared with placebo
• Using pulse oximetry, determine whether lemborexant decreases the mean oxygen saturation 
(SpO2) during total sleep time (TST) on Days 1 and 8 of treatment compared with placebo
• Using pulse oximetry, determine whether lemborexant increases the percentage of TST during 
which the peripheral capillary oxygen saturation (SpO2) is <90%, <85%, and <80% on Days 1 
and 8 of treatment compared with placebo
• Using pulse oximetry, determine whether lemborexant increases the mean oxygen desaturation 
index (ODI) on Days 1 and 8 of treatment compared with placebo (revised per 
Amendment 01)
• Using pulse oximetry, determine whether lemborexant increases the absolute number of 
desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of treatment compared 
with placebo (revised per Amendment 01)
• Evaluate safety and tolerability of lemborexant compared with placebo
Chronic Obstructive Pulmonary Disease Cohort:
Primary Objective
• Using pulse oximetry, determine whether lemborexant decreases mean SpO2 during TST on 
Day 8 of treatment in adult and elderly subjects (adults ≥45 to <65 years; elderly ≥65 to 


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90 years) with moderate to severe chronic obstructive pulmonary disease (COPD) compared 
with placebo
Secondary Objectives
• Using pulse oximetry, determine whether lemborexant decreases mean SpO2 during TST on 
Day 1 of treatment compared with placebo
• Using PSG, determine whether lemborexant increases the AHI on Days 1 and 8 of treatment 
compared with placebo
• Using pulse oximetry, determine whether lemborexant increases the percentage of TST during 
which the SpO2 is <90%, <85%, and <80% on Days 1 and 8 of treatment compared with 
placebo
• Using pulse oximetry, determine whether lemborexant increases the mean ODI on Days 1 and 
8 of treatment compared with placebo (revised per Amendment 01)
• Using pulse oximetry, determine whether lemborexant increases the absolute number of 
desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of treatment compared 
with placebo (revised per Amendment 01)
• Evaluate safety and tolerability of lemborexant compared with placebo
OSA and COPD Cohorts:
Exploratory Objectives
Explore the effects of lemborexant compared with placebo on the following for Days 1 and 8 of 
treatment:
• The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, and 
wake
• AHI during REM and NREM sleep
• Determine whether lemborexant increases the AHI, and decreases the mean SpO2 during TST 
separately for adult and elderly subjects
• Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10)
• Explore the effect of lemborexant on blood biomarkers potentially related to dementia, OSA 
and/or COPD
Study Design
In both the OSA and COPD Cohorts, this will be a randomized, double-blind, placebo-controlled, 
2-period crossover study.  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.  In the Randomization Phase subjects will be randomized in treatment sequences A or B 
(OSA Cohort), or treatment sequences C or D (COPD Cohort) consisting of 2 Treatment Periods, 
each of 8 days duration, separated by a washout interval of at least 14 days, and a Follow-up Period 
of approximately 28 days.  Approximately 28 days after the final study dose, there will be an end of 
study (EOS) Visit.
Prerandomization Phase: 
Screening Period
The Screening Period will begin no more than 21 days before the subject is randomized and during 
which 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.  Subjects eligible for the COPD 
Cohort will then undergo screening spirometry between Visit 1 and Visit 2 (designated Visit 1A), 


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which may be performed at the study site, or offsite, so long as a final report is available for review at 
the study site by Visit 2.  Spirometry will be performed based on Global Initiative for Obstructive 
Lung Disease (GOLD) recommendations.  
After at least 6 days of the initial Screening visit, (to allow subjects the opportunity to complete the 
sleep diary for at least 5 nights), subjects will return to the clinic for the second Screening Visit to 
undergo PSG.  For subjects being evaluated for the COPD Cohort, results of screening spirometry 
will also be reviewed.
Subjects who continue to meet the eligibility criteria will remain overnight in the sleep laboratory.  
The mean 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 severity (only mild for the OSA 
Cohort, and moderate to severe for the COPD Cohort), periodic limb movement disorder, 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
At the Baseline Period (1 day) eligible subjects will be admitted to the clinic.  After completion of 
routine safety assessments, including the Columbia-Suicide Severity Rating Scale (C-SSRS), blood 
samples will be collected for the exploratory biomarker analyses, including potentially related to 
dementia, COPD, and OSA-related biomarkers and then subjects will enter the Randomization Phase.  
Randomization Phase 
In the Randomization Phase subjects will be randomized in treatment sequences A or B (OSA 
Cohort), or treatment sequences C or D (COPD Cohort) 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 (adults ≥45 and <65 years, vs 
elderly ≥65 to 90 years).  A sufficient number of subjects will be randomized to ensure that, for each 
Cohort, 20 evaluable adult subjects and 10 evaluable elderly subjects complete the study.  Within 
each age stratum, subjects will be randomized to 1 of the 2 treatment sequences in a 1:1 ratio and 
enter Treatment Period 1.
Treatment Periods 1 and 2
Subjects will remain overnight in the sleep laboratory.  On Day 1, 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.  If SpO2 is <80% for ≥20% of TST during the first night of 
treatment, the subject must be early terminated. Continuing subjects will be provided with study 
medication to be administered for 6 consecutive nights at home and will be instructed to take the 
medication immediately (within 5 minutes) before bedtime and then subjects may leave the clinic 
after the investigator determines that it is safe for them to do so. 
On Day 5 (with a window of ±2 days to accommodate a weekend), the site will telephone the subject 
to assess adverse events (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.
Subjects will return to the clinic after 6 consecutive nights of administering study drug at home, 
subjects will return to the clinic and receive 8th  dose of study drug at the sleep laboratory within 
5 min before the lights off  and will remain overnight in the sleep laboratory.  A predose (trough) PK 


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blood sample will be taken within 1 hour before dosing.  The following morning, blood samples will 
be collected for PK and exploratory biomarker assessments.  Routine safety assessments will also 
conducted.  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, including re-review of inclusion and exclusion criteria, and
oxygen desaturation.  However, spirometry will only be performed during the Screening Period
(revised per Amendment 01).  Upon completion of Treatment Period 2, the subject will be discharged 
from the clinic and enter the Follow-up Period.
At specified visits throughout the Prerandomization Phase and the Randomization Phase, all subjects 
will undergo routine safety assessments, including 12-lead ECG, physical examination, vital signs, 
weight, hematology, blood clinical chemistry analysis, urinalysis, reporting of AEs, and assessment 
of suicidality.  At each clinic visit, subjects will also undergo a urine drug screen.
Follow-up Period
During the Follow-up Period (approximately 28 days), subjects will not receive any 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. 
If subjects discontinue prematurely, they will undergo an Early Termination (ET) Visit and will then 
be followed for 28 days, after which an EOS visit should be scheduled.
Number of Subjects
OSA Cohort: A sufficient number of subjects will be randomized in order to ensure that a total of 
30 evaluable subjects complete the study (20 evaluable adult subjects [≥45 and <65 years] and 
10 evaluable elderly subjects [≥65 to 90 years]).  Discontinued subjects may be replaced to ensure 
20 adults and 10 elderly subjects complete both Treatment Periods. However, subjects who 
discontinue for a serious adverse drug reaction (SADR) cannot be replaced.
COPD Cohort: A sufficient number of subjects will be randomized in order to ensure that a total of 
30 evaluable subjects complete the study (20 evaluable adult subjects (≥45 and <65 years) and 
10 evaluable elderly subjects [≥65 to 90 years]).  Discontinued subjects may be replaced to ensure 
20 adults and 10 elderly subjects complete both Treatment Periods. However, subjects who 
discontinue for a SADR cannot be replaced.
Inclusion Criteria
Inclusion Criteria (OSA and COPD Cohorts)
1.
Male or female, age ≥45 and ≤90 at the time of informed consent
2.
Voluntary agreement and ability to provide written informed consent
3.
Body mass index (BMI) <40 kg/m2
4.
Reports habitually sleeping for at least 5.5 hours per night 
5.
Reports habitual bedtime between 21:00 and midnight
6.
Agrees to stay in bed for 7 hours per night for the duration of the study
7.
At Screening Visit 2:  Has completed the sleep diary for at least 5 consecutive nights
8.
At Screening Visit 2:  Confirmation of MHB between 21:00 and midnight (sleep diary)
Additional Inclusion Criteria (OSA Cohort)
9.
Moderate to severe OSA diagnosed according to the criteria of the International Classification of 
Sleep Disorders (ICSD), confirmed by PSG (home sleep testing by portable monitor is 
acceptable) within the previous 5 years or a repeated PSG during screening
10. On screening PSG:  moderate OSA (defined as 15≤AHI <30) or severe OSA (defined as AHI 
≥30 per hour)


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11. SpO2 ≥94% assessed as part of vital signs at Screening Visit 1
Additional Inclusion Criteria (COPD Cohort)
12. Screening spirometry performed as per the GOLD recommendations
13. On screening spirometry, based on post-bronchodilator Forced Expiratory Volume in 1 second 
(FEV1):
•
FEV1/Forced Vital Capacity (FVC) <0.70 and one of the following:
-
50%≤ FEV1 <80% predicted (GOLD 2 Classification for moderate COPD) or
-
30%≤ FEV1 <50% predicted (GOLD 3 Classification for severe COPD)
11. Moderate to severe COPD according to medical history and screening spirometry as per the 
GOLD criteria (GOLD 2019)
12. On screening PSG
•
AHI<15
•
SpO2 during wakefulness >90% (both supine and sitting)
•
SpO2 during sleep ≥80% for at least 75% of the recording period with no more than 
5 continuous minutes <80% and with no SpO2 readings <70%
Exclusion Criteria (OSA and COPD Cohorts)
1.
Females of childbearing potential
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and 
without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, 
total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
2.
A current diagnosis of restless legs syndrome, periodic limb movement disorder, circadian 
rhythm sleep disorder, or narcolepsy
3.
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
4.
A history of symptoms of REM Behavior Disorder, sleep-related violent behavior, sleep-driving, 
or sleep-eating, or symptoms of another parasomnia that in the investigator’s opinion make the 
subject unsuitable for the study
5.
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
6.
A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at Screening
7.
Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
C-SSRS)
8.
Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS) within 10 years 
of Screening
9.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments
10. Hypersensitivity to the study drug or any of the excipients
11. Used any prohibited prescription or over-the-counter medications within 1 week or 5 half-lives, 
whichever is longer, before the screening PSG


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12. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study
13. Scheduled for surgery during the study that requires general anesthesia or administration of 
prohibited medications
14. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics 
or prior suicide attempt(s) within approximately the last 2 years
15. History of drug or alcohol dependency or abuse within approximately the last 2 years
16. Use of illegal recreational drugs (includes marijuana, regardless of whether prescribed for 
medicinal use)
17. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5× the half-life, whichever is longer preceding informed consent
18. Previously participated in other clinical trial of lemborexant
19. Exposure within the last 14 days to an individual with confirmed or probable corona virus disease
2019 (COVID-19) or symptoms within the last 14 days that are on the most recent Centers for 
Disease Control and Prevention (CDC) list of COVID symptoms or any other reason to consider 
the subject at potential risk for an acute COVID-19 infection (revised per Amendment 01)
Additional Exclusion Criteria (OSA Cohort)
20. SpO2 <80% for ≥5% of TST during the screening PSG
21. Use of a continuous positive airway pressure (CPAP) device or dental appliance within 2 weeks 
of the screening PSG, and does not agree to abstain from the use of a CPAP device or dental 
appliance from the Screening Visit through the last study visit
22. Current evidence of a clinically significant, active respiratory disorder other than OSA.  This 
includes bronchiectasis, emphysema, asthma, COPD, 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.
23. Current evidence of other clinically significant disease (eg, 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.
Additional Exclusion Criteria (COPD Cohort)
24. Use of continuous (>16 h/day) oxygen therapy
25. Use of oxygen therapy during PSG
26. Determination that, in the opinion of the investigator, removal of oxygen therapy could affect the 
subject’s safety or interfere with the study assessments
27. Recent changes to COPD medications or recent acute exacerbation of COPD (ie, needing 
hospitalization or treatment with oral corticosteroids and/or antibiotics) within 3 months of 
enrollment (revised per Amendment 01)
28. On screening spirometry:
•
FEV1/FVC ≥0.70
•
FEV1 ≥80% predicted (GOLD 1 Classification for mild COPD)


