Clinical trial NCT03001557
Conditions: Irregular Sleep-Wake Rhythm Disorder
Keywords: Mild to Moderate Alzheimer's Disease Dementia sleep circadian rhythms
Sponsor: Eisai Inc.
Start date: 2016-12-20; Completion date: 2020-04-17
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to determine the dose response of lemborexant (LEM) on the change from baseline in actigraphy-derived sleep-related parameters, wake-related parameters, and circadian-rhythm related parameters. Following the eligibility screening period, eligible participants will be assigned at random to 1 of 4 doses of LEM or to placebo for 4 weeks. After a 2-week follow-up period, eligible participants may enter an open-label extension period for up to 30 months or until the program discontinuation.

Detailed description:

Arms: arm 1: Participants will take one lemborexant 2.5 mg tablet and one lemborexant-matched placebo tablet orally each night for 28 consecutive nights immediately (i.e., within 5 minutes) before the time the participant intends to try to sleep. arm 2: Participants will take one lemborexant 5 mg tablet and one lemborexant-matched placebo tablet orally each night for 28 consecutive nights immediately (i.e., within 5 minutes) before the time the participant intends to try to sleep. arm 3: Participants will take one lemborexant 10 mg tablet and one lemborexant-matched placebo tablet orally each night for 28 consecutive nights immediately (i.e., within 5 minutes) before the time the participant intends to try to sleep. arm 4: Participants will take one lemborexant 5 mg tablet and one lemborexant 10 mg tablet orally each night for 28 consecutive nights immediately (i.e., within 5 minutes) before the time the participant intends to try to sleep. arm 5: Participants will take two lemborexant-matched placebo tablets orally each night for 28 consecutive nights immediately (i.e., within 5 minutes) before the time the participant intends to try to sleep.
Interventions: intervention 1: Lemborexant 2.5 mg intervention 2: Lemborexant 5 mg intervention 3: Lemborexant 10 mg intervention 4: Lemborexant 15 mg intervention 5: Lemborexant-matched placebo
Intervention descriptions: intervention 1: Lemborexant 2.5 mg tablets intervention 2: Lemborexant 5 mg tablets intervention 3: Lemborexant 10 mg tablets intervention 4: Lemborexant 5 mg and 10 mg tablets intervention 5: Lemborexant-matched placebo tablets

Protocol documents:
SAP_004.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN (Extension Phase)
Study Protocol 
Number:
E2006-G000-202
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study with Open-Label Extension Phase of the Efficacy and 
Safety of Lemborexantin Subjects with Irregular Sleep-Wake Rhythm 
Disorder and Mild to Moderate Alzheimer’s Disease Dementia
Date:
27 AUG 2018
Version:
Final Version 1.0


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TABLE OF CONTENTS
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
2
INTRODUCTION .............................................................................................................6
2.1
STUDY OBJECTIVES............................................................................................6
2.2
Overall Study Design and Plan................................................................................6
2.2.1
Extension Phase .............................................................................................6
2.2.2
Follow-Up Period...........................................................................................7
2.2.1
END OF EXTENSION PHASE....................................................................9
3
DETERMINATION OF SAMPLE SIZE..........................................................................9
4
STATISTICAL METHODS..............................................................................................9
4.1
Study Endpoints.......................................................................................................9
4.1.1
Efficacy Endpoints.........................................................................................9
4.1.2
Safety Endpoints..........................................................................................10
4.2
Study Subjects........................................................................................................10
4.2.1
Definitions of Analysis Sets.........................................................................10
4.2.2
Subject Disposition......................................................................................10
4.2.3
Protocol Deviations......................................................................................10
4.2.4
Demographic and Other Baseline Characteristics .......................................10
4.2.5
Prior and Concomitant Therapy...................................................................10
4.2.6
Treatment Compliance.................................................................................11
4.3
Efficacy Analyses ..................................................................................................11
4.4
Safety Analyses......................................................................................................11
4.4.1
Extent of Exposure.......................................................................................11
4.4.2
Adverse Events ............................................................................................11
4.4.3
Laboratory Values........................................................................................13
4.4.4
Vital Signs....................................................................................................13
4.4.5
Electrocardiograms ......................................................................................14
4.4.6
Other Safety Analyses..................................................................................14
5
INTERIM ANALYSES...................................................................................................14
6
CHANGES IN THE PLANNED ANALYSES...............................................................14
7
DATA ANALYSIS GENERAL CONSIDERATIONS ..................................................15
7.1.1
Examination of Subgroups...........................................................................15
7.1.2
Handling of Missing Data, Dropouts, and Outliers .....................................15
7.1.3
Other Considerations ...................................................................................15
7.1.4
Visit Window...............................................................................................15
8
PROGRAMMING SPECIFICATIONS ..........................................................................15
9
STATISTICAL SOFTWARE..........................................................................................16


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10
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................16
11
REFERENCES ................................................................................................................17
12
APPENDICES .................................................................................................................18
Appendix 12.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results....................................................................................................................18


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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
AE
adverse event
AMP
Amplitude of the rest-activity rhythm
ANCOVA
analysis of covariance
aSE
Actigraphy sleep efficiency
ATC
anatomical therapeutic class
aWE
Actigaphy wake efficiency
BMI
body mass index
CGIC- ISWRD
Clinician’s Global Impression of Change - Irregular Sleep-Wake 
Rhythm Disorder version
CI
confidence interval
CRF
case report form
CSR
clinical study report
E2006
lemborexant
EQ-5D-5L
EuroQOL version 5D-5L
FAS
full analysis set
IS
Interdaily Stability 
ISWRD
Irregular Sleep-Wake Rhythm Disorder
IV
Intradaily Variability
LEM
lemborexant
LEM2.5 
lemborexant 2.5 mg
LEM5 
lemborexant 5 mg
LEM10 
lemborexant 10 mg
LEM15
lemborexant 15 mg 
LS
least squares
OLE
Open Label Extension
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
NPI-10
Neuropsychiatric Inventory


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Abbreviation
Term
PBO
Placebo
PD
pharmacodynamic
PK
pharmacokinetic
PSG
Polysomnography
PSQI
Pittsburgh Sleep Quality Index
RA
Relative amplitude of the rest-activity rhythm
SAE
serious adverse event
SAP
statistical analysis plan
SD
Standard deviation
SDI
Sleep Disorders Inventory
SE
Sleep efficiency (PSG)
SFI
Sleep Fragmentation Index
SI
Système International
TEAE
treatment-emergent adverse event
TIB
Time in bed
TLG
tables, listings, and graphs
WFI
Wake Fragmentation Index
WHO
World Health Organization
ZBI
Zarit Burden Interview – short form