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•
FEV1 <30% predicted (GOLD 4 Classification for very severe COPD)
29. On screening PSG:
•
Moderate to severe OSA (AHI ≥15)
•
SpO2 <90% during wakefulness (supine and sitting)
•
SpO2 during sleep <80% for 25% or more of the recording with >5 consecutive minutes 
<80% and any SpO2 reading <70%
30. ECG evidence of right ventricular hypertrophy or right heart failure
31. Screening hematocrit >55%
32. Use of a CPAP device or dental appliance within 2 weeks of the screening PSG, and does not 
agree to abstain from the use of a CPAP device or dental appliance from the Screening Visit 
through the last study visit
33. Current evidence of a clinically significant, active respiratory disorder other than COPD and mild 
OSA.  This includes 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.
34. Current evidence of other clinically significant disease other than COPD and mild OSA (eg,
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.
Study Treatment(s)
The following treatments will be administered to subjects in this study:
•
lemborexant 10-mg film-coated tablets, taken immediately (within 5 minutes) before “lights 
off”
•
lemborexant-matched placebo tablets, taken immediately (within 5 minutes) before “lights 
off”
Duration of Treatment
A maximum of 16 days, comprising 2 Treatment Periods each with a duration of 8 days.
Concomitant Drug/Therapy
Subjects with OSA 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 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 and moderate 
cytochrome P450 (CYP)3A inhibitors and strong and moderate CYP3A inducers.  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 


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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 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 and 
moderate CYP3A inhibitors and strong and moderate CYP3A inducers will not be permitted at any 
time for any duration during the study.
Assessments
Screening Assessments
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.  
Spirometry will be performed for subjects evaluated for the COPD Cohort as per GOLD 
recommendations.  Spirometry assesses the integrated mechanical function of the lung, chest wall, 
and respiratory muscles by measuring the total volume of air exhaled from a full lung to maximal 
expiration.  Spirometry is the most reproducible and reliable measurement of airflow limitation, and 
is required to establish the diagnosis of COPD based on the measurement of FEV1 and FVC. 
Spirometry is also used to classify COPD severity (GOLD 2019).
Efficacy Assessments
Not applicable
Pharmacokinetic Assessments
A single blood sample for plasma concentrations of lemborexant 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.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
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
•
Desaturation: Decrease in the mean SpO2 of ≥3% (over the last 120 seconds) that lasts for at 
least 10 seconds (revised per Amendment 01)


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•
ODI: (oxygen desaturations ≥3%×60)/TST (ie, the average number of oxygen desaturations 
≥3% per hour of sleep), as defined by the American Academy of Sleep Medicine (revised per 
Amendment 01)  
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 2 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.
Biomarker Assessments
Blood Biomarkers
Blood samples will be collected as indicated in the Schedule of Assessment for the exploratory 
analyses of biomarkers potentially related to dementia, COPD, and OSA.
Pharmacogenomic Assessments
Not applicable 
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; regular laboratory evaluation for 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and 
the performance of physical examinations.
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.  
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 method.
Statistical Methods
Study Endpoints
Primary Endpoint (OSA Cohort)
•
AHI on Day 8 of treatment
Secondary Endpoint (OSA Cohort)
•
AHI on Day 1 of treatment
•
Mean SpO2 during TST on Day 1 and Day 8 of treatment
•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and 
Day 8 of treatment
•
Mean ODI on Days 1 and 8 of treatment (revised per Amendment 01)
•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of 
treatment (revised per Amendment 01)
Primary Endpoint (COPD Cohort)
•
Mean SpO2 during TST on Day 8 of treatment


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Secondary Endpoint (COPD Cohort)
•
Mean SpO2 during TST on Day 1 of treatment
•
AHI on Day 1 and Day 8 of treatment
•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and 
Day 8 of treatment
•
Mean ODI on Days 1 and 8 of treatment (revised per Amendment 01)
•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of 
treatment (revised per Amendment 01)
Exploratory Endpoints (OSA and COPD Cohorts)
•
Mean SpO2 during REM sleep, NREM and wake on Day 1 (and Day 8 for OSA Cohort) of 
treatment
•
AHI during REM and NREM sleep on Day 1 and Day 8 of treatment
•
AHI separately for adult and elderly subjects at all days assessed
•
Mean SpO2 during TST separately for adult and elderly subjects at all days assessed
•
Lemborexant and its metabolites plasma concentrations at all days assessed
•
Change from baseline for biomarkers will be evaluated
Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at 
least 1 postdose safety assessment.
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 dose of test drug 
and had at least 1 quantifiable plasma concentration after dosing with lemborexant.
The Pharmacodynamic (PD) Analysis Set is the group of subjects who received at least 1 dose of 
study drug and had sufficient PD data to derive at least 1 primary PD parameter.
Efficacy Analyses
Not applicable
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual lemborexant and its metabolites plasma 
concentration listings.  The PK Analysis Set will be used for summaries of lemborexant plasma 
concentrations.
Pharmacodynamic Analyses
The following analyses will be performed on the PD Analysis Set for each cohort.
Analysis for the Primary Endpoint
OSA Cohort: Mean AHI will be analyzed on the PD analysis set using repeated measures analysis of 
variance (ANOVA), for Day 8 of each treatment period.  The model will include fixed effects for age 
group, sequence, period, and treatment, and a random effect for subject within sequence.  The 
following will be presented: Least square (LS) means, difference in LS mean of lemborexant 10 mg 
compared to placebo, a 2-sided 90% CI (equivalent to a 1-sided upper 95% CI) for the true mean 
difference (lemborexant − placebo) in AHI.  If the upper bound of the 1-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 moderate to severe OSA 
compared with placebo.  Further details will be provided in the statistical analysis plan (revised per 
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Plots of AHI and SpO2 treatment difference data (both individual and LS Mean) will be used to 
explore the results.
COPD Cohort: Mean SpO2 will be analyzed on the PD analysis set using repeated measures 
ANOVA, of values on Day 1 of each treatment for subjects in the PD analysis set.  The model will 
include fixed effects for age group, 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 2-sided 90% CI (equivalent to a 1-sided lower 95% CI) for the true 
mean difference (lemborexant − placebo) in SpO2.  If the lower bound of the 1-sided 95% CI of the 
treatment difference of SpO2 is greater than -2 (for active – placebo), this will provide evidence that 
the given dose of lemborexant does not result in a clinically significant decrease in SpO2 compared to 
placebo.  Further details will be provided in the statistical analysis plan (revised per Amendment 01).
Analysis for the Secondary Endpoints
The secondary endpoints will be analyzed using the same model as the primary endpoint.  
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.
Pharmacogenomic Analyses
Not applicable
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.
Interim Analyses
No interim analysis is planned.
Sample Size Rationale
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 less than 5.
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
COPD Cohort:
A 2% decrease in mean SpO2 during TST is considered a clinically meaningful change.  For the 
primary hypothesis (mean SpO2 during TST on Day 8), assuming a true within subject variance of 
1.07% for mean SpO2, a total of 30 subjects completing the crossover study, and significance level 
alpha 0.05, there is 0.95 probability that the lower bound of the 90% confidence interval (CI) for the 
true mean difference in mean SpO2 (LEM- placebo) on Day 8 would be greater than 2 percent points, 
if the true difference is 1 percent point.  The true difference could be as low as 1.23% and the study 
still would have had 80% power to support the hypothesis.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................3
2
CLINICAL PROTOCOL SYNOPSIS............................................................................4
3
TABLE OF CONTENTS.............................................................................................16
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................21
5
ETHICS.......................................................................................................................23
5.1
Institutional Review Boards/Independent Ethics Committees.............................23
5.2
Ethical Conduct of the Study..............................................................................23
5.3
Subject Information and Informed Consent ........................................................24
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................24
7
INTRODUCTION.......................................................................................................25
7.1
Compound Overview .........................................................................................26
7.2
Clinical Experience............................................................................................26
7.3
Study Rationale..................................................................................................26
8
STUDY OBJECTIVES................................................................................................26
8.1
Primary Objective(s)..........................................................................................26
8.2
Secondary Objective(s) ......................................................................................27
8.3
Exploratory Objective(s)....................................................................................28
9
INVESTIGATIONAL PLAN ......................................................................................28
9.1
Overall Study Design and Plan...........................................................................28
9.1.1
Prerandomization/Pretreatment Phase.......................................................29
9.1.1.1
Screening Period...............................................................................30
9.1.1.2
Baseline Period.................................................................................30
9.1.2
Randomization/Treatment Phase ..............................................................30
9.1.2.1
Follow-Up Period .............................................................................32
9.2
Discussion of Study Design, Including Choice of Control Groups......................32
9.3
Selection of Study Population ............................................................................33
9.3.1
Inclusion Criteria......................................................................................34
9.3.2
Exclusion Criteria.....................................................................................34
9.4
Treatments.........................................................................................................37
9.4.1
Treatments Administered..........................................................................37
9.4.2
Identity of Investigational Product(s)........................................................38
9.4.2.1
Chemical Name of E2006.................................................................38
9.4.2.2
Comparator Drug..............................................................................38
9.4.2.3
Labeling for Study Drug ...................................................................38
9.4.2.4
Storage Conditions ...........................................................................38
9.4.3
Method of Assigning Subjects to Treatment Groups.................................38


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9.4.4
Selection of Doses in the Study ................................................................39
9.4.5
Selection and Timing of Dose for Each Subject........................................39
9.4.6
Blinding ...................................................................................................39
9.4.7
Prior and Concomitant Therapy................................................................39
9.4.8
Prohibitions and Restrictions During Study Period ...................................40
9.4.8.1
Food and Water ................................................................................40
9.4.8.2
Beverage and Other Restrictions.......................................................40
9.4.8.3
Physical Activity Restrictions ...........................................................40
9.4.9
Treatment Compliance .............................................................................41
9.4.10
Drug Supplies and Accountability ............................................................41
9.5
Study Assessments.............................................................................................42
9.5.1
Assessments .............................................................................................42
9.5.1.1
Screening Assessments.....................................................................42
9.5.1.1.1
Demography ...............................................................................42
9.5.1.1.2
Medical History ..........................................................................42
9.5.1.1.3
Sleep Diary.................................................................................43
9.5.1.1.4
Spirometry..................................................................................43
9.5.1.2
Efficacy Assessments .......................................................................43
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................43
9.5.1.3.1
Pharmacokinetic Assessments.....................................................43
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments................................................................................43
9.5.1.4
Safety Assessments...........................................................................44
9.5.1.4.1
Adverse Events...........................................................................44
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................46
9.5.1.4.3
Laboratory Measurements...........................................................47
9.5.1.4.4
Vital Signs and Weight Measurements........................................48
9.5.1.4.5
Physical Examinations ................................................................49
9.5.1.4.6
Electrocardiograms .....................................................................49
9.5.1.4.7
Other Safety Assessments ...........................................................49
9.5.1.5
Other Assessments............................................................................49
9.5.1.5.1
Pregnancy Test ...........................................................................49
9.5.1.5.2
Urine Drug and Cotinine Test .....................................................49
9.5.2
Schedule of Procedures/Assessments........................................................50
9.5.2.1
Schedule of Procedures/Assessments................................................50
9.5.2.2
Description of Procedures/Assessments Schedule .............................54


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9.5.2.3
Total Volume of Blood Sampling .....................................................54
9.5.3
Appropriateness of Measurements............................................................54
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................54
9.5.4.1
Reporting of Serious Adverse Events................................................54
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................55
9.5.4.3
Reporting of Events Association with Special Situations...................56
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................56
9.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........56
9.5.4.3.3
Reporting of Study-Specific Events.............................................57
9.5.4.4
Expedited Reporting .........................................................................57
9.5.4.5
Breaking the Blind............................................................................57
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................57
9.5.5
Completion/Discontinuation of Subjects...................................................58
9.5.6
Abuse or Diversion of Study Drug............................................................58
9.5.7
Confirmation of Medical Care by Another Physician................................58
9.6
Data Quality Assurance......................................................................................58
9.6.1
Data Collection.........................................................................................58
9.6.2
Clinical Data Management .......................................................................59
9.7
Statistical Methods.............................................................................................59
9.7.1
Statistical and Analytical Plans.................................................................59
9.7.1.1
Study Endpoints................................................................................59
9.7.1.1.1
Primary Endpoint (OSA Cohort).................................................59
9.7.1.1.2
Secondary Endpoints (OSA Cohort)............................................59
9.7.1.1.3
Primary Endpoint (COPD Cohort) ..............................................60
9.7.1.1.4
Secondary Endpoints (COPD Cohort).........................................60
9.7.1.1.5
Exploratory Endpoints (OSA and COPD Cohorts) ......................60
9.7.1.1.6
Pharmacokinetic Endpoint (OSA and COPD Cohorts) ................60
9.7.1.1.7
Pharmacokinetic/Pharmacodynamic (Exposure-Response) 
Endpoint (OSA and COPD Cohorts)...........................................60
9.7.1.2
Definitions of Analysis Sets..............................................................60
9.7.1.3
Subject Disposition...........................................................................61
9.7.1.4
Demographic and Other Baseline Characteristics..............................61
9.7.1.5
Prior and Concomitant Therapy ........................................................61
9.7.1.6
Efficacy Analyses.............................................................................61


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9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................62
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................62
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .....................................................................................62
9.7.1.8
Safety Analyses ................................................................................63
9.7.1.8.1
Extent of Exposure......................................................................63
9.7.1.8.2
Adverse Events...........................................................................63
9.7.1.8.3
Laboratory Values.......................................................................64
9.7.1.8.4
Vital Signs ..................................................................................65
9.7.1.8.5
Electrocardiograms .....................................................................65
9.7.1.8.6
Other Safety Analyses.................................................................65
9.7.1.9
Other Analyses .................................................................................65
9.7.2
Determination of Sample Size ..................................................................65
9.7.3
Interim Analysis.......................................................................................66
9.7.4
Other Statistical/Analytical Issues ............................................................66
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................66
10
REFERENCE LIST.....................................................................................................67
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......69
11.1
Changes to the Protocol......................................................................................69
11.2
Adherence to the Protocol..................................................................................69
11.3
Monitoring Procedures.......................................................................................69
11.4
Recording of Data..............................................................................................70
11.5
Identification of Source Data..............................................................................70
11.6
Retention of Records..........................................................................................70
11.7
Auditing Procedures and Inspection ...................................................................71
11.8
Handling of Study Drug .....................................................................................71
11.9
Publication of Results ........................................................................................71
11.10 Disclosure and Confidentiality ...........................................................................72
11.11 Discontinuation of Study....................................................................................72
11.12 Subject Insurance and Indemnity........................................................................72
12
APPENDICES.............................................................................................................73
LIST OF IN-TEXT TABLES
Table 1
Treatments Administered (OSA Cohort).................................................37
Table 2
Treatments Administered (COPD Cohort) ..............................................37
Table 3
Clinical Laboratory Tests........................................................................48


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Table 4
Schedule of Procedures/Assessments in Study E2006-A001-113............51
Table 5
Summary of Blood Sample Volumes (OSA and COPD Cohorts)............54
Table 6
Estimation of Sample Size (OSA and COPD Cohorts)............................66
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for OSA and COPD Cohorts (revised per Amendment 
01)..........................................................................................................29
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................73
Appendix 2
GOLD Recommendations for Performing Spirometry ............................76
Appendix 3
Pharmacodynamic, and Other Biomarker Research.................................77


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AEs
adverse events
AHI
apnea hypopnea index
BMI
body mass index
BP
blood pressure
CA
Competent Authority
CDC
Centers for Disease Control and Prevention
CPAP
continuous positive airway pressure
COPD
Chronic obstructive pulmonary disease
COVID-19
Corona Virus Disease 2019
CRAs
clinical research associates
CRF
case report form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
curriculum vitae
CYP
cytochrome P450
EMG
electromyography
EOG
electrooculography
EOS
end of study
ET
early termination
FEV1
Forced Expiratory Volume in 1 Second
FVC
forced vital capacity
GOLD
Global Initiative for Obstructive Lung Disease
ICF
informed consent form
ICH
International Council for Harmonisation
ICSD
International Classification of Sleep Disorders
IRB
Institutional Review Board
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LEM
lemborexant
LNH
low/normal/high


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Abbreviation
Term
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MHB
mean habitual bedtime
NREM
non- rapid eye movement
ODI
oxygen desaturation index
OSA
obstructive sleep apnea
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetic
PLMAI
Periodic Limb Movement with Arousal Index
PMDA
Pharmaceuticals and Medical Devices Agency
PMR
postmarketing requirement
PSG
polysomnography
PT
preferred term
REM
rapid eye movement
SADR
serious adverse drug reaction
SAE
serious adverse event
SaO2
arterial oxygen saturation
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
SpO2
peripheral capillary oxygen saturation
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TST
total sleep time
WHO DD
World Health Organization Drug Dictionary


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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 (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 associates [CRAs], 
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 IRBs 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 or designee should notify the IRB and Competent 
Authority (CA) 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 CA 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 standard operating procedures (SOP) of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following:
•
Principles of the World Medical Association Declaration of Helsinki 


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•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
•
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 or designee must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s); or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF 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.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor or designee and kept 
on file according to local procedures at the site.  
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 and Contract Research Organization (CRO) are listed in the Investigator Study 
File provided to each site.


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7
INTRODUCTION
Lemborexant (LEM) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide), also known as E2006, is 
an orally-administered, novel competitive dual orexin receptor antagonist (DORA) that has 
been developed for the treatment of insomnia 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 apnea hypopnea index (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.
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).
It has long been known that sleep is disturbed in patients with chronic obstructive pulmonary 
disease (COPD). Insomnia is a comorbid condition in about 17% of patients with COPD. 
There are general concerns about administering sedative-hypnotics to patients with 
compromised respiratory function, since traditional sedative-hypnotics that bind to the 
benzodiazepine receptor at the gamma amino butyric acid (GABA)-A complex (eg, 
tri-azolam, flurazepam) have the potential to cause depression of central respiratory drive and 
decreased muscle tone in the upper airways. Research suggests that there may be differences 
among benzodiazepine receptor agonists with regard to respiratory safety. Consequently, the 
respiratory safety of any new sleep-promoting agent should be carefully evaluated (Sun, 
et al., 2015).
Orexin receptor antagonism represents a new approach to the treatment of insomnia.  Orexin 
receptor antagonists may promote sleep by selectively blocking the brain’s orexin-mediated 
wake system thereby enabling the transition to sleep. Orexin neurons originate in the lateral 
hypothalamus and project throughout the brain, including to respiratory centers in the brain 
stem.  This suggests that orexin may have a role in regulating respiration (Sun, et al., 2015).


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7.1
Compound Overview
Lemborexant (LEM) is a novel competitive dual orexin receptor antagonist that is approved
for the treatment of insomnia by the Food and Drug Administration (FDA) and 
Pharmaceuticals and Medical Devices Agency (PMDA) and under development for irregular 
sleep-wake rhythm disorder.  The clinical development program established the safety, 
tolerability, and efficacy (both short- and long-term) of LEM versus placebo in adult and 
elderly subjects, including demonstration of respiratory safety in healthy volunteers and 
subjects with mild OSA (E2006-A001-102; Study 102).
7.2
Clinical Experience
Study 102 was a randomized, double-blind, placebo-controlled, crossover study to evaluate 
the respiratory safety of LEM in adult and elderly (≥65 to 90 years) healthy subjects and 
adult and elderly subjects with mild OSA.  In healthy adult and elderly subjects and subjects 
with mild OSA, compared with placebo, LEM did not decrease peripheral oxygen saturation 
(SpO2) during total sleep time (TST) after a single dose of treatment, increase the proportion 
of subjects with at least 1 incident of desaturation (defined as SpO2 <90% for at least 
30 seconds during TST compared to placebo, increase the percentage of TST during which 
SpO2 was <90%; or increased the AHI after a single dose of treatment.  Study 102 concluded 
LEM was well tolerated in healthy adult and elderly subjects, as well as subjects with mild 
OSA.  The approved prescribing information for LEM (Dayvigo®) states that: “In a study of 
patients with mild OSA (AHI <15 events per hour of sleep), DAYVIGO did not increase the 
frequency of apneic events or cause oxygen desaturation.”
7.3
Study Rationale
Per the DAYVIGO approval letter (20 Dec 2019) Eisai was tasked with specific 
Postmarketing Requirements (PMR), including a request to conduct a randomized, 
double-blind, placebo-controlled study to evaluate the short-term respiratory safety of LEM 
in subjects with moderate to severe OSA and in subjects with moderate to severe COPD
(PMR 3753-1).  The following study is proposed to fulfill this PMR.
8
STUDY OBJECTIVES
8.1
Primary Objective(s)
OSA Cohort:
•
Using PSG, determine whether lemborexant increases the AHI on Day 8 of treatment 
in adult and elderly subjects (adults ≥45 to <65 years; elderly ≥65 to 90 years) with 
moderate to severe obstructive sleep apnea (OSA) compared with placebo


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COPD Cohort:
•
Using pulse oximetry, determine whether lemborexant decreases mean SpO2 during 
TST on Day 8 of treatment in adult and elderly subjects (adults ≥45 to <65 years; 
elderly ≥65 to 90 years) with moderate to severe COPD compared with placebo
8.2
Secondary Objective(s)
OSA Cohort:
•
Using PSG, determine whether lemborexant increases the AHI on Day 1 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the mean SpO2 
during TST on Days 1 and 8 of treatment compared with placebo
•
Using pulse oximetry, determine whether lemborexant increases the percentage of 
TST during which the SpO2 is <90%, <85%, and <80% on Days 1 and 8 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant increases the mean oxygen 
desaturation index (ODI) on Days 1 and 8 of treatment compared with placebo
(revised per Amendment 01)
•
Using pulse oximetry, determine whether lemborexant increases the absolute number 
of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of treatment 
compared with placebo (revised per Amendment 01)
•
Evaluate safety and tolerability of lemborexant compared with placebo
COPD Cohort:
•
Using pulse oximetry, determine whether lemborexant decreases mean SpO2 during 
TST on Day 1 of treatment compared with placebo
•
Using PSG, determine whether lemborexant increases the AHI on Days 1 and 8 of 
treatment compared with placebo
•
Using pulse oximetry, determine whether lemborexant increases the percentage of 
TST during which the SpO2 is <90%, <85%, and <80% on Days 1 and 8 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant increases the mean ODI on 
Days 1 and 8 of treatment compared with placebo (revised per Amendment 01)
•
Using pulse oximetry, determine whether lemborexant increases the absolute number 
of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of treatment 
compared with placebo (revised per Amendment 01)
•
Evaluate safety and tolerability of lemborexant compared with placebo


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8.3
Exploratory Objective(s)
OSA and COPD Cohorts:
Explore the effects of lemborexant compared with placebo on the following for Days 1 and 8 
of treatment:
•
The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, 
and wake
•
AHI during REM and NREM sleep
•
Determine whether lemborexant increases the AHI, and decreases the mean SpO2 
during TST separately for adult and elderly subjects
• Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10)
• Explore the effect of lemborexant on blood biomarkers potentially related to dementia, 
OSA, and/or COPD
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
In both the OSA and COPD Cohorts, this will be a randomized, double-blind, 
placebo-controlled, 2-period crossover study.  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.  In the Randomization Phase subjects will be 
randomized in treatment sequences A or B (OSA Cohort), or treatment sequences C or D 
(COPD Cohort) consisting of 2 Treatment Periods, each of 8 days duration, separated by a 
washout interval of at least 14 days, and a Follow-up Period of approximately 28 days.  
Twenty-eight days after the final study dose, there will be an end of study (EOS) Visit.
At specified visits throughout the Prerandomization Phase and the Randomization Phase, all 
subjects will undergo routine safety assessments, including 12-lead ECG, physical 
examination, vital signs, weight, hematology, blood clinical chemistry analysis, urinalysis, 
reporting of AEs, and assessment of suicidality.  At each clinic visit, subjects will also 
undergo a urine drug screen.
Approximately 75 subjects each will be screened for OSA and COPD cohorts in order to 
ensure that a total of 30 evaluable subjects complete the study in each cohort (20 evaluable 
adult subjects [≥45 and <65 years] and 10 evaluable elderly subjects [≥65 to 90 years]).  
Discontinued subjects may be replaced to ensure 20 adults and 10 elderly subjects complete 
both Treatment Periods.  However, subjects who discontinue for a serious adverse drug 
reaction (SADR) cannot be replaced.


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Figure 1
Study Design for OSA and COPD Cohorts (revised per 
Amendment 01)
BL1 = Period 1 Baseline, BL2 = Period 2 Baseline, COPD = chronic obstructive pulmonary disease, EOS = End 
of Study, ET = Early Termination, OSA = Obstructive sleep apnea, S = Sleep laboratory, R = Randomization, 
UN = Un-Scheduled visit.
a:
Visit 1A only applies to subjects being evaluated for the COPD Cohort, in whom spirometry is required. 
Spirometry may be performed at the study site, or offsite, so long as a final report is available for review at the 
study site by Visit 2
b:
Telephone visit
c:
Assessments as shown will be conducted at the EOS visit and for subjects who discontinue the study early 
after Visit 3.  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 ET Visit and will then be followed for 28 days, after which, an 
EOS visit should be scheduled.
d:
The assessments at an Unscheduled Visit will be conducted at the Investigator’s discretion.
e:
Visit must be followed by a washout interval of at least 14 days in duration.  This may be extended by up to 
2 days if necessary to accommodate a weekend, in which case, subsequent visits will be up to 2 days later than 
target.
9.1.1
Prerandomization/Pretreatment Phase
The Prerandomization Phase will include a Screening Period and a Baseline Period.