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2
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Eisai Protocol E2006-G000-202 open 
label extension (Extension Phase). Additional exploratory or post-hoc analyses not identified in 
this SAP may be performed to facilitate interpretation of study results and documented in the 
clinical study report. A separate SAP has already been finalized for the core study.
This document is prepared on the basis of the final study protocol version 10.0 (dated 20 Jun
2018). The reader is referred to the study protocol, the case report form (CRF), general CRF
completion guidelines, and various data collection instruments employed in the study for details 
of study design, conduct, and data collection.  
This SAP is to be reviewed and approved prior to study database lock.  If any updates are made 
upon blinded review of study data or for any other reasons in the course of the study, such 
modifications and rationale are likewise to be documented and approved prior to unblinding of 
study database.
2.1
STUDY OBJECTIVES
The objective of the Extension Phase is to evaluate the long-term safety and tolerability of 
flexible doses of Lemborexant 5 mg (LEM5), Lemborexant 10 mg (LEM10) and Lemborexant
15 mg (LEM15) once per day over a period of 30 months in subjects with Alzheimer’s disease 
dementia (AD-D) who have Irregular Sleep-Wake Rhythm Disorder (ISWRD).
2.2
Overall Study Design and Plan
2.2.1
Extension Phase
The Extension Phase comprises a 30-month Maintenance Period (Treatment Period) and a 14-
day Follow-Up Period.
Subjects who complete the Core Study End of Study (EOS) Visit within 30 days prior to 
enrollment in the Extension Phase will be eligible for participation.
For subjects continuing directly from the Core Study to the Extension Phase, the End of Study 
(EOS) Visit of the Core Study will be the start of the Extension Phase.
Subjects who complete the Core Study, but who do not elect to immediately roll over to the 
Extension Phase will be required to return to the site within 30 days of completion of the Core 
Study and repeat selected assessments before being dispensed drug for the Extension Phase. If 
subjects return before 30 days of the last study visit, the tests that are required at that time are 
vital signs, weight, the Sleep Disorders Inventory (SDI), and the electronic Columbia-Suicide 
Severity Rating Scale (eC-SSRS). All other data will be carried over from Visit 6A. If subjects 
return on Day 30, all tests listed for Visit 6B will be performed.  Details are as in (Figure 1).  


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During the Treatment Period, all subjects initially will receive lemborexant 10 mg per day 
(LEM10). At the discretion of the investigator, subjects will have the option of increasing the
dose to lemborexant 15 mg per day (LEM15) or decreasing to lemborexant 5 mg per day 
(LEM5). All dose adjustments will be performed at an unscheduled visit or at the next 
scheduled visit.  
All doses will be taken orally in tablet form each night for the duration of the Extension Phase 
immediately (ie, within 5 minutes) before the time the subject intends to sleep. The dose can be 
adjusted more than once during the Extension Phase.  Subjects will receive 1 or 2 tablets as 
described below:

LEM5:  one lemborexant 5-mg tablet

LEM10:  one lemborexant 10-mg tablet

LEM15:  one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
Study visits, either in person or by telephone, will be conducted according to the Schedule of
Procedures and Assessments for the Extension Phase. If the phone visit indicates an ongoing
adverse event (AE), the subject should be brought to the clinic for an Unscheduled Visit.
Subjects may discontinue from study drug for any reason. A subject who prematurely
discontinues taking study drug should return to the clinic within 2 weeks of discontinuation to
complete an Early Termination (ET) Visit. The assessments of the E T  Visit are the same as
those for the EOS Visit for the Core Study.
If the subject discontinues from the study due to an AE, the subject must complete an ET Visit,
and the AE must be followed to resolution for a period of 4 weeks, whichever comes sooner.
2.2.2
Follow-Up Period
The Follow-Up Period will be 14 to 18 days in duration and begins when subjects leave the 
clinic at the end of the Maintenance Period. Subjects and caregivers will return to the clinic at 
least 14 days but no more than 18 days after the end of the Maintenance Period for the End of 
Study Visit, including the recording of AEs and concomitant medications, and assessment of 
clinical laboratory tests, vital signs, and weight, and measurement of an electrocardiogram 
(ECG).
Treatment in the Extension Phase will last for a maximum duration of 30 months or until the 
lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder 
(ISWRD) is discontinued.  A study design that includes the Extension Phase is presented in 
Figure 1.


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Figure 1
Study Design
Note:  Visit 1 is an optional Prescreening Period for subjects and caregivers who are unsure whether the subject has Irregular Sleep-Wake Rhythm Disorder (ISWRD). Subjects will wear an activity 
tracker for approximately 4 days, then return to the site to have the data from the activitytracker downloaded and analyzed to determine whether they are candidates for the study.  (revised per 
Amendment 05)
Note:  Visit 2 is a caregiver visit for downloading actigraphy data to determine eligibility; Visit 3 is the baseline visit for both subject and caregiver; Visit 4 is a visit for both subject and caregiver to 
download actigraphy data and perform safety assessments; Visit 5 is the end-of-treatment assessments visit; and Visit 6A is for end-of-study assessments for the Core Study.  For subjects continuing 
directly from the Core Study into the Extension Phase, Visit 6A will be the start of the Extension Phase.  Subjects who complete the Core Study, but who do not elect to immediately continue into the 
Extension Phase have up to 30 days after Visit 6A to participate.  These subjects will be required to repeat selected assessments (Visit 6B) before being dispensed drug for the Extension Phase.  Some 
subjects will have fewer visits based on the availability of lemborexant commercially.  
ISWRD = Irregular Sleep-Wake Rhythm Disorder, V = Visit.
V6A
V7 to V24
   V5
  V4
VE25
Extension Phase
Maintenance
(up to 30 months)
Follow-Up
(2 weeks)
V 1
   V2
   V1
   V3
Phase
Prerandomization
Randomization
Optional
Pre-
Screen-
ing
Screening
(up to 6 weeks)
(≥2 weeks
actigraphy)
Treatment (4 weeks)
(4 weeks actigraphy)
Follow-Up
(2 weeks 
actigraphy)
Period
Baseline /
Randomi-
zation
V6A
EOS Visit for Core 
Study / First visit 
for Extension 
Phase
V7 and V8
Days 73 and 
103
Clinic visits
V9, V12, V15, V18, V19, V20, V21, V22, V23, V24
Days 133, 223, 313, 403, 493, 583, 673, 763, 853, 
and 943
Clinic visits
V10, V11, V13, V14, V16, V17
Days 163, 193, 253, 283, 343, and 373
Telephone visits
V25
Day 957
End of Study


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2.2.1
END OF EXTENSION PHASE
The End of the Extension Phase will be the date of the last study visit for the last subject in the 
Extension Phase.
Duration of Treatment: Up to 30 months or until the lemborexant clinical development program 
for ISWRD is discontinued.
3
DETERMINATION OF SAMPLE SIZE
While approximately 60 subjects will enroll in the Core Study, any subject who completed the  
Core Study after the protocol was amended to include the the Extension Phase will be allowed 
to enroll in this Extension Phase, if eligible. 
4
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.
There will be no hypothesis testings, and data will be only be summarized by timepoint and by 
modal dose received by the subject.
Modal dose will be calculated as follows:
If subject has one dose start date and no dose end date, then subject has been on initial10 mg 
dose, model dose = 10 mg.
If a subject has start dose date and only one end date, and a second dose start date; then subject 
has been on 10 mg dose till first end dose date, the number of days on 10 mg is calculated as 
follows: first end date - first start date +1 , and number of days on the new dose is calculated as: 
database snapshot date- second start date +1.  The modal dose is the most frequent of these two 
numbers, ... and so on.
4.1
Study Endpoints
4.1.1
Efficacy Endpoints
The SDI, completed by the caregiver as proxy for the subject, will be performed according to the 
Schedule of Procedures and Assessments.


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4.1.2
Safety Endpoints
Subjects will have routine safety assessments during the Extension Phase, including monitoring, 
questioning and recording of AEs, measurements for ECGs, vital signs, and weight, and blood 
and urine collection for clinical hematology and chemistry analysis, urinalysis, and the eC-SSRS.
4.2
Study Subjects
4.2.1
Definitions of Analysis Sets
Safety Analysis Set: the group of Extension Phase subjects who received at least 1
dose of Treatment Phase study drug and had at least 1 postdose safety assessment
4.2.2
Subject Disposition
The number of subjects entered in the Extension Phase and the number of subjects completing 
the Extension Phase will be presented. Subjects who prematurely terminated their participation 
in this extension phase will be summarized by their primary reason for study termination. Other 
reasons for study drug and study terminations will also be summarized. These tabulations will be 
produced for all subjects by modal dose.
4.2.3
Protocol Deviations
Protocol deviations, as specified by the monitor, will be categorized into major and minor 
deviations prior to unblinding and will be listed.  Major protocol deviations will be summarized 
by modal dose group.
4.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
by modal dose using descriptive statistics.  Continuous demographic and baseline variables 
include age, height, and weight; body mass index (BMI); categorical variables include sex, age 
group (60 to <65, 65 to <75, 75 to <85, and 85 to 90), BMI group (<18.5, 18.5 to <25, 25 to ≤30, 
and >30 kg/m2, or other suitable categorization), race, ethnicity, and country.  
4.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2016 or latest version). 
The number (percentage) of subjects who take prior and concomitant medications will be 
summarized on the Safety Analysis Set by modal dose group, Anatomical Therapeutic Chemical 
class (ATC), and WHO DD -preferred term (PT). 


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Prior medications are defined as medications that stopped before the first dose of Extension
Phase study drug.
Concomitant medications are defined as medications that (1) started before the first Extension 
Phase dose of study drug and continued at the time of the first dose of study drug, or (2) started 
on or after the date of the first Extension Phase dose of study drug to the last dose day plus 14 
days. All medications will be presented in subject data listings.
4.2.6
Treatment Compliance
Compliance will be summarized by visit as reported by investigators.
Compliance for lemborexant will also be calculated on the basis of the number of tablets 
dispensed, lost, and returned as (total number of tablets dispensed – total number of tablets 
returned – total number of tablets lost)/total of number of tablets should have been taken.
Summaries will provide descriptive summary statistics and number (percentage) of subjects 
below 80%, between 80% and 120%, and greater than 120%.
4.3
Efficacy Analyses
SDI will be summarized by visit and modal dose based on the Safety Analysis Set.
4.4
Safety Analyses
Safety analyses will be performed on the Safety Analysis Set. Safety data, presented by modal 
dose 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, eC-SSRS.  Study Day 1 for all safety 
analyses is defined as the date of the first dose of study drug in the Core Study.
4.4.1
Extent of Exposure
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study drug 
will be summarized descriptively for lemborexant by modal dose based on the Safety Analysis 
Set.
4.4.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 18.0 or higher) lower level term 
closest to the verbatim term. The linked MedDRA PT and primary system organ class (SOC) are 
also captured in the database.  


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A TEAE for Extension Phase is defined as an AE that emerges during Extension Phase
treatment, having been absent during the interval between the end of the Core and before 
Extension Phase Baseline) or 
•
Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsened in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. AEs will be classified 
as TEAEs up to 14 days after the last study treatment.
An overview of the TEAEs will be summarized by modal dose group, including the number and 
percentage of subjects who experience TEAEs, treatment-related TEAEs, severe TEAEs, TEAEs 
leading to death and discontinuation from study/study drug.  
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT. A subject will be counted only once within an SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT. The number (percentage) of 
subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of non-serious TEAEs with an incidence of greater than 5% will be 
summarized.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). Treatment-related TEAEs include those events 
considered by the investigator to be related to study treatment. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each modal dose.  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 modal dose. A subject data listing of all SAEs will be provided.  
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug, the 
number (percentage) of subjects with TEAEs leading to dose reduction, and The number 
(percentage) of subjects with TEAEs leading to dose interruption will be summarized by 
MedDRA SOC and PT and by modal dose.
Subject data listings of all AEs leading to 
discontinuation, leading to dose reduction, and leading to dose interruption  will be provided. 
The number (percentage) of subjects with TEAEs of cataplexy that are characterized according 
to the customized MedDRA query PT as potential cataplexy-related events (Section 9.2.8 of the 
Protocol), or as seizure-related events will be summarized as deemed necessary. Adjudicated 
events may also be presented separately.


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The following adverse event tables will be also summarized by dose at first AE onset:  The 
number (percentage) of subjects with TEAE by MedDRA SOC and PT, the number (percentage) 
of subjects with TEAE summarized by PT sorted by decreasing frequency, and the summary of 
selected AEs.  A flag for dose at first AE onset will be created, and this set of tables will be then 
produced accordingly by ONSET dosing group ( 5 mg, 10 mg, and 15 mg) within the modal 
dose. 
4.4.3
Laboratory Values
Clinical laboratory values will be evaluated for each laboratory parameter by subject for 
Extension Phase.  
Abnormal laboratory values will be identified as those outside (above or below) the normal 
range.  Reference (normal) ranges for laboratory parameters will be included in the clinical study 
report for this study.  Descriptive summary statistics (eg, mean, SD, median, minimum, 
maximum for continuous variables, and number and percentage for categorical variables) for the 
laboratory parameters and changes from baseline will be evaluated by modal dose and visit.  
Laboratory test results will be assigned a low-normal-high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons will be based on 3 by 3 tables (shift tables) that, for a 
particular laboratory test, compare the Study Baseline LNH classification to the LNH 
classification at end of study/early termination, by modal dose.
Clinical laboratory results post-baseline will be evaluated for markedly abnormal values.  A 
laboratory test will be considered markedly abnormal if the result worsens to meet Eisai grading 
criteria for laboratory values limit of Grade 2 or higher.  If the Grade 2 limit is missing, the 
Grade 1 limit will be considered.  Appendix 12.1 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.
While this section covers laboratory data starting from Extension Phase baseline, laboratory data 
before Extension Phase might be presented if deemed appropriate.
4.4.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, respiration 
rate, temperature) and weight, and changes from Baseline will be presented by visit and 
treatment group. 
Vital sign values will be listed. Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 1). Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital sign 
ranges will also be presented by modal dose group and visit.


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Table 1
Vital Sign and Weight
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.
Clinically notable means that a value must meet the criterion value and must attain the specified magnitude of 
change relative to baseline.
4.4.5
Electrocardiograms
Descriptive statistics for ECG parameters and changes from Baseline will be presented by modal 
dose group. Shift tables will present changes from Baseline in ECG interpretation (categorized as 
normal; abnormal, not clinically significant; and abnormal, clinically significant) by visit. Later 
on, shift tables may be presented by post baseline year instead of visit as deemed appropriate.
For each subject, the maximum observed corrected QT interval calculated using Fridericia’s 
formula (QTcF), and the maximum prolongation from baseline in QTcF will be compiled.  
Categorical analyses of subjects (number and percent) with maximum observed QTcF values 
>450 msec, >480 msec, and >500 msec and maximum prolongations (from Baseline) in QTcF 
>30 msec and >60 msec will be presented by modal dose group and by time point. Categorical 
analyses of subjects (number and percent) with maximum observed PR values >220 msec, and 
QRS values > 120 msec will be presented by modal dose group and by visit.
4.4.6
Other Safety Analyses
The results of eC-SSRS assessments will be listed for each subject. The incidence of treatment-
emergent suicidal ideation or suicidal behavior will be summarized by modal dose group and 
visit using descriptive statistics as appropriate.
5
INTERIM ANALYSES
Interim analyses will be performed for this study to provide data for a synoptic report to support 
new drug applications.
6
CHANGES IN THE PLANNED ANALYSES
No efficacy analysis set has been defined for extension phase and safety set will be used for all 
analysis.