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9.1.1.1
Screening Period
The Screening Period will begin no more than 21 days before the subject is randomized and 
during which 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.  Subjects 
eligible for the COPD Cohort will then undergo screening spirometry between Visit 1 and 
Visit 2 (designated Visit 1A), which may be performed at the study site, or offsite, so long as 
a final report is available for review at the study site by Visit 2.  Spirometry will be 
performed based on Global Initiative for Obstructive Lung Disease (GOLD) 
recommendations (Appendix 2).  
After at least 6 days of the initial Screening visit, (to allow subjects the opportunity to 
complete the sleep diary for at least 5 nights), subjects will return to the clinic for the second 
Screening Visit to undergo PSG.  For subjects being evaluated for the COPD Cohort, results 
of screening spirometry will also be reviewed.
Subjects who continue to meet the eligibility criteria will remain overnight in the sleep 
laboratory.  The mean 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 severity (only mild for the 
OSA Cohort, and moderate to severe for the COPD Cohort), periodic limb movement 
disorder, 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.
9.1.1.2
Baseline Period
At the Baseline Period (1 day) eligible subjects will be admitted to the clinic.  After 
completion of routine safety assessments, including the Columbia-Suicide Severity Rating 
Scale (C-SSRS), blood samples will be collected for the exploratory analyses related to 
potential dementia, COPD, and OSA-related biomarkers.  Subject will then enter the 
Randomization Phase.
9.1.2
Randomization/Treatment Phase
In the Randomization Phase, subjects will be randomized into treatment sequence A or B 
(OSA Cohort), or treatment sequence C or D (COPD Cohort) 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 
(adults ≥45 and <65 years, vs elderly ≥65 to 90 years).  A sufficient number of subjects will 
be randomized to ensure that, for each Cohort, 20 evaluable adult subjects and 10 evaluable 


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elderly subjects complete the study. Within each age stratum, subjects will be randomized to 
1 of the 2 treatment sequences in a 1:1 ratio and enter Treatment Period 1.
Subjects will remain overnight in the sleep laboratory. 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 (Table 4).  
Subjects will be provided with study medication to be administered for 6 consecutive nights 
at home, and will be instructed to take the medication immediately (within 5 minutes) before
bedtime.  Subjects will also be instructed on study restrictions related to prohibited 
medications/drugs, caffeine and alcohol, and the prohibitions regarding the use of continuous 
positive airway pressure (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 study physician in case of any new complaints or 
exacerbation of current symptoms.
On Day 5 (with a window of ±2 days to accommodate a weekend), 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 and receive 8th  dose of study drug at the sleep laboratory within 5 min before the 
lights off 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 and urine drug test), in addition to which, a blood sample for pre-dose (trough) PK 
will be taken within 1 hour before dosing. The following morning, blood samples will be 
collected for PK, and exploratory biomarker assessments. Routine safety assessments will 
also conducted, as indicated in the Schedule of Procedures/Assessments (Table 4).  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.  After the 
washout interval, subjects will return to the clinic for Treatment Period 2, which will follow 
the same schedule and procedures as did in Treatment Period 1, including re-review of 
inclusion and exclusion criteria, and oxygen desaturation.  However, spirometry will only be 
performed during the Screening Period (revised per Amendment 01).
At specified visits throughout the Prerandomization Phase and the Randomization Phase, all 
subjects will undergo routine safety assessments, including 12-lead ECG, physical 
examination, vital signs, weight, hematology, blood clinical chemistry analysis, urinalysis, 


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reporting of AEs, and assessment of suicidality.  At each clinic visit, subjects will also 
undergo a urine drug screen.
9.1.2.1
Follow-Up Period
During the Follow-up Period (approximately 28 days), subjects will not receive any 
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. 
If subjects discontinue prematurely, they will undergo an Early Termination (ET) Visit and 
will then be followed for 28 days, after which, an EOS visit should be scheduled.
9.2
Discussion of Study Design, Including Choice of Control Groups
Dose Selection
The approved dose of LEM 10 mg was chosen based on the safety and efficacy studies from 
the clinical development program.
Justification of the Endpoints
The primary analysis in the OSA Cohort compares the mean AHI (assessed by PSG) on the 
final night of LEM dosing with the AHI on the final night of placebo dosing.  The AHI is the 
index by which OSA is diagnosed, is used to categorize the severity of disease, and is the 
standard primary endpoint in clinical studies of the safety of drugs in patients with OSA; for 
example, this was used for LEM Study 102, suvorexant (Sun, et al., 2016), ramelteon 
(Kryger, et al., 2007), and eszopiclone (Rosenberg, et al., 2007).  Like the study of 
suvorexant, Study 113 will use the mean AHI at the end of each treatment period as the 
primary endpoint, as LEM will have reached steady state.
The primary analysis in the COPD Cohort compares mean SpO2 over total sleep time (TST) 
on the final night of LEM dosing with mean SpO2 during TST on the final night of placebo 
dosing.  Specifically, a 2% decrease in mean SpO2 during TST is considered a clinically 
meaningful change.  SpO2 measures hypoxia, which can serve as a proxy for hypoventilation 
during sleep (Piper and Yee, 2014).  In the ramelteon study of subjects with moderate to 
severe COPD (Kryger, et al., 2009), the mean SpO2 during TST at baseline was 92.6%, thus 
a 2% or greater decrease from 92% could result in hypoxia (SpO2 <90%).  Of note, this was 
also used as the primary endpoint in the suvorexant study (Sun, et al., 2015).
Justification of the sample size for the OSA cohort
In the suvorexant study, 26 subjects with mild to moderate OSA were studied; in Study 102, 
30 subjects with mild OSA were evaluated.  This was acceptable to FDA and PMDA.  Thus, 
the proposed sample size for Study 113 OSA is 30 (Sun, et al., 2016).


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Inclusion and Exclusion Criteria for the OSA and COPD Cohorts
The eligibility criteria in Study 113 are largely standard for safety studies in subjects, with 
particular criteria that are standard for studies of sleep agents (exclusion of significant 
periodic limb movement disorder or parasomnias; certain restrictions on habitual bedtime).  
Insomnia disorder is not specifically excluded unless subjects habitually sleep less than 
5.5 hours.  The screening PSG will be key for inclusion, since subjects tend to sleep less well 
in a sleep laboratory than at home.  This is important since the AHI tends to be higher during 
REM sleep, which is more frequent during the second half of the night, the time when elderly 
poor sleepers tend to be awake.
Of note, CPAP and oral devices will be prohibited throughout the study.  The study requires 
uncorrected values for AHI.  The phenomenon of “CPAP washout” has been reported, in 
which, following cessation of CPAP use, AHI increases gradually over days or weeks 
(Vroegop, et al., 2015).  Although the existence of this phenomenon is not universally 
accepted, there is no doubt that daytime sleepiness increases when CPAP is stopped, and 
those patients with OSA will accommodate to the increased levels of sleepiness, but that 
takes time, and the duration varies among patients.  To avoid dosing with LEM (which may 
cause somnolence during the day in some subjects) against an unstable baseline of daytime 
sleepiness, Study 113 requires that CPAP not be used from 2 weeks before the screening 
PSG until the end of the second treatment period.  This should not interfere with the medical 
care of OSA patients, or be a significant impediment to recruitment; many patients do not 
tolerate CPAP, such that non-compliance rates are high, as stated above.  Further, the 
exclusion criterion specifies that there must not be a requirement that subjects use CPAP 
during the study, thereby excluding any for whom CPAP is a medical necessity.  Whether 
subjects had been prescribed CPAP or other treatments for OSA in the past will be noted at 
Screening.
Inclusion and Exclusion criteria for the COPD Cohort
The COPD cohort will include subjects with moderate to severe COPD and an AHI <15 
based on PSG.  A diagnosis of mild OSA is permissible, as OSA is a common co-morbidity 
in patients with COPD, and high-level evidence for the benefit of mild OSA treatment is 
sparse (Gay, et al., 2006).  Subjects will also be required to have a SpO2 during wakefulness 
greater than 90% (both supine and sitting), and a SpO2 during sleep ≥80% for at least 75% of 
the recording period with no more than five continuous minutes less than 80% and with no 
SpO2 readings less than 70%.  These criteria are similar to the ramelteon study in subjects 
with moderate to severe COPD (Kryger, et al., 2009).  Subjects who use continuous oxygen 
therapy (>16 hours per day) or who, in the opinion of the investigator, the removal of oxygen 
therapy could affect the subject’s safety or interfere with the study assessments, are also 
excluded, which also aligns with prior respiratory safety studies in COPD.
9.3
Selection of Study Population
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.


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9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study (OSA and COPD 
cohorts):
1. Male or female, age ≥45 and ≤90 at the time of informed consent
2. Voluntary agreement and ability to provide written informed consent
3. Body mass index (BMI) <40 kg/m2
4. Reports habitually sleeping for at least 5.5 hours per night 
5. Reports habitual bedtime between 21:00 and midnight
6. Agrees to stay in bed for 7 hours per night for the duration of the study
7. At Screening Visit 2:  Has completed the sleep diary for at least 5 consecutive nights
8. At Screening Visit 2:  Confirmation of MHB between 21:00 and midnight (sleep diary) 
Additional Inclusion Criteria (OSA Cohort)
9. Moderate to severe OSA diagnosed according to the criteria of the ICSD, confirmed by 
PSG (home sleep testing by portable monitor is acceptable) within the previous 5 years or 
a repeated PSG during screening
10. On screening PSG:  moderate OSA (defined as 15≤AHI<30) or severe OSA (defined as 
AHI ≥30 per hour)
11. SpO2 ≥94% assessed as part of vital signs at Screening Visit 1
Additional Inclusion Criteria (COPD Cohort)
12. Screening spirometry performed as per the GOLD recommendations
13. On screening spirometry, based on post-bronchodilator Forced Expiratory Volume in 
1 second (FEV1):
•
FEV1/Forced Vital Capacity (FVC) < 0.70 and one of the following:
-
50%≤ FEV1 <80% predicted (GOLD 2 Classification for moderate COPD) or
-
30%≤ FEV1 <50% predicted (GOLD 3 Classification for severe COPD)
14. Moderate to severe COPD according to medical history and screening spirometry as per 
the GOLD criteria (GOLD 2019)
15. On screening PSG
•
AHI<15
•
SpO2 during wakefulness >90% (both supine and sitting)
•
SpO2 during sleep ≥80% for at least 75% of the recording period with no more than 
five continuous minutes <80% and with no SpO2 readings <70%
9.3.2
Exclusion Criteria
1. Females of childbearing potential
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 


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bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 
1 month before dosing).
2. A current diagnosis of restless legs syndrome, periodic limb movement disorder, 
circadian rhythm sleep disorder, or narcolepsy
3. 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
4. A history of symptoms of REM Behavior Disorder, sleep-related violent behavior, 
sleep-driving, or sleep-eating, or symptoms of another parasomnia that in the 
investigator’s opinion make the subject unsuitable for the study
5. 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
6. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at 
Screening
7. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the C-SSRS)
8. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS) within 
10 years of Screening
9. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments
10. Hypersensitivity to the study drug or any of the excipients
11. Used any prohibited prescription or over-the-counter medications within 1 week or 
5 half-lives, whichever is longer, before the screening PSG
12. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study
13. Scheduled for surgery during the study that requires general anesthesia or administration 
of prohibited medications
14. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years
15. History of drug or alcohol dependency or abuse within approximately the last 2 years
16. Use of illegal recreational drugs (includes marijuana, regardless of whether prescribed for 
medicinal use)
17. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days or 5× the half-life, whichever is longer preceding informed consent
18. Previously participated in other clinical trial of lemborexant
19. Exposure within the last 14 days to an individual with confirmed or probable corona virus 
disease 2019 (COVID-19) or symptoms within the last 14 days that are on the most 