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7
DATA ANALYSIS GENERAL CONSIDERATIONS
The Safety Set will be used for all analyses.  
7.1.1
Examination of Subgroups
No subgroup analysis is planned for this Extension Phase.
7.1.2
Handling of Missing Data, Dropouts, and Outliers
Data will not be imputed, unless otherwise specified; i.e., all missing values will remain as 
missing in all statistical summaries and listings, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers.
7.1.3
Other Considerations
Individual subject data in the database will be presented in data listings.
7.1.4
Visit Window
All efficacy and safety data will be presented using derived visits as follows.
Visit
Target Visit Day (in study days)
Visit Window (in study days)
Ext. Visit 6B
On or prior to the study day of first dose of Extension 
Phase
Ext. Visit 7
73
Post study day of first dose of Extension Phase - 88
Ext. Visit 8
103
89-118
Ext. Visit 9
133
119-148
Ext. Visit 10
163
149-178
Ext. Visit 11
193
179-208
Ext. Visit 12
223
209-238
Ext. Visit 13
253
239-268
Ext. Visit 14
283
269-298
Ext. Visit 15
313
299-328
..etc
X
(X  -14, X+15)
  
8
PROGRAMMING SPECIFICATIONS
All efficacy and safety data will be presented using derived visit window described in this SAP.
The rules for programming derivations and dataset specifications are provided in separate 
documents.


Statistical Analysis Plan
   E2006-G000-202
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Final:  v1.0 27Aug2018
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Page 16 of 20
9
STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS v 9.3 or later.
10 MOCK TABLES, LISTINGS, AND GRAPHS
The study table, listing, and graph (TLG) shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail.


Statistical Analysis Plan
   E2006-G000-202
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Final:  v1.0 27Aug2018
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Page 17 of 20
11 REFERENCES
Bornkamp B, Pinheiro J, Bretz F.  MCPMod: An R Package for the Design and Analysis of
Dose-Finding Studies.  J Statistical Software. 2009 (7):29.
Gehrman PR, Marler M, Martin JL, et al. The timing of activity rhythms in patients with 
dementia is related to survival. J Gerontol Biol Sci Med Sci. 2004;59A:1050–1055.
Marler MR, Gehrman P, Ancoli-Israel S, et al. The sigmoidally transformed cosine curve: a 
mathematical model for circadian rhythms with non-sinusoidal shapes. Stat Med. 2006;25:3893–
3904. 
Martin et al, Sleep and Sleep Disorders in Older Persons: A Multicomponent 
Nonpharmacological Intervention Improves Activity Rhythms Among Nursing Home Residents 
With Disrupted Sleep/Wake Patterns Journal of Gerontology: MEDICAL SCIENCES, 2007, Vol. 
62A, No. 1, 67–72
Martin J, Marler MR, Shochat T, et al. Circadian rhythms of agitation in institutionalized patients 
with Alzheimer’s disease. Chronobiol Int. 2000;17:405–418.
Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light
therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatrica
Scandinavica. 1994; 89: 1–7.


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12 APPENDICES
Appendix 12.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results
The following table of Sponsor’s Grading for Laboratory Values is taken from the protocol.
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<55 – 40 mg/dL
<40 – 30 mg/dL
<30 mg/dL


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
<LLN – 3.0 mmol/L
<3.0 – 2.2 mmol/L
<2.2 – 1.7 mmol/L
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 28 May 2009 (v4.03: 14 Jun, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, , LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.


Statistical Analysis Plan
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27Aug2018
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Page 20 of 20
SIGNATURE PAGE
Author:  
Date
Approval:
Date
Date
PPD
PPD
PPD

Prot_002.pdf: 
Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page i of ii
Revision History 
Previous Version:  v9.0
Current Version:  v10.0
Date of Latest Revision: 20 June 2018 (revised per Amendment 06)
Change
Rationale
Affected Protocol Section(s)
Revised objectives
To reflect exploratory 
nature of this Phase 2 
study

Synopsis:

Objectives

Section 8
Updated Adjudication Committee
information
To harmonize with other 
protocols in the 
lemborexant clinical 
program

Synopsis

Adjudication 
Committee

Section 9.2.8
Provided definition of Mean Calculated 
Bedtime in footnote
Correction

Table 3
Clarified assessments to be conducted 
at Visits 6A and 6B
Correction
•
Table 3
•
Appendix 4, Extension Phase

Table 8
Revised Endpoints
To reflect exploratory 
nature of this Phase 2 
study and align with 
objectives

Synopsis

Statistical Methods

Sections 9.7.1.1 to 9.7.1.6
Revised visit windows during the 
Open-Label Extension Phase of the 
study (including footnotes on the 
Extension Schedule of Assessments)
and added electronic Columbia-Suicide 
Severity Rating Scale (eC-SSRS) to the 
End of Study Visit/Early Termination 
Visit
Correction and 
clarification

Appendix 4, Extension Phase

Design and Plan

Appendix 4, Extension Phase

Table 8
Added study drug dispensing at Visit 8d
To correct an oversight as
this is a clinic visit

Appendix 4, Extension Phase

Table 8
Updated (reduced) sample size
For correction as fewer 
subjects are needed to 
achieve objectives

Synopsis

End of Core Study

Number of Subjects

Sample Size 
Rationale

Section 9.3

Section 9.7.2
Clarified the interim analysis procedure
To reflect change in 
analysis strategy

Synopsis

Interim Analysis

Section 9.7.3
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page ii of ii
Revision History 
Previous Version:  v9.0
Current Version:  v10.0
Date of Latest Revision: 20 June 2018 (revised per Amendment 06)
Added to the prohibited concomitant 
medication lis
Added information to Phase 1 study 
descriptions
Probibited moderate 
cytochrome P450 (CYP) 
3A inhibitors
Reported results of Study 
012, which reported 
moderate CYP3A 
interaction

Synopsis

Concomitant Drug Therapy

Section 7.1.4.3

Section 9.4.7.2

Appendix 3

Section 7.1.4.1
Updated Protocol Signature Page
Correction

Protocol Signature Page
Eisai
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Page 3 of 847


Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page i of i
Revision History 
Previous Version:  v8.0
Current Version:  v9.0
Date of Latest Revision: 17 Nov 2017 (revised per Administrative Change)
Change
Rationale
Affected Protocol Section(s)
Corrected typographical error
Maintain consistency
Synopsis

Efficacy assessments

Section 9.5.1.3
Eisai
Confidential
Page 4 of 847


Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page i of xiii
Revision History 
Previous Version:  v7.0
Current Version:  v8.0
Date of Latest Revision: 17 Nov 2017 (revised per Amendment 05)
Change
Rationale
Affected Protocol Section(s)
Added an Extension Phase of up to 30
months specifying that eligible subjects 
who elect to receive open-label 
treatment after completing the End of 
Study (EOS) Visit will receive 
lemborexant (E2006) 5, 10, or 15 mg 
per day. A detailed description of the 
Extension Phase was added in 
Appendix 4.
Revised references to Prerandomization 
and Randomization Phases to specify as 
the “Core Study.”
Added to assess long-term 
safety and tolerability of 
lemborexant (E2006) 5, 10, or 
15 mg per day.
For clarity of presentation 
where description of the 
Extension Phase procedures 
have been added.
Synopsis

Title

Study Period

Investigators

Objectives

Study Design

Number of Subjects

Inclusion Criteria

Exclusion Criteria

Study Treatment

Duration of Treatment

Assessments

Statistical Methods

Study Endpoints

Efficacy Analysis

Pharmacokinetic Analysis

Safety Analysis

Section 7.1.4.1

Section 8.1

Section 9.1

Section 9.1.2.1

Section 9.1.3.1

Section 9.1.3.2

Section 9.1.4

Section 9.2.4

Section 9.3

Section 9.3.1

Section 9.3.2

Section 9.4.1

Section 9.5.1.2.3

Section 9.5.1.3

Section 9.5.1.4.1

Section 9.5.1.5.4

Section 9.5.1.5.8

Section 9.5.2.1

Section 9.5.4.1

Section 9.7.1

Section 9.7.1.1.1

Section 9.7.1.1.3

Section 9.7.1.6.1

Section 9.7.1.6.2

Section 9.7.1.8.6

Section 9.7.3

Appendix 3

Appendix 4
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Clinical Study Protocol
(Per Amendment 06)
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FINAL (v10.0):  20 Jun 2018
Confidential
Page ii of xiii
Revision History 
Previous Version:  v7.0
Current Version:  v8.0
Date of Latest Revision: 17 Nov 2017 (revised per Amendment 05)
Change
Rationale
Affected Protocol Section(s)

Protocol Signature page

Investigator signature page
Revised language to reflect changes in 
the actigraphy requirement

Section 9.1.2.1

Section 9.1.2.2

Section 9.1.3.1
Revised inclusion criterion #8; updated 
actigraphy requirement
To facilitate enrollment

Section 9.3.1

Section 9.3.2
Revised the number of subjects 
screened
Reflects the actual study 
experience to date

Section 9.3
Revised assessments of 
Neuropsychiatric Inventory – 10 Item 
(NPI-10), Mini Mental State 
Examination (MMSE), Alzheimer’s
Disease Assessment Scale – Cognitive 
(ADAS-cog), and Sleep Disorders 
Inventory (SDI) from the Safety 
Assessments for the Core Study, and to 
the Efficacy Assessments.
Correction

Section 9.5.1.3

Section 9.5.1.5

Section 9.7.1.6.2

Section 9.7.1.8.6
Correction of typos
Clarity

Section 9.5.1.4.1
Revised the primary endpoint 
description and the primary endpoint 
analysis description to provide a 
statement detailing the change in 
analysis, ie, now based on 8-hour 
defined sleep period
Due to a change in definition 
of the baseline requirements

Section 9.7.1.1.1

Section 9.7.1.6.1
Revised to reflect addition of activity 
tracker
Updated the description of the 
Screening process with a new 
section, “Optional 
Prescreening” that details the 
addition of an activity tracker
Synopsis:

Optional Prescreening

Section 9.1.2.1
Revised signature pages
Inclusion of the EudraCT 
number

Protocol Signature Page

Investigator Signature Page
Revised viral test from safety to 
Screening
Assessment is only performed 
during screening

Section 9.5.1.2.3

Section 9.5.1.5.8
Revised list of prohibited medications
Added orexin receptor 
antagonists
Appendix 3
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page iii of xiii
Revision History 
Previous Version:  v6.0
Current Version:  v7.0
Date of Latest Revision: 11 Oct 2017 (revised per Administrative Change)
Change
Rationale
Affected Protocol Section(s)
Updated SAE reporting information
Administrative change

Section 9.5.4.1
Eisai
Confidential
Page 7 of 847


Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page iv of xiii
Revision History 
Previous Version:  v5.0
Current Version:  v6.0
Date of Latest Revision: 10 Aug 2017 (revised per Amendment 04)
Change
Rationale
Affected Protocol Section(s)
Revised protocol to include the conduct 
of the study in the European Union
To facilitate enrollment

Title Page

Synopsis – Sites

Section 4

Section 5.2

Section 6

Section 9.5.4.6

Section 11.5
Revised total number of sites from 
approximately 40 to approximately 60
To facilitate enrollment

Synopsis – Sites

Section 6

Section 9.3
Revised sponsor signature page
To reflect current study 
sponsor approvers

Sponsor Signature Page
Eisai
Confidential
Page 8 of 847


Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page v of xiii
Revision History 
Previous Version:  v4.0
Current Version:  v5.0
Date of Latest Revision: 05 April 2017 (revised per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised inclusion (#4) MMSE lower 
end of range from 15 to 10
To allow for subjects with 
lower MMSE scores within 
the moderate range

Synopsis – Inclusion 
Criteria

Section 9.3.1
Clarified inclusion (#5) that the report 
of ISWRD symptoms can be from the 
subject or caregiver
To be consistent with ICSD 
definition

Synopsis – Inclusion 
Criteria

Section 9.3.1
Clarified exclusion (#20) the type of 
surgery that would be prohibited
For clarity

Synopsis – Exclusion  
Criteria

Section 9.3.2
Clarified exclusion (#22) of
concomitant treatments for ISWRD that 
are prohibited
For clarity

Synopsis – Exclusion  
Criteria

Section 9.3.2

Appendix 3
Revised the screening and baseline 
window
For flexibility in scheduling 

Synopsis – Study Design

Section 9.1

Section 9.1.1.1

Section 9.1.2.3

Figure 3

Table 3
Revised prohibited medications
To allow for subjects taking 
stable doses of medications 
used to treat ISWRD-related 
symptoms but who continue to 
manifest ISWRD symptoms

Synopsis – Concomitant 
Drug/Therapy

Section 9.4.7.2
Clarified instructions Site are to give to 
subjects for actigraphy and log
For clarity

Synopsis – Study Design

Section 9.1.1.1

Section 9.5.1.3
Clarified measurement of cognitive 
enhancers for PK 
For clarity

Synopsis – Bioanalytical 
Methods

Section 9.5.1.4.1

Table 2
Revised unit (days vs nights) for aWE 
throughout
For consistency throughout 
document

Synopsis – Statistical 
Methods

Section 9.7.1.1.3
Revised Schedule of Assessments 
footnote assignments
For clarity 

Table 3
Revised footnotes to clarify testing for 
glucose
It is not required to measure 
fasting glucose in this protocol

Appendix 1
Revised sponsor signature page
To reflect current sponsor 
representatives

Sponsor Signature Page
Eisai
Confidential
Page 9 of 847


Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page vi of xiii
Revision History 
Previous Version:  v3.0
Current Version:  v4.0
Date of Latest Revision: 01 Mar 2017 (revised per Amendment 02)
Change
Rationale
Affected Protocol 
Section(s)
Revised minimum criterion for 
actigraphy sleep efficiency from <75% 
to <85%
To be consistent with 
insomnia program
Synopsis – Inclusion Criteria
Section 9.3.1
Revised definition of desired 8 hours 
sleep period
For clarity 

Synopsis – Study Design

Section 9.1.2.2
Revised time of day to complete the 
sleep log
To correct instructions

Synopsis – Study Design

Section 9.1.2.2

Section 9.5.1.3
Revised name and description of 
Adjudication Committee, and added 
potential seizures as adverse events to 
be adjudicated
As requested by FDA, to 
include information on 
potential seizures for 
adjudication as potential 
symptoms of cataplexy 