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recent Centers for Disease Control and Prevention (CDC) list of COVID symptoms or 
any other reason to consider the subject at potential risk for an acute COVID-19 infection
(revised per Amendment 01)
Additional Exclusion Criteria (OSA Cohort)
20. SpO2 <80% for ≥5% of TST during the screening PSG
21. Use of a CPAP device or dental appliance within 2 weeks of the screening PSG, and does 
not agree to abstain from the use of a CPAP device or dental appliance from the 
Screening Visit through the last study visit
22. Current evidence of a clinically significant, active respiratory disorder other than OSA.  
This includes bronchiectasis, emphysema, asthma, COPD 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.
23. Current evidence of other clinically significant disease (eg, 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.
Additional Exclusion Criteria (COPD Cohort)
24. Use of continuous (>16 h/day) oxygen therapy
25. Use of oxygen therapy during PSG
26. Determination that, in the opinion of the investigator, removal of oxygen therapy could 
affect the subject’s safety or interfere with the study assessments
27. Recent changes to COPD medications or recent acute exacerbation of COPD (ie, needing 
hospitalization or treatment with oral corticosteroids and/or antibiotics) within 3 months 
of enrollment (revised per Amendment 01)
28. On screening spirometry:
•
FEV1/FVC ≥0.70
•
FEV1 ≥80% predicted (GOLD 1 Classification for mild COPD)
•
FEV1 <30% predicted (GOLD 4 Classification for very severe COPD)
29. On screening PSG:
•
Moderate to severe OSA (AHI ≥15)
•
SpO2 <90% during wakefulness (supine and sitting)
•
SpO2 during sleep <80% for 25% or more of the recording with >5 consecutive 
minutes <80% and any SpO2 reading <70%
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31. Screening hematocrit >55%
32. Use of a CPAP device or dental appliance within 2 weeks of the screening PSG, and does 
not agree to abstain from the use of a CPAP device or dental appliance from the 
Screening Visit through the last study visit
33. Current evidence of a clinically significant, active respiratory disorder other than COPD 
and mild OSA.  This includes 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.
34. Current evidence of other clinically significant disease other than COPD and mild OSA 
(eg, 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.
9.4
Treatments
9.4.1
Treatments Administered
The following treatments will be administered to subjects in this study:
•
lemborexant 10-mg film-coated tablets, taken immediately (within 5 minutes) before
“lights off”
•
lemborexant-matched placebo tablets, taken immediately (within 5 minutes) before
“lights off”
Table 1
Treatments Administered (OSA Cohort)
Treatment Sequence
Treatment Periods in the OSA Cohort
1 (8 nights)
2 (8 nights)
A
lemborexant-matched placebo
lemborexant 10 mg
B
lemborexant 10 mg
lemborexant-matched placebo
Table 2
Treatments Administered (COPD Cohort)
Treatment Sequence
Treatment Periods in the COPD Cohort
1 (8 nights)
2 (8 nights)
C
lemborexant-matched placebo
lemborexant 10 mg
D
lemborexant 10 mg
lemborexant-matched placebo


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9.4.2
Identity of Investigational Product(s)
Lemborexant 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 
sponsor will provide the study drug packaged as double-blinded supplies. Each subject’s 
study drug will consist of lemborexant tablets supplied in bottles.
9.4.2.1
Chemical Name of E2006
•
Test drug code:  E2006
•
Generic name:  Lemborexant
•
Chemical name:  (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)
•
Molecular formula:  C22H20F2N4O2
•
Molecular weight:  410.42
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range. The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
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.


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9.4.4
Selection of Doses in the Study
The approved dose of LEM 10 mg was chosen based on the safety and efficacy studies from 
the clinical development program.
9.4.5
Selection and Timing of Dose for Each Subject
All randomized subjects will receive lemborexant 10 mg or placebo for 8 nights in each 
treatment period per the randomization scheme for OSA and COPD cohorts.  The Treatment 
Periods will be separated by a washout interval of at least 14 days.
Subjects will receive the 1st dose of study treatment at the sleep laboratory within 5 min 
before the lights off and will remain overnight in the sleep laboratory.  Subjects will be 
provided with the study medication to be administered for 6 consecutive nights at home, and 
will be instructed to take the medication immediately (within 5 minutes) before bedtime.  
After 6 consecutive nights of administering the study drug at home, subjects will return to the 
clinic and receive 8th dose of study drug at the sleep laboratory within 5 min before the lights 
off and remain overnight in the sleep laboratory.  
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 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 by the 
sponsor.  In addition, master code breaker reports or envelopes identifying the treatment 
group of each subject number will be provided to the site and to the sponsor in sealed 
envelopes.  These code breaker reports or envelopes are not to be opened unless an 
emergency occurs and knowledge of the subject’s randomization code may affect his/her 
medical treatment.  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 of opening the code breaker report or envelope and the reason for breaking the 
code.  At the conclusion of the study, where possible, all unused drug supplies at the site, 
together with master code breaker reports or envelopes, are to be returned to the clinical 
supply vendor for final reconciliation and disposition.  
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 case 
report form (CRF) or Non-Pharmacological Procedures CRF.  The investigator will record on 
the AE CRF any AE for which the concomitant medication/therapy was administered. 


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Subjects with OSA 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 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 and 
moderate cytochrome P450 (CYP)3A inhibitors and strong and moderate CYP3A inducers.  
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 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 and moderate CYP3A inhibitors and strong and moderate CYP3A inducers 
will not be permitted at any time for any duration during the study.
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


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9.4.9
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  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
•
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 for the institution where the study is to be 
conducted
•
A copy of the IRB-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB 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 FDA Form FDA 1572 or a completed Investigator 
and Site Information Form
•
Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 
1572 or Investigator and Site Information Form
•
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s 
current medical license or medical registration number (if applicable) on the CV
•
A signed and dated Clinical Trial 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 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) 


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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 or designee, 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).  As applicable, all unused study drugs and empty and partially empty containers from 
used study drugs are to be returned to the investigator by the subject and together with 
unused study drugs that were shipped to the site but not dispensed to subjects are to be 
returned to the sponsor’s designated central or local depot(s) during the study or at the 
conclusion of the study, 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
Screening Assessments
9.5.1.1.1
DEMOGRAPHY
Subject demographic information will be collected at the Screening Visit.  Demographic 
information includes date of birth (or age), sex, race/ethnicity.
9.5.1.1.2
MEDICAL HISTORY
Medical, surgical, psychiatric, and sleep history (including history of OSA, and its 
treatments, history of somnambulism, history of periodic limb movement disorder, restless 
leg syndrome, circadian rhythm disorder, and narcolepsy) and current medical conditions 
will be recorded at the Screening Visit.  All medical and surgical history must be noted in the 
Medical History and Current Medical Conditions CRFs.


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9.5.1.1.3
SLEEP DIARY
A paper sleep diary will be completed by the subjects within 1 hour of wake time on at least 
5 consecutive mornings during screening, before Screening Visit 2.  Sleep diaries will be 
reviewed to determine eligibility before or during check-in at Screening Visit 2.  
9.5.1.1.4
SPIROMETRY
Spirometry will be performed for subjects evaluated for the COPD Cohort as per GOLD 
recommendations.  Spirometry assesses the integrated mechanical function of the lung, chest 
wall, and respiratory muscles by measuring the total volume of air exhaled from a full lung to 
maximal expiration.  Spirometry is the most reproducible and reliable measurement of 
airflow limitation, and is required to establish the diagnosis of COPD based on the 
measurement of FEV1 and FVC. Spirometry is also used to classify COPD severity 
(GOLD 2019).
9.5.1.2
Efficacy Assessments
Not applicable
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
Collection and handling of PK, PD, and biomarker samples will be detailed in the central 
laboratory manual to be provided to clinical sites.
Pharmacogenomic assessments are not applicable for this study.
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
A single blood sample (4 mL) for determination of plasma concentrations of lemborexant 
and its metabolites M4, M9 and M10 will be taken at predefined visits (see Table 4).  The 
time and date of the 2 most recent doses administered before each sample will be 
documented.  Plasma concentrations of lemborexant and its metabolite will be quantified in 
active subjects only by liquid chromatography- tandem mass spectrometry (LC-MS/MS) 
methodology using a previously validated assay.
9.5.1.3.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Phamacodynamic 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.


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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
•
Desaturation:  Decrease in the mean SpO2 of ≥3% (over the last 120 seconds) that 
lasts for at least 10 seconds (revised per Amendment 01)
•
ODI: (oxygen desaturations ≥3%×60)/TST (ie, the average number of oxygen 
desaturations ≥3% per hour of sleep), as defined by the American Academy of Sleep 
Medicine (revised per Amendment 01)
Transmissive pulse oximetry is a noninvasive method for monitoring 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 2 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.
Blood Biomarkers
Blood samples will be collected as indicated in the Schedule of Assessment (Table 4) for the 
exploratory analyses of biomarkers potentially related to dementia, COPD, and OSA.
Pharmacogenomic Assessments
Not applicable
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; regular monitoring of 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and 
ECGs; suicidality, weight, and performance of physical examinations as detailed in Table 4.
9.5.1.4.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 


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have a causal relationship with the medicinal product.  For this study, the study drug is
lemborexant. 
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study drug, or 
withholding of study drug, whether prescribed in the protocol or not
All AEs 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.  Subject 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 
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 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 9.5.1.4.7 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 serious adverse events (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.


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Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.4.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A SAE is any untoward medical occurrence that at any dose:
• Results in death


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• Is life-threatening (ie, the subject was at immediate risk of death from the adverse 
event as it occurred; this does not include an event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death)
• Requires inpatient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity
• Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care 
•
Planned hospitalizations required by the protocol
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 4) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.


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Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Calcium, chloride, potassium, sodium 
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
Albumin, cholesterol, globulin, glucose, lactate dehydrogenase, 
phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the study will be performed by central laboratory.  All blood 
and urine samples will be collected and sent to the central laboratory on the day of collection 
unless otherwise instructed.  In cases of a safety concern, blood samples will be split (or
2 samples drawn) to allow a local laboratory analysis in addition to the central laboratory. 
Central laboratories 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 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF
(see Section 9.5.4.3.2).
9.5.1.4.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained as designated in the Schedule of Procedures/Assessments (Table 4) 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 before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.


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9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examination will be performed as designated in the Schedule of 
procedures/Assessments (Table 4).  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.
9.5.1.4.6
ELECTROCARDIOGRAMS
Twelve-lead electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 4). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.4.7
OTHER SAFETY ASSESSMENTS
Columbia-Suicide Severity Rating Scale
The C-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  An assessment of suicidality using the C-SSRS will be performed at 
Screening, Baseline, at the Follow-up Visit, and as designated in the Schedule of 
Procedures/Assessments (Table 4).
9.5.1.5
Other Assessments
9.5.1.5.1
PREGNANCY TEST
A serum β-hCG test will be performed for premenopausal women and postmenopausal 
women who have been amenorrheic for less than 12 consecutive months at Screening Visit 1.  
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 4).
9.5.1.5.2
URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 4).  This sample will be tested for common 


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drugs of use/abuse: eg, ethyl alcohol, cocaine, cannabinoids, PCP, nicotine/cotinine, opioids 
(as a group), benzodiazepines, barbiturates, and amphetamines.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for the study


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Table 4
Schedule of Procedures/Assessments in Study E2006-A001-113
Phase
Prerandomization
Randomization
UNd
Period
Screening
BL1
Treatment 1
BL2
Treatment 2
Follow-Up
Visit
1
1Aa
2A
2B
3A
3B
4b
5A
5B
6A
6B
7
b
8A
8B
9 EOS/ETc
Study Day
21 
to 


15 
to
2
14 
to
1
1
2
5
8
9
e
23
24
27
30
31
59
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
Medical, surgical, psychiatric, and 
sleep
Historyf
X
Physical examination
X
X
X
X
Sleep diaryg
-------------
Urine drug testh
X
X
X
X
X
X
X
Height
X
Weight
X
X
Clinical laboratory testsi
X
X
X
X
PK blood samplingj
X
X
X
X
X
X
Biomarker blood samplingk
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
Spirometryn
X


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Randomization
X
Administer study drug in clinico
X
X
X
X
Dispense study drug
X
X
Study drug taken at home
---------
---------
PSG (with Pulse Oximetry)
p
X
Xq
X
Xr
X
C-SSRS
X
X
X
Adverse events
--------------------------------------------------------------------------------------------------------------------------------------------
Prior and concomitant medications
--------------------------------------------------------------------------------------------------------------------------------------------
Admit to clinic
X
X
X
X
X
Discharge from clinic
X
X
X
X
X
Discharge from study
X
Study drug return
X
X
BL1 = Period 1 Baseline, BL2 = Period 2 Baseline, COPD = chronic obstructive pulmonary disease, 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:
Visit 1A only applies to subjects being evaluated for the COPD Cohort, in whom spirometry is required. Spirometry may be performed at the study site, or offsite, 
so long as a final report is available for review at the study site by Visit 2.
b:
Telephone visits.
c:
Assessments as shown will be conducted at the EOS visit and for subjects who discontinue the study early after Visit 3. 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 ET Visit and will 
then be followed for 28 days, after which, an EOS visit should be scheduled.
d:
The assessments at an Unscheduled Visit will be conducted at the Investigator’s discretion.
e:
Visit must be followed by a washout interval of at least 14 days in duration. This may be extended by up to 2 days if necessary to accommodate a weekend, in 
which case, subsequent visits will be up to 2 days later than target.
f:
Sleep history will include: history of OSA, including treatments, history of somnambulism, history of 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 mean 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.