Synopsis – Study Design

Synopsis – Statistical 
Methods

Section 9.2.8
Added the requirement for monitoring 
of falls
Per request of FDA and to 
explicitly evaluate this safety 
parameter in at-risk population
Table 3
Revised List of Prohibited Concomitant 
Medications (Appendix 3)
To correct lists of strong 
CYP3A inhibitors and CYP3A 
inducers
Appendix 3
Revised text regarding ECG 
interpretation categories
For clarity
Section 9.7.1.8.5
Eisai
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page vii of xiii
Revision History 
Previous Version:  v2.0
Current Version: v3.0
Date of Latest Revision: 26 Jan 2017 (revised per Amendment 01)
Change
Rationale
Affected Protocol 
Section(s)
Modified primary objective wording
For consistency
Synopsis – Primary Objectives
Section 8.1
Modified secondary objective wording 
Correction
Synopsis – Secondary Objectives
Section 8.2
Added allowance for caregiver 
informants and actigraphy data 
informants
For flexibility in caregiving 
situations without 
compromising data collection
Synopsis – Study Design, 
Inclusion Criteria for Caregivers,
Statistical Methods
Section 9.1
Section 9.1.2
Section 9.1.3
Section 9.3.1
Section 9.5.1.3
Table 3
Section 9.7.1.9
Added allowance for subjects to attend 
day care
For flexibility regarding 
daytime activities
Synopsis – Study Design
Section 9.1
Added allowance for split baseline 
visits if necessary
For flexibility regarding 
scheduling
Synopsis – Study Design
Section 9.1.2.3
Revised minimum age from 65 years to 
60 years
To enhance inclusion of mild 
AD subjects, who tend to be 
younger
Synopsis – Inclusion Criteria for 
Subjects, Study Design
Section 9.1
Section 9.3.1
Section 9.7.1.4
Revised title of Figure 2
For clarity
Section 7.1.1
Revised minimal MMSE score from 18 
to 15
To enhance inclusion of 
subjects in the moderate range 
of AD
Synopsis – Inclusion Criteria for 
Subjects
Section 9.3.1
Revised the requirement to remain in 
bed for at least 7 hours per night
To recognize that subjects may 
try to stay in bed, but may not 
be able to remain for the entire 
7 hour period
Section 9.3.1
Revised the allowable residences for 
subjects
For clarity
Synopsis – Inclusion Criteria for 
Subjects
Section 9.3.1
Added allowance for subjects with 
suicidal behavior in the past, but not 
within 10 years
To avoid excluding subjects 
unnecessarily
Synopsis – Exclusion Criteria for 
Subjects
Section 9.3.2
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page viii of xiii
Revision History 
Previous Version:  v2.0
Current Version: v3.0
Date of Latest Revision: 26 Jan 2017 (revised per Amendment 01)
Change
Rationale
Affected Protocol 
Section(s)
Added allowance for subjects with 
bundle branch block, if considered not 
clinically significant
For consistency across the  
lemborexant clinical program
Synopsis – Exclusion Criteria for 
Subjects
Section 9.3.2
Added allowance for participate of 
subjects who are enrolled in 
observational studies without treatment 
components
To avoid excluding subjects 
unnecessarily
Synopsis – Exclusion Criteria for 
Subjects
Section 9.3.2
Revised definition of Sleep 
Fragmentation Index
Correction
Synopsis – Assessments
Section 9.5.1.3
Revised definition of Wake 
Fragmentation Index
Correction
Synopsis – Assessments 
Section 9.5.1.3
Revised pharmacodynamic analysis 
wording
Clarification that all PD 
variables are efficacy variables
Synopsis – Statistical Methods
Section 9.7.1.7.2
Replaced the ADCS-CGIC with the 
Clinician’s Global Impression of 
Change Irregular Sleep-Wake Rhythm 
Disorder (CGIC-ISWRD) Scale
To focus the clinical rating of 
improvement on the symptoms 
related to ISWRD
Synopsis – Secondary Objectives, 
Exploratory Objectives, Study 
Design, Efficacy Assessments, 
Statistical Methods
Section 8.2
Section 8.3
Section 9.1.2.3
Section 9.1.3
Section 9.5.1.3
Table 3
Section 9.7.1.1.4
Section 9.7.1.6.2
Deleted “mean” from analysis of IV, 
IS, L5, M10, AMP and RA
Correction (as they are derived 
over 7 days)
Synopsis – Statistical Methods
Section 9.7.1.7.2
Revised population for caregiver 
endpoints for caregivers who do not 
live with subject
To allow for analyses based on 
caregiving situations
Synopsis – Statistical Methods
Section 9.7.1.9
Revised analysis of QT interval
Correction for consistency 
across lemborexant clinical 
program
Section 9.7.1.8.5
Added location of source data
For clarity
Section 11.5
Revised total number of sites from 25 
to 40
To assist with enrollment
Synopsis – Number of Subjects
Section 9.3
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Clinical Study Protocol
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E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
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Page ix of xiii
Revision History 
Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions:  19 Oct 2016
Change
Rationale
Affected Protocol 
Section(s)
Reworded title
To focus on the disorder of 
primary interest
Title page
Synopsis – Study Protocol Title
Added relative amplitude of the rest-
activity rhythm as a measure of the 
onset and course of treatment effect
For completeness of standard 
actigraphy measures
Synopsis – Objectives
Synopsis – Assessments
Synopsis – Statistical Methods
Section 8.2
Section 8.3
Section 9.5.1.3
Section 9.5.1.4
Section 9.7.1.1.4
Section 9.7.1.1.5
Section 9.7.1.6.2
Section 9.7.1.7
Changed exploratory objective for 
health outcomes to include caregiver 
outcomes
To clarify that caregiver 
outcomes from the EQ-5D-5L 
will be part of the exploratory 
objectives
Synopsis -- Objectives
Added text to allow determination of 
plasma concentrations of other 
cognitive enhancers in addition to 
donepezil
Per regulatory feedback 
(FDA)
Synopsis – Objectives
Synopsis – Study Design
Synopsis – Assessments
Synopsis – Bioanalytical Methods
Synopsis – Statistical Methods
Section 7.1.4.3
Section 8.3
Section 9.1.2.3
Section 9.5.1.4.1
Table 3
Section 9.7.1.1
Section 9.7.1.7
Replaced term “actiwatch” with 
“actigraph”
To ensure correct terminology
Synopsis, Study Design
Synopsis -- Assessments
Section 9.1.2
Section 9.1.3
Section 9.1.3.2
Section 9.5.1.3
Deleted statement regarding the need to 
log the time of actigraph removal
To clarify that only the times 
when the actigraph was 
returned to the wrist is 
required for the log
Synopsis -- Study Design
Section 9.1.2
Section 9.5.3
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page x of xiii
Revision History 
Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions:  19 Oct 2016
Change
Rationale
Affected Protocol 
Section(s)
Removed PSG and allowed for 
diagnostic sleep study to be conducted 
at home
To allow screening for sleep-
disordered breathing from  
subjects who would not be 
able to tolerate being 
evaluated in a sleep laboratory 
setting
Synopsis – Study Design
Synopsis – Exclusion Criteria for 
Subjects
Section 9.1.2
Section 9.2.2
Table 3
Stipulated that central scoring will 
determine whether inclusion criteria 
quality standards have been met at 
screening
For clarity
Synopsis – Study Design
Section 9.1.2
Stipulated that in addition to subjects, 
caregivers will also return to the clinic 
for the end of study visit
To correct omission
Synopsis – Study Design
Section 9.1.3.2
Revised wording to clarify that the 
Follow-up Period will include the End 
of Study visit
For clarity
Synopsis – Study Design
Deleted distinction between mild and 
moderate AD-D as inclusion criteria
To clarify that the inclusion 
criteria are to be applied to the 
diagnosis of Alzheimer’s 
disease, not to stage of disease
Synopsis – Inclusion Criteria for 
Subjects
Section 9.3.1
Changed criterion frequency of 
complaints of sleep and wake 
fragmentation to ≥ 3 days per week 