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h:
Urine drug screen will be conducted using adipstick.
i:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
j:
One blood sample (approximately 4 mL) for determination of plasma concentrations of lemborexant will be obtained at the following time points: within 1 hour 
predose in the clinic (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 
will berecorded.
k:
Blood samples (approximately 6 mL per timepoint) will be collected for determination of biomarkers
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, Visit 3A, and Visit 6A. (revised per Amendment 01)
n:
Only for subjects being evaluated for the COPD cohort.
o:
At Visit 3A, administered after all baseline assessments have been completed.
p:
Screening PSG will include channels for assessment of symptoms of periodic limb movement disorder (PLMD).
q:
PSG will occur after randomization and study drug administration during period BL1. (revised per Amendment 01)
r:
PSG will occur after study drug administration during period BL2. (revised per Amendment 01)


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9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 4.
9.5.2.3
Total Volume of Blood Sampling
Table 5 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study for the OSA and COPD cohorts. 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 5
Summary of Blood Sample Volumes (OSA and COPD Cohorts)
Sample Volume
per Collection 
(mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Baseline 1:  1
Follow-up: 1
123=36
PK blood sampling
4
Treatment Period 1:  3
Treatment Period 2:  3
46=24
Biomarker blood sampling
6
Baseline 1: 1
Baseline 2:  1
Treatment Period 1: 1
Treatment Period 2:  1
64=24
Total
84
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of respiratory 
safety and in particular, OSA and COPD.
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 SAEs, 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.


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SAEs, regardless of causality assessment, must be collected for 28 days after the subject’s 
last dose.  All SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any SAE judged by the investigator to be related to the study treatment or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator 
Study File.
For urgent safety issues call:  
(24/7 number). .
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours
of its receipt.  If the relevant follow-up information changes the investigator’s assessment of 
causality, this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
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.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus are considered to be an SAE 
and should be reported in the same time frame and in the same format as all other SAEs (see
Section 9.5.4.1).
PPD


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Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours 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 24 hours 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.  
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 and Intentional Overdose, even if 
asymptomatic, are always to be captured as an AE.  If the AE associated with an overdose, 
misuse, abuse, or medication error does not meet serious criteria, it must still be reported 
using the SAE form and in an expedited manner but should be noted as nonserious on the 
SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the Adverse Event CRF and reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1).  If the event does not meet 
serious criteria, the seriousness criteria on the SAE form should be indicated as “nonserious.”  


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•
Elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal 
AND
•
Elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal 
AND AT THE SAME TIME
•
Alkaline phosphatase lab value that is less than 2X the upper limit of normal
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
9.5.4.3.3
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
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.


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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 4).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, 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.
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 9.5.1.4.1.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  
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 


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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 or Investigator and Site Information Form or Site Delegation Log must sign the 
completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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
9.7.1.1.1
PRIMARY ENDPOINT (OSA COHORT)
•
AHI on Day 8 of treatment
9.7.1.1.2
SECONDARY ENDPOINTS (OSA COHORT)
•
AHI on Day 1 of treatment
•
Mean SpO2 during TST on Day 1 and Day 8 of treatment
•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 
and Day 8 of treatment
•
Mean ODI on Days 1 and 8 of treatment (revised per Amendment 01)


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•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 
and 8 of treatment (revised per Amendment 01)
9.7.1.1.3
PRIMARY ENDPOINT (COPD COHORT)
•
Mean SpO2 during TST on Day 8 of treatment
9.7.1.1.4
SECONDARY ENDPOINTS (COPD COHORT)
•
Mean SpO2 during TST on Day 1 of treatment
•
AHI on Day 1 and Day 8 of treatment
•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 
and Day 8 of treatment
•
Mean ODI on Days 1 and 8 of treatment (revised per Amendment 01)
•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 
and 8 of treatment (revised per Amendment 01)
9.7.1.1.5
EXPLORATORY ENDPOINTS (OSA AND COPD COHORTS)
•
Mean SpO2 during REM sleep, NREM and wake on Day 1 (and Day 8 for OSA 
Cohort) of treatment
•
AHI during REM and NREM sleep on Day 1 and Day 8 of treatment
•
AHI separately for adult and elderly subjects at all days assessed
•
Mean SpO2 during TST separately for adult and elderly subjects at all days assessed
9.7.1.1.6
PHARMACOKINETIC ENDPOINT (OSA AND COPD COHORTS)
•
Lemborexant plasma concentrations at all days assessed
9.7.1.1.7
PHARMACOKINETIC/PHARMACODYNAMIC (EXPOSURE-RESPONSE) ENDPOINT (OSA
AND COPD COHORTS)
•
Change from baseline for biomarkers will be evaluated
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 dose of 
test drug and had at least 1 quantifiable plasma concentration after dosing with lemborexant.
The Pharmacodynamic Analysis Set is the group of subjects who received at least 1 dose of 
study drug and had sufficient PD data to derive at least 1 primary PD 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 OSA and COPD cohorts 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 and treatment discontinuation.  Other reasons for study treatment and study 
terminations will also be summarized.  These tabulations will be produced for all randomized 
subjects by randomized treatment groups.
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 for all study drug groups combined using descriptive 
statistics.  Continuous demographic and baseline variables include age, height, BMI, and 
weight variables; categorical variables include sex, age group (adults ≥45 to <65 years; 
elderly ≥ 65 to 90 years), 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) (March 2019 or later).  
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 (PT).  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
OSA Cohort: Mean AHI will be analyzed on the PD analysis set using repeated measures 
ANOVA, for Day 8 of each treatment period.  The model will include fixed effects for age 
group, sequence, period, and treatment, and a random effect for subject within sequence.  
The following will be presented: least square (LS) means, difference in LS mean of 
lemborexant 10 mg compared to placebo, a 2-sided 90% CI (equivalent to a 1-sided upper 
95% CI) for the true mean difference (lemborexant − placebo) in AHI.  If the upper bound of 
the 1-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 moderate to severe OSA compared with placebo.  Further details will be 
provided in the statistical analysis plan (revised per Amendment 01).
Plots of AHI and SpO2 treatment difference data (both individual and LS Mean) will be used 
to explore the results.
COPD Cohort: Mean SpO2 will be analyzed on the PD analysis set using repeated 
measures ANOVA, of values on Day 1 of each treatment for subjects in the PD analysis set.  
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 2-sided 90% CI (equivalent to a 1-sided 
lower 95% CI) for the true mean difference (lemborexant − placebo) in SpO2.  If the lower 
bound of the 1-sided 95% CI of the treatment difference of SpO2 is greater than -2 (for 
active – placebo), this will provide evidence that the given dose of lemborexant does not 
result in a clinically significant decrease in SpO2 compared to placebo.  Further details will 
be provided in the statistical analysis plan (revised per Amendment 01).
Analysis for the Secondary Endpoints
The secondary endpoints will be analyzed using the same model as the primary endpoint.  
Analysis for the Exploratory Endpoints


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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 secondary endpoints.
Pharmacogenomic Analyses:
Not applicable
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, 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 treatment-emergent adverse events (TEAEs), 
clinical laboratory parameters, vital signs, 12-lead ECG results, and the C-SSRS.  Study 
Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
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 by treatment 
for OSA and COPD cohorts using descriptive statistics.
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 Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 22.1) lower level term 
(LLT) closest to the verbatim term.  The linked MedDRA 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 
• 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 


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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 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 (adults ≥45 and 
<65 years; elderly ≥65 to 90 years), sex (male, female), and race (white, black, other) if there 
are sufficient numbers in the category.
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 group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.


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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, body temperature, and weight) and changes from baseline will be presented 
by day and time after dosing and treatment for both OSA and COPD cohorts.
9.7.1.8.5
ELECTROCARDIOGRAMS
ECG assessments will be performed at visits specified in the Schedule of Assessments table 
(Table 4).  
9.7.1.8.6
OTHER SAFETY ANALYSES
Not applicable
9.7.1.9
Other Analyses
Not applicable
9.7.2
Determination of Sample Size
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 less than 5.


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Table 6
Estimation of Sample Size (OSA and COPD Cohorts)
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
AHI = apnea hypopnea index
COPD Cohort:
A 2% decrease in mean SpO2 during TST is considered a clinically meaningful change.  For 
the primary hypothesis (mean SpO2 during TST on Day 8), assuming a true within subject 
variance of 1.07% for mean SpO2, a total of 30 subjects completing the crossover study, and 
significance level alpha 0.05, there is 0.95 probability that the lower bound of the 90% 
confidence interval for the true mean difference in mean SpO2 (LEM- placebo) on Day 8 
would be greater than 2 percent points, if the true difference is 1 percent point.  The true 
difference could be as low as 1.23% and the study still would have had 80% power to support 
the hypothesis.
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.
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.
Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for sleep 
related breathing disorders in adults. Sleep. 2006;29(3):381–401
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management and prevention of COPD. Global Initiative for Chronic Obstructive 
Lung Disease website. https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-
FINAL-ver1.2-03Dec19_WMV.pdf. [updated December 2019. accessed 17 Dec 2019].
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(3):159–64.
Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during 
sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep 
Breath. 2009;13(1):79-84.
Lee YJ, Kim JW, Lee Y-U G, Jeong DU. Sleep EEG Characteristics in Young and Elderly 
Patients with Obstructive Sleep Apnea Syndrome. Psychiatry 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.
Piper AJ, Yee BJ. Hypoventilation syndromes. Compr Physiol. 2014; 4(4):1639-76
Rosenberg R, Roach JM, Scharf M, Amato DA. A pilot study evaluating acute use of 
eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. Sleep Med. 
2007;8(5):464–70.


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Sun H, Palcza J, Rosenberg R, Kryger M, Siringhaus T, Rowe J, et al. Effects of suvorexant, 
an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive 
pulmonary disease. Respir med. 2015;109(3), 416-26.
Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, et al. Effects of suvorexant, an 
orexin receptor antagonist, on respiration during sleep in patients with obstructive sleep 
apnea. J Clin Sleep Med. 2016;12(1):9–17.
Vroegop AV, Smithuis JW, Benoist LBL, Vanderveken OM, de Vries N. CPAP washout prior 
to reevaluation polysomnography: a sleep surgeon’s perspective. Sleep Breath. 2015 
19(2):433–9.
C-SSRS Reference
http://www.cssrs.columbia.edu/scales_cssrs.html
GOLD 2019
https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-
03Dec19_WMV.pdf


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs.  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 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 sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator 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 review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts


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•
Copies or transcribed health care provider notes which have been certified for 
accuracy after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, ECGs, rhythm strips, EEGs, polysomnograms, pulmonary function tests) 
regardless of how these images are stored, including microfiche and photographic 
negatives
•
Medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs
•
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.  
The data collected by electronic Patient-Reported Outcome are also considered as source 
data.  
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 


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protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites).  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 15 years following the completion of the study.
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 CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.


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The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
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 and will 
not be disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of the sponsor.  No data collected as part of 
this study will be used in any written work, including publications, without the written 
consent of the sponsor.  These obligations of confidentiality and non-use shall in no way 
diminish such obligations as set forth in either the Confidentiality Agreement or Clinical 
Trial Agreement executed between the sponsor/CRO and the institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB 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
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 – 2.5ULN if 
baseline was normal; 
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
ALT
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
AST
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN if 
baseline was normal; 
1.0 – 1.5baseline if 
baseline was abnormal
>1.5 – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 10.0ULN if 
baseline was normal; 3.0 
– 10.0baseline if 
baseline was abnormal
>10.0ULN if 
baseline was normal; 
>10.0baseline if 
baseline was 
abnormal
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
Ionized calcium <LLN 
- 1.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
Ionized calcium <1.0 -
0.9 mmol/L; 
symptomatic
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
Ionized calcium <0.9 -
0.8 mmol/L; 
hospitalization indicated
<6.0 mg/dL
<1.5 mmol/L
Ionized calcium <0.8 
mmol/L; life-
threatening 
consequences


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium >ULN 
- 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium >1.5 -
1.6 mmol/L; 
symptomatic
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium >1.6 -
1.8 mmol/L; 
hospitalization indicated
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 - 3.0baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes
Insulin therapy initiated; 
hospitalization indicated
life-threatening 
consequences; urgent 
intervention indicated
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated
Oral replacement 
therapy indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L; 
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L and 
asymptomatic
<125 – 129  mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms
<120 mmol/L
life-threatening 
consequences


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN without 
physiologic 
consequences 
N/A
>ULN with physiologic 
consequences 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: January 5, 2018.


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Appendix 2
GOLD Recommendations for Performing Spirometry
Preparation
• Spirometers need calibration on a regular basis
• Spirometers should produce hard copy or have a digital display of the expiratory curve 
to permit detection of technical errors or have an automatic prompt to identify an 
unsatisfactory test and the reason for it
• The supervisor of the test needs training in optimal technique and quality performance
• Maximal patient effort in performing the test is required to avoid underestimation of 
values and hence errors in diagnosis and management 
Bronchodilation
• Possible dosage protocols are 400 mcg short acting beta agonist, 160 mcg short acting 
anticholinergic, or the two combined.  Forced Expiratory Volume in 1 Second (FEV1) 
should be measured 10 to 15 minutes after short acting β2 agonist is given, or 30 to 
45 minutes after a short acting anticholinergic or a combination of both classes of 
drugs
Performance
• Spirometry should be performed using techniques that meet published standard
• The expiratory volume/time traces should be smooth and free from irregularities.  The 
pause between inspiration and expiration should be <1 second
• The recording should go on long enough for a volume of plateau to be reached, which 
may take more than 15 seconds in severe disease
• Both forced vital capacity (FVC) and FEV1 should be the largest value obtained from 
any of 3 technically satisfactory curve and the FVC and FEV1 values in these 3 curves 
should vary by no more than 5% or 150 mL, whichever is greater
• The FEV1 and FVC ratio should be taken from technically acceptable curve with the 
largest sum of FVC and FEV1
Evaluation
•
Spirometry measurements are evaluated by comparison of the results with appropriate 
reference values based on age, height, sex, and race
•
The presence of postbronchodilator FEV1/FVC<0.70 confirms the presence of airflow 
limitation


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Appendix 3
Pharmacodynamic, and Other Biomarker Research
Objective
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), and other biomarker analysis.  These samples may be used for 
discovery and validation to identify biomarkers that may be used for exploratory evaluation 
of response and/or safety-related outcomes as well as for use in diagnostic development
Collection of the PD, and other biomarker samples will be bound by the sample principles 
and processes outlined in the instructions manual / laboratory manual and the informed 
consent for the study.  Sample collection for PD, and other biomarker analysis is required as 
per the study protocol unless the collection and use of the samples is prohibited by specific 
country laws.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-A001-113
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
2-Period, Crossover Study to Evaluate the Respiratory Safety of 
Lemborexant in Adult and Elderly Subjects With Moderate to 
Severe Obstructive Sleep Apnea and Adult and Elderly Subjects 
With Moderate to Severe Chronic Obstructive Pulmonary 
Disease
Investigational Product 
Name:
E2006/lemborexant
IND Number:
111871
SIGNATURES
Authors:
 
 
 
Eisai, Inc
Date
Eisai Inc.
Date
 
Eisai Inc.
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-113
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
2-Period, Crossover Study to Evaluate the Respiratory Safety of 
Lemborexant in Adult and Elderly Subjects With Moderate to 
Severe Obstructive Sleep Apnea and Adult and Elderly Subjects 
With Moderate to Severe Chronic Obstructive Pulmonary 
Disease
Investigational Product 
Name:
E2006/lemborexant
IND Number:
111871
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 Registration of 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

SAP_001.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2006-A001-113
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
2-Period, Crossover Study to Evaluate the Respiratory Safety of 
Lemborexant in Adult and Elderly Subjects With Moderate to 
Severe Obstructive Sleep Apnea and Adult and Elderly Subjects 
With Moderate to Severe Chronic Obstructive Pulmonary Disease
Date:
19 Aug 2020
Version:
Version 1.0


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................4
3
INTRODUCTION.........................................................................................................6
3.1
Study Objectives..................................................................................................6
3.1.1
Primary Objectives.....................................................................................6
3.1.2
Secondary Objectives .................................................................................6
3.1.3
Exploratory Objectives...............................................................................7
3.2
Overall Study Design and Plan.............................................................................8
4
DETERMINATION OF SAMPLE SIZE.......................................................................8
5
STATISTICAL METHODS..........................................................................................9
5.1
Study Endpoints...................................................................................................9
5.1.1
Efficacy Endpoints .....................................................................................9
5.1.2
Safety Endpoints ........................................................................................9
5.1.3
Pharmacokinetic (PK) Endpoints................................................................9
5.1.4
Pharmacodynamic (PD) Endpoints.............................................................9
5.2
Study Subjects ...................................................................................................10
5.2.1
Definitions of Analysis Sets......................................................................10
5.2.2
Subject Disposition...................................................................................11
5.2.3
Protocol Deviations ..................................................................................11
5.2.4
Demographic and Other Baseline Characteristics......................................11
5.2.5
Prior and Concomitant Therapy................................................................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
5.4
Efficacy Analyses ..............................................................................................13
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................13
5.5.1
Pharmacodynamic Analyses.....................................................................13
5.5.2
Pharmacokinetic/Pharmacodynamic Analyses ..........................................14
5.5.3
Pharmacogenomic/Pharmacogenetic and Other Biomarker Analyses........14
5.6
Safety Analyses..................................................................................................14
5.6.1
Extent of Exposure...................................................................................15


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5.6.2
Adverse Events.........................................................................................15
5.6.3
Laboratory Values ....................................................................................15
5.6.4
Vital Signs................................................................................................16
5.6.5
Electrocardiograms...................................................................................17
5.6.6
Other Safety Analyses ..............................................................................17
5.7
Other Analyses...................................................................................................17
5.8
Exploratory Analyses.........................................................................................17
6
INTERIM ANALYSES...............................................................................................18
7
CHANGES IN THE PLANNED ANALYSES ............................................................18
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................18
8.1
Pharmacokinetic Data Handling .........................................................................18
8.1.1
Lower Limit of Quantification of E2006 Plasma Concentration................18
8.1.2
BLQ Handling for Calculation of PK Parameters......................................18
8.1.3
BLQ Handling for Developing Concentration-Time Profiles ....................18
8.1.4
Handling of Anomalous Concentration Values .........................................18
8.1.5
General Rules for Presentation of Drug Concentrations ............................18
8.1.6
General Rules for Presentation of PD Parameters .....................................18
9
PROGRAMMING SPECIFICATIONS .......................................................................19
10
STATISTICAL SOFTWARE......................................................................................19
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................19
12
REFERENCES............................................................................................................19
13
APPENDICES.............................................................................................................22
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results.....22
13.2
SAS Code for ANOVA......................................................................................25


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AHI
apnea hypopnea index 
ANOVA
analysis of variance
ATC
anatomical therapeutic class
BLQ
below the limit of quantification
BMI
body mass index
CI
confidence interval
COPD
chronic obstructive pulmonary disease
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
ECG
electrocardiogram
EOS
end of study
E-R
exposure response
GOLD
Global Initiative for Chronic Obstructive Lung Disease
MedDRA
Medical Dictionary for Regulatory Activities
NREM
non rapid eye movement
ODI
oxygen desaturation index
OSA
obstructive sleep apnea
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PSG
polysomnography
REM
rapid eye movement
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
Système International
SOC
system organ class


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Abbreviation
Term
SpO2
mean oxygen saturation
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
TST
total sleep time
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-
A001-113.
3.1
Study Objectives
3.1.1
Primary Objectives
OSA Cohort:
•
Using polysomnography (PSG), determine whether lemborexant increases the apnea 
hypopnea index (AHI) on Day 8 of treatment in adult and elderly subjects (adults ≥45 to 
<65 years; elderly ≥ 65 to 90 years) with moderate to severe obstructive sleep apnea 
(OSA) compared with placebo
COPD Cohort:
•
Using pulse oximetry, determine whether lemborexant decreases mean oxygen saturation 
(SpO2) during TST on Day 8 of treatment in adult and elderly subjects with moderate to 
severe chronic obstructive pulmonary disease (COPD) compared with placebo
3.1.2
Secondary Objectives
OSA Cohort:
•
Using PSG, determine whether lemborexant increases the AHI on Day 1 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the mean oxygen 
saturation (SpO2) during total sleep time (TST) on Days 1 and 8 of treatment compared 
with placebo
•
Using pulse oximetry, determine whether lemborexant increases the percentage of TST 
during which the SpO2 is <90%, <85%, and <80% on Days 1 and 8 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the mean oxygen desaturation 
index (ODI) during TST on Days 1 and 8 of treatment compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the absolute number of
desaturations (≥3% reduction from Baseline SpO2) during TST on Days 1 and 8 of treatment 
compared with placebo
•
Evaluate safety and tolerability of lemborexant compared with placebo
COPD Cohort:


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•
Using pulse oximetry, determine whether lemborexant decreases mean SpO2 during TST 
on Day 1 of treatment compared with placebo
•
Using PSG, determine whether lemborexant increases the AHI on Days 1 and 8 of 
treatment compared with placebo
•
Using pulse oximetry, determine whether lemborexant increases the percentage of TST 
during which the SpO2 is <90%, <85%, and <80% on Days 1 and 8 of treatment 
compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the mean oxygen desaturation 
index (ODI) on Days 1 and 8 of treatment compared with placebo
•
Using pulse oximetry, determine whether lemborexant decreases the absolute number of 
desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 of treatment compared with 
placebo 
•
Evaluate safety and tolerability of lemborexant compared with placebo
3.1.3
Exploratory Objectives
OSA and COPD Cohorts:
Explore the effects of lemborexant compared with placebo on the following for Days 1 and 8 
of treatment:
•
The mean SpO2 during rapid eye movement (REM) sleep, non-REM (NREM) sleep, and 
wake
•
The mean ODI during REM sleep and NREM sleep
•
The absolute number of desaturations during REM sleep and NREM sleep
•
AHI during REM and NREM sleep
•
Determine whether lemborexant increases the AHI, and decreases the mean SpO2 during 
TST separately for adult and elderly subjects
•
Determine whether lemborexant increases the mean ODI, and increases the absolute 
number of desaturations, during TST separately for adult and elderly subjects
In addition, explore the following pharmacokinetic (PK) endpoints for both OSA and COPD 
Cohorts:
•
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10)
•
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, percentage of TST in which SpO2 is <90%, <85%, and 
<80%, means ODI, and absolute number of desaturations).


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3.2
Overall Study Design and Plan
In the OSA and COPD Cohorts, this will be a randomized, double-blind, placebo-controlled, 
2-period crossover study.  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 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. Twenty-eight days after the final study dose, there will be an end of study (EOS) 
Visit.  
4
DETERMINATION OF SAMPLE SIZE
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 (Kruger, 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 less than 5.
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


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COPD Cohort:
A 2% decrease in mean SpO2 during TST is considered a clinically meaningful change.  For 
the primary hypothesis (mean SpO2 during TST on Day 8), assuming a true within subject 
variance of 1.07% for mean SpO2, a significance level of 0.05, and a true difference of -1 
percent point, a total of 30 subjects completing the crossover study provides 99% power that 
the lower bound of the 90% confidence interval for the mean difference in mean SpO2 
(LEM- placebo) on Day 8 would be greater than -2 percent points.  The true difference could 
be as low as -1.23% and the study still would have had 80% power to support the hypothesis.
5
STATISTICAL METHODS
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.  All analyses will be performed separately for OSA and 
COPD cohorts.
5.1
Study Endpoints
5.1.1
Efficacy Endpoints
Not applicable.
5.1.2
Safety Endpoints
OSA AND COPD COHORTS
Safety assessments will be based on medical review of adverse event reports and the results 
of vital sign measurements, electrocardiograms, and clinical laboratory tests separately for 
each cohort.
5.1.3
Pharmacokinetic (PK) Endpoints 
OSA AND COPD COHORTS
Lemborexant plasma concentrations at all days assessed for separately both cohorts
5.1.4
Pharmacodynamic (PD) Endpoints 
PRIMARY ENDPOINT (OSA COHORT)
•
AHI on Day 8 of treatment
SECONDARY ENDPOINTS (OSA COHORT)
•
AHI on Day 1 of treatment
•
Mean SpO2 during TST on Day 1 and Day 8 of treatment


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•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and 
Day 8 in of treatment
•
Mean oxygen desaturation index (ODI) on Days 1 and 8 of treatment
•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 
of treatment
PRIMARY ENDPOINT (COPD COHORT)
•
Mean SpO2 during TST on Day 8 of treatment
SECONDARY ENDPOINTS (COPD COHORT)
•
Mean SpO2 during TST on Day 1 of treatment
•
AHI on Day 1 and Day 8 of treatment
•
The percentage of TST during which the SpO2 is <90%, <85% and <80% on Day 1 and 
Day 8 of treatment
•
Mean oxygen desaturation index (ODI) on Days 1 and 8 of treatment
•
Absolute number of desaturations (≥3% reduction from Baseline SpO2) on Days 1 and 8 
of treatment
EXPLORATORY ENDPOINTS (OSA AND COPD COHORTS)
•
Mean SpO2 during REM sleep, NREM and wake on Day 1 (and Day 8 for OSA Cohort) 
of treatment separately for each cohort
•
AHI during REM and NREM sleep on Day 1 and Day 8 of treatment separately for each 
cohort
•
AHI separately for adult and elderly subjects at all days assessed separately for each 
cohort
•
Mean SpO2 during TST separately for adult and elderly subjects at all days assessed
separately for each cohort
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
Enrolled subjects will be defined as all subjects who provided informed consent.  The two 
cohorts will be treated separately for all summaries and analyses.  For the purposes of 
analysis the following analysis sets have been identified separately for each cohort:
•
The Safety Analysis Set for each cohort is the group of subjects who received at least 1
dose of study drug and had at least 1 postdose safety assessment.