To correct a typographical 
error
Synopsis – Inclusion Criteria for 
Subjects
Changed criterion frequency for sleep-
wake fragmentation recorded by 
actigraphy to ≥ 3 days per week 
For consistency with history
Synopsis – Inclusion Criteria for 
Subjects
Section 9.3.1
Clarified that central sleep apnea (as 
well as obstructive sleep apnea) is an 
exclusion criterion, and reworded 
definition
To ensure such patients are 
appropriately excluded 
Synopsis – Exclusion Criteria for 
Subjects
Section 9.3.2
Deleted the metric of >15 events per 
hour from the exclusion criterion, 
periodic limb movement disorder 
Determined that the periodic 
limb movement index was not 
needed as an exclusion 
criterion
Synopsis -- Exclusion Criteria for 
Subjects
Section 9.3.2
Table 3
Corrected exclusion criterion for 
Apnea-Hypopnea Index (can be equal 
to 15 events/hour or greater)
To be consistent with 
conventional definition of 
moderate sleep apnea
Synopsis -- Exclusion Criteria for 
Subjects
Section 9.3.2
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page xi of xiii
Revision History 
Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions:  19 Oct 2016
Change
Rationale
Affected Protocol 
Section(s)
Added text to clarify the interval during 
which designated medications will be 
prohibited 
For consistency
Synopsis – Exclusion Criteria for 
Subjects
Synopsis – Assessments
Section 9.3.2
Stipulated that anticholinergic drugs are 
included in prohibited medications
For clarity
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.7
Added definition of an alcoholic drink
For clarity
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.7
Added details to instructions for use of 
rescue medications
Subject safety
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.7.2
Provided definition of phototherapy
For clarity
Synopsis – Concomitant 
Drug/Therapy
Provided 
definition 
of 
Sleep 
Fragmentation Index
For clarity
Synopsis – Assessments
Section 9.5.1.3
Deleted “long” from definition of sleep 
bouts
For clarity
Section 9.5.1.3
Specified that the ADCS-CGIC will be 
administered by an independent rater 
who has no access to other data or 
scores
To minimize bias when the 
ADCS-GCIC is administered
Synopsis, Assessments
Section 9.5.1.3
Deleted abbreviation, 
“aMeanDurLongAw” and inserted new 
abbreviations “aMeanDurWB” 
To ensure correct abbreviation
Synopsis, Statistical Methods
Section 9.7.1.1
Section 9.7.1.6
Changed wording for aSE endpoint, 
from “longer” to “higher”
To use appropriate unit of 
measurement
Synopsis, Statistical Methods
Section 9.7.1.1
Corrected year of Mishima et al. 
reference
To correct editorial error
Synopsis, Statistical Methods
Section 9.7.1.2
Updated list of abbreviations
For consistency with changes 
in text
Section (List of Abbreviations)
Added statement to stipulate that 
subject 
and 
caregiver 
should 
be 
informed if there is new information  
relevant to their study participation
To 
be 
consistent 
with 
information 
shared 
with 
participants in the informed 
consent forms
Section 5.3
Added that the subject will complete 
the EQ-5D-5L but not the SDI
To 
correct 
error 
(SDI 
completed by caregiver)
Section 9.1.2.3
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
Eisai
FINAL (v10.0):  20 Jun 2018
Confidential
Page xii of xiii
Revision History 
Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions:  19 Oct 2016
Change
Rationale
Affected Protocol 
Section(s)
Provided that the site on the arm where 
the actigraph is applied will be 
examined
Safety of subjects – look for 
possible local irritation
Section 9.1.3
Provided that at the end of study visit, 
actigraphy data and the sleep log will 
be transmitted to a central reader
For consistency with other 
study visits and to correct an 
omission
Section 9.1.3.2
Corrected 
wording 
of 
eC-SSRS 
exclusion criterion
For consistency
Section 9.3.2
Corrected 
description 
of 
blister 
containers; “packs” not “blisters”
Updated on basis of new 
packaging information
Section 9.4.2
Provided that a medical registration 
number in the PI curriculum vita can 
substitute for a copy of the PI’s medical 
license
To 
allow 
flexibility 
in 
collection of PI information
Section 9.4.9
Added text explaining the method of 
scoring data from an actigraph
For clarity of instruction
Section 9.5.1.3
Specified blood sample volumes and 
timing and method of collection for 
plasma 
concentration 
of 
cognitive 
enhancers
To list appropriate volumes 
following 
additional 
of 
assessments of all cognitive 
enhancers 
and 
to 
correct 
mistake in addition
Section 9.5.1.4
Table 3
Deleted bands from hematology tests
This test is not needed
Table 1
Revised 
blood 
sampling 
volume 
instructions 
to 
indicate 
that 
the 
specified volume is approximate, and 
added collection time points for Visit 5
To allow flexibility in the 
collection of blood sample 
volumes, and provide details 
of timing
Table 2
Deleted cross-reference from EOS to 
footnote “c”
To correct an inaccuracy, as 
subjects who discontinue will 
undergo an early termination 
visit
Table 3
In footnote, specified that at least 2 
days must intervene between screening 
and the Baseline Visit.
For consistency
Table 3
Clarified that sample collection for PG 
analysis is not required
To address requirement in 
Japan for samples to be 
optional
Appendix 2
Updated 
list 
of 
strong 
CYP3A4 
inhibitors
For completeness   
Appendix 3
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
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Page xiii of xiii
Revision History 
Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions:  19 Oct 2016
Change
Rationale
Affected Protocol 
Section(s)
Added Yi-gan-sun to the list of 
prohibited medications
For completeness
Appendix 3
Corrected occurrences of abbreviation 
definitions
Editorial quality
Various
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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FINAL (v10.0):  20 Jun 2018
Confidential
Page 1 of 123
1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E2006-G000-202
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study with Open-Label Extension Phase of the Efficacy and Safety of 
Lemborexant in Subjects with Irregular Sleep-Wake Rhythm Disorder and Mild to 
Moderate Alzheimer’s Disease Dementia (revised per Amendment 05)
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake,
New Jersey 07677
US
Eisai Ltd.
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire
AL10 9SN UK
(revised per Amendment 04)
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112-8088
Japan
Investigational Product:
Lemborexant (E2006)
Indication:
Irregular Sleep-Wake Rhythm Disorder
Phase:
2
Approval Date:
V1.0
V2.0
V3.0
V4.0
V5.0
V6.0
V7.0
V8.0
V9.0
V10.0
11 Aug 2016 (original protocol)
19 Oct 2016 (revised original protocol)
26 Jan 2017 (revised per Amendment 01)
01 Mar 2017 (revised per Amendment 02)
05 Apr 2017 (revised per Amendment 03)
10 Aug 2017 (revised per Amendment 04)
11 Oct 2017 (revised per Administrative Change)
17 Nov 2017 (revised per Amendment 05)
17 Nov 2017 (revised per Administrative Change)
20 Jun 2018 (revised per Amendment 06)
IND Number:
130798
EudraCT Number:
2017-003306-40 (revised per Amendment 04)
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.
Eisai
Confidential
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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Page 2 of 123
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.
E2006/lemborexant
Name of Active Ingredient
(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl) 
cyclopropanecarboxamide
Study Protocol Title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study with Open-