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•
The PK Analysis Set for each cohort is the group of subjects who received at least 1 dose 
of lemborexant and had at least 1 quantifiable plasma concentration after dosing with 
lemborexant.
•
The Pharmacodynamic Analysis Set for each cohort is the group of subjects who had 
sufficient PD data to derive at least 1 PD parameter. 
5.2.2
Subject Disposition
Reasons for screening failure will be summarized.
The number and percentage of subjects who completed the study will be summarized by 
treatment group and by sequence, and the number who discontinued prematurely will be 
summarized by reason for discontinuation by treatment group and by sequence. 
5.2.3
Protocol Deviations
Major protocol deviations will be presented as a listing.
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 for all study drug groups combined using descriptive 
statistics.  Continuous demographic and baseline variables include age, height, BMI, and 
weight variables; categorical variables include sex, age group (adults ≥45 to <65 years; elderly 
≥ 65 to 90 years), race, and ethnicity.
MEDICAL HISTORY
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) (March 2019 or later).  
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.  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. A concomitant medication in Treatment Period 1 is counted up to 
predosing of Treatment Period 2; a concomitant medication in Treatment Period 2 is counted 
up to the final study visit.
All medications will be presented in subject data listings.


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5.2.6
Treatment Compliance
Compliance for the both the OSA and COPD cohorts for each study drug will be calculated on 
the basis of the number of tablets dispensed, lost and returned, for all randomized subjects. 
Compliance = Number of tablets dispensed - number of tablets returned or lost x 100
                       Number of tablets expected to be taken by the subject for the treatment period
If subject’s treatment period was extended for any reason then the number of tablets expected 
to be taken will be increased appropriately.  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.
5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses.
5.3.2
Adjustments for Covariates
The randomization stratification by age group will be reflected in models for the analysis of 
the primary and secondary PD endpoints by incorporating age group as a fixed effect.
5.3.3
Multiple Comparisons/Multiplicity
No multiplicity adjustments will be made for this is a Phase 1 safety study. 
5.3.4
Examination of Subgroups
Separate analyses will be performed for the 2 age groups (≥45 and <65 years and ≥65 to 90 years) 
for the primary and secondary PD endpoints in addition to the analyses in which age group is 
treated as a covariate.   Separate analyses also will be performed for subjects with moderate 
OSA (15≤AHI<30) and severe OSA (AHI≥30) and for subjects with moderate COPD (GOLD 
2 Classification) and severe COPD (GOLD 3 Classification) if there are sufficient numbers of 
subjects in the subgroups.
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.
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. 
No formal statistical analyses will be performed to detect and/or remedy the presence of 
statistical outliers.


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5.3.6
Other Considerations
The OSA and COPD cohorts will be analyzed separately.  If one of the cohorts completes 
earlier than the other, the database may be locked for that cohort and the data analyzed before 
the database is locked for the other cohort.
Individual subject data in the database will be presented in data listings.
For the analyses of the primary and secondary endpoints the estimands will be the difference 
between lemborexant and placebo for the difference from baseline.  The PD analysis set will 
be used for these analyses and since the endpoints are safety endpoints, the assignment of 
treatment group will be the treatment actually received.  Any missing values will be considered 
to be missing at random.  In a previous lemborexant study in subjects with OSA, missing values 
were due to dropout for administrative reasons.
5.4
Efficacy Analyses
No efficacy data will be collected in this study.
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker 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.  Since only 1 blood sample for 
PK determination will be obtained on each study day, no PK parameters will be calculated.                            
5.5.1
Pharmacodynamic Analyses
The following analysis will be performed on the PD Analysis Set for each cohort.
Analysis for the Primary Endpoint
OSA Cohort: Mean AHI will be analyzed on the PD Analysis Set using repeated measures 
ANOVA, for Day 8 of each treatment period.  The model will include fixed effects for age 
group, 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, and the two-sided 90% CI (equivalent to a one-sided upper 95% CI) for 
the true mean difference (lemborexant − placebo) in AHI.  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.
Plots of AHI treatment difference data (both individual and LS Mean) will be used to explore 
the results.
COPD Cohort: Mean SpO2 will be analyzed on the PD Analysis Set using repeated 
measures ANOVA, of values on Day 1 of each treatment period. The model will include 


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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 compared to placebo, and the two-sided 90% CI (equivalent to a one-
sided lower 95% CI) for the true mean difference (lemborexant − placebo) in SpO2.  If the 
lower bound of the one-sided 95% CI of the treatment difference of SpO2 is greater than -2 
(for active – placebo), this will provide evidence that the given dose of lemborexant does not 
result in a clinically significant decrease in SpO2 compared to placebo.
Plots of SpO2 treatment difference data (both individual and LS Mean) will be used to 
explore the results.
Analysis for the Secondary Endpoints
The secondary endpoints will be analyzed using the same model as the primary endpoint.  
5.5.2
Pharmacokinetic/Pharmacodynamic Analyses
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, ODI, absolute number of desaturations, 
and percentage 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.
5.5.3
Pharmacogenomic/Pharmacogenetic and Other Biomarker Analyses
Not applicable.
5.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] 
for categorical variables).  Safety variables include treatment-emergent adverse events 
(TEAEs), clinical laboratory parameters, vital signs, 12-lead ECG results, and the C-SSRS.  
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
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 by treatment for 
OSA and COPD cohorts using descriptive statistics.


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5.6.1
Extent of Exposure
The extent of exposure (mean daily dose, cumulative dose [calculated as the sum of the daily 
doses], and duration of exposure) to each treatment will be summarized descriptively by 
treatment and cohort, and a listing will also be provided.
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities
(MedDRA).  Adverse events will be coded to the MedDRA (Version 19.0 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged 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 
was continuous.
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group separately for each cohort. 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 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) (or by highest CTCAE grade).
A TEAE in Treatment Period 1 is counted up to predosing of Treatment Period 2 a TEAE in 
Treatment Period 2 is counted up to the final study visit.
Separate listings will be provided for subjects with deaths, SAEs, and AEs leading to 
discontinuation.
5.6.3
Laboratory Values
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in protocol Section 9.5.1.5 Safety Assessments 
(Laboratory Measurements), the actual value and the change from baseline to each postbaseline 


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visit and to the end of treatment (defined as the last on-treatment value) will be summarized 
by cohort using descriptive 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. 
Qualitative parameters listed in protocol Section 9.5.1.5 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.
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.  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-cohort 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.
5.6.4
Vital Signs
Descriptive summary statistics for vital sign parameters (diastolic and systolic blood 
pressure, pulse, and respiration rate) will be evaluated by treatment at predose and at 
postdose for Day 1 and Day 8.  In addition, change from predose to each postdose time will 
be summarized by treatment.  Baseline will be the pre-dose value in each treatment period.  
Each cohort will be analyzed separately.


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Clinically notable ranges will be summarized by treatment and time point and will be defined 
as follows:
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.
Vital sign values will be listed on an individual basis by cohort, treatment and subject.  
Abnormal vital sign values will be identified on the listings as those above (H) or below (L) a 
clinically notable range. 
5.6.5
Electrocardiograms
A 12-lead safety ECG will be recorded for all subjects at Screening, Baseline, and at follow-
up. The overall number and percentage of subjects with normal, abnormal, clinically, and 
non clinically-significant ECG results will be summarized at Screening, Baseline, and at 
Follow-up.  Investigator assessments of normality/abnormality will also be listed.  
5.6.6
Other Safety Analyses
No other safety analyses are planned for this study.
5.7
Other Analyses
Not applicable.
5.8
Exploratory Analyses
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 secondary endpoints. Exploratory endpoints will be analyzed using the same model as 
the primary endpoints.


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6
INTERIM ANALYSES
No interim analyses are planned for this study.
7
CHANGES IN THE PLANNED ANALYSES
Not applicable.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
No missing data will be imputed.
8.1
Pharmacokinetic Data Handling
8.1.1
Lower Limit of Quantification of E2006 Plasma Concentration
The LLOQ of E2006 as well as metabolites M4, M9 and M10 plasma concentration is 0.0500
ng/mL.
8.1.2
BLQ Handling for Calculation of PK Parameters
Not applicable.
8.1.3
BLQ Handling for Developing Concentration-Time Profiles
Not applicable.
8.1.4
Handling of Anomalous Concentration Values
The handling of anomalous concentration values will follow the guidance in the NCA-MNL.
8.1.5
General Rules for Presentation of Drug Concentrations 
When presenting individual/raw (raw, hereafter) values and summary statistics, the following 
rule will be applied: for drug concentrations all summary statistics (mean, median, geometric 
mean, SD, and CV) will have 3 significant digits.  
8.1.6
General Rules for Presentation of PD Parameters
When presenting individual/raw (raw, hereafter) values and summary statistics, the following 
rule will be applied:  for pharmacodynamic parameters, all summary statistics (mean, 
median, geometric mean, SD and CV) will have 3 significant digits.  


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Typical variable
N
Digit rule
Raw
Minimum
Maximum
Mean
Median
SD
AHI
X
Fixed decimal 
places
2
2
3
SpO2
…
Fixed decimal 
places
2
2
2
% of TST
X
Fixed decimal 
places
3
3
2
ODI
X
Fixed decimal 
places
2
2
2
Number of 
desaturations
X
Fixed decimal 
places
…
1
2
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
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. 
10 STATISTICAL SOFTWARE
Analysis will be performed using SAS (release 9.4 or newer), Phoenix WinNonlin (version 
6.4 or newer), PDx-POP (version 5.2 or newer). Pharsight Knowledgebase Server (version 
3.0 or newer), Microsoft Excel (2010 or newer), and NONMEM (version 7.3 or newer), R 
(3.3.2 or newer). 
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
American Academy of Sleep Medicine. International classification of sleep disorders, 
3rdedition. Darien, IL: American Academy of Sleep Medicine, 2014.


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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.
Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for sleep 
related breathing disorders in adults. Sleep. 2006;29(3):381–401
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management and prevention of COPD. Global Initiative for Chronic Obstructive 
Lung Disease website. https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-
FINAL-ver1.2-03Dec19_WMV.pdf. [updated December 2019. accessed 17 Dec 2019].
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(3):159–64.
Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during 
sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep 
Breath. 2009;13(1):79-84.
Lee YJ, Kim JW, Lee Y-U G, Jeong DU. Sleep EEG Characteristics in Young and Elderly
Patients with Obstructive Sleep Apnea Syndrome. Psychiatry 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.
Piper AJ, Yee BJ. Hypoventilation syndromes. Compr Physiol. 2014; 4(4):1639-76
Rosenberg R, Roach JM, Scharf M, Amato DA. A pilot study evaluating acute use of 
eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. Sleep Med. 
2007;8(5):464–70.
Sun H, Palcza J, Rosenberg R, Kryger M, Siringhaus T, Rowe J, et al. Effects of suvorexant, 
an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive 
pulmonary disease. Respir med. 2015;109(3), 416-26.


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Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, et al. Effects of suvorexant, an 
orexin receptor antagonist, on respiration during sleep in patients with obstructive sleep 
apnea. J Clin Sleep Med. 2016;12(1):9–17.
Vroegop AV, Smithuis JW, Benoist LBL, Vanderveken OM, de Vries N. CPAP washout prior 
to reevaluation polysomnography: a sleep surgeon’s perspective. Sleep Breath. 2015 
19(2):433–9.
C-SSRS Reference
http://www.cssrs.columbia.edu/scales_cssrs.html
GOLD 2019
https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-
03Dec19_WMV.pdf


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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.


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


Statistical Analysis Plan
E2006-A001-113
Eisai (Version 1.0) 
Confidential
Page 24 of 26
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium >ULN 
- 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium >1.5 -
1.6 mmol/L; 
symptomatic
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium >1.6 -
1.8 mmol/L; 
hospitalization indicated
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 - 3.0baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes
Insulin therapy initiated; 
hospitalization indicated
life-threatening 
consequences; urgent 
intervention indicated
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated
Oral replacement 
therapy indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L; 
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L and 
asymptomatic
<125 – 129  mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms
<120 mmol/L
life-threatening 
consequences


Statistical Analysis Plan
E2006-A001-113
Eisai (Version 1.0) 
Confidential
Page 25 of 26
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN without 
physiologic 
consequences 
N/A
>ULN with physiologic 
consequences 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: January 5, 2018.
13.2
SAS Code 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 period treatment /solution
ddfm=satterth;
random patient(sequence);
lsmeans treatment / pdiff cl e;
run;
For subgroup analyses use the above code with by variable.


Statistical Analysis Plan
E2006-A001-113
Eisai (Version 1.0) 
Confidential
Page 26 of 26
SIGNATURE PAGE
Author:  
 
 
Neurology Business Group
Eisai Inc.
Date
Approval:
 
Neurology Business Group
Eisai Inc.
Date
 
 
Neurology Business Group
Eisai Inc.
Date
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