Label Extension Phase of the Efficacy and Safety of Lemborexant in Subjects with Irregular Sleep-
Wake Rhythm Disorder and Mild to Moderate Alzheimer’s Disease Dementia (revised per 
Amendment 05)
Investigators (revised per Amendment 05)
Core Study and Extension Phase: Investigators in North America, European Union, and Japan
Sites
Approximately 60 sites in North America, European Union, and Japan (revised per Amendments 01
and 04)
Study Period and Phase of Development (revised per Amendment 05)
Core Study:  Approximately 18 months
Extension Phase:  Up to 30 months, or until lemborexant is commercially available, or until the 
lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is 
discontinued.
Objectives
(revised per Amendments 05 and 06)
Sleep-Related Objectives
◦
To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 
10 mg (LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change 
from baseline in actigraphy-derived Sleep Efficiency (aSE) during the last week 
of treatment in subjects with ISWRD and Alzheimer’s disease dementia (AD-D). 
(revised per Amendments 01 and 06)
◦
To determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to 
PBO on the change from baseline of aSE during each week of treatment.  (revised 
per Amendment 06) 
◦
To determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to 
PBO on the change from baseline on the Sleep Fragmentation Index (SFI) during 
each week of treatment. (revised per Amendment 06)
◦
To determine the change from baseline of the mean duration of wake bouts
(aMeanDurWB) over each week of treatment.  (revised per Amendment 06)
Wake-Related Objectives 
◦
To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 
10 mg (LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change 
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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Page 3 of 123
from baseline in actigraphy-derived Wake Efficiency (aWE) during the last week 
of treatment in subjects with ISWRD and Alzheimer’s disease dementia (AD-D). 
(revised per Amendments 01 and 06)
◦
To determine the efficacy of lemborexant LEM2.5, LEM5, LEM10 and LEM15 
compared to PBO on the change from baseline of actigraphy-derived Wake 
Efficiency (aWE) during each week of treatment. (revised per Amendment 06)
◦
To determine the efficacy of LEM2.5, LEM5, LEM10, and LEM15 compared to 
PBO on the change from baseline of Wake Fragmentation Index (WFI) during 
each week of treatment. (revised per Amendments 01 and 06)
◦
To determine the change from baseline of the mean duration of sleep bouts
(aMeanDurSB) over each week of treatment.  (revised per Amendment 06)
Circadian Rhythm-Related Objectives
◦
Onset and course of treatment effect as measured by change from baseline of 
intradaily variability (IV), interdaily stability (IS), amplitude of the rest-activity 
rhythm (AMP), relative amplitude of the rest-activity rhythm (RA), and other 
actigraphy variables during each week of treatment (revised per Amendment 06)
Additional Objectives (revised per Amendment 06)
◦
To evaluate the safety and tolerability of lemborexant.
◦
To explore the effects of LEM2.5, LEM5, LEM10, LEM15 and PBO at the end of 
4 weeks of treatment (unless otherwise specified) on the following:
◦
Change from baseline of sum of activity counts and number of bouts >10 
minutes of sleep in the first 3 hours after morning waketime on each of the 
first 3 days and last 3 days of treatment as an indicator of next-morning 
residual effects.
◦
Potential rebound ISWRD in the 2 weeks following 4 weeks of treatment.
◦
Change from baseline in Clinician’s Global Impression of Change-ISWRD 
(CGIC-ISWRD) Scale on symptoms of ISWRD total score and domains.  
(revised per Amendments 01 and 06)
◦
Change from baseline of Alzheimer’s Disease Assessment Scale – Cognitive 
Subscale (ADAS-cog).
◦
Change from baseline of Mini Mental State Examination (MMSE).
◦
Change from baseline of sleep quality in caregivers as measured by the 
Pittsburgh Sleep Quality Index (PSQI).
◦
Change from baseline of caregiver burden on the Zarit Burden Interview –
short form (ZBI).
◦
Change from baseline of health outcomes of the subject and/or caregiver on 
the EuroQOL version 5D-5L (EQ-5D-5L) (subject Self Version, caregiver 
Self Version, caregiver Proxy 1 Version).
◦
Change from baseline of Mood and behavior on the Neuropsychiatric 
Inventory (NPI-10; by caregiver as proxy for the subject).
◦
Change from baseline of on the Sleep Disorders Inventory (SDI; by caregiver 
as proxy for the subject).
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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◦
Characterize the pharmacokinetics (PK) of lemborexant using the population 
approach.
◦
To explore the PK/pharmacodynamic (PD) relationship between exposure to 
lemborexant and selected efficacy variables and most frequently occurring 
treatment-emergent adverse events (TEAEs).
◦
To assess the plasma concentrations of cognitive enhancers (cholinesterase 
inhibitors and/or memantine) and lemborexant in subjects taking such drugs.
◦
To evaluate the long-term safety and tolerability of flexible doses of LEM5, 
LEM10, and LEM15 per day over a period of 30 months in subjects with ISWRD 
who have completed the Core Study. (revised per Amendments 05 and 06)
Study Design (revised per Amendment 05)
This study will consist of a Core Study and an Open-Label Extension Phase.
Core Study
E2006-G000-202 is a multicenter, randomized, double-blind, PBO-controlled, parallel-group study of 
lemborexant (4 dose levels) or PBO taken daily for 4 weeks in approximately 60 male or female 
subjects, ages 60 to 90 years, with mild or moderate AD-D who complain of disrupted sleep or 
multiple awakenings at night along with frequent periods of falling asleep during the day that impact 
the quality of life of the subject.  For each subject, an individual who knows the subject well and will 
provide the information about themselves will also be enrolled in the study (Caregivers and 
Informants – see below).  Additional Informants may also be associated with the study, but will not 
be required to complete a consent form. (revised per Amendments 01 and 06)
The study will have 3 phases:
the Prerandomization Phase, the Randomization Phase, and the 
Extension Phase. The Prerandomization Phase will comprise 2 periods that will last up to a 
maximum of 42 days: a Screening Period and a Baseline Period. The Randomization Phase will 
comprise a Treatment Period during which subjects will be treated for 4 weeks, and a minimum 14-
day Follow-Up Period before an End of Study visit. The Extension Phase will consist of a 30-month
Maintenance Period and a 14-day Follow-Up Period. (revised per Amendments 03 and 05)
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will undergo 
routine safety assessments at specified visits, including questioning regarding adverse events (AEs) 
and suicidality, 12-lead electrocardiograms (ECGs), vital signs, weight, clinical hematology and 
chemistry analysis; and urinalysis.
Subjects will not be excluded if they attend adult day care as long as the day care staff can ensure that 
the actigraph remains on the subject’s wrist and, if removed, is returned as promptly as possible, with 
notation of the time of the replacement noted for inclusion on the sleep log.  (revised per 
Amendment 01)
Caregivers and Informants (revised per Amendment 01)
For the subject to participate in the study, there must be 1 or more persons who can provide the 
required information for assessments, complete the sleep log, and ensure that the subject is dosed at 
the appropriate time.  These roles can be fulfilled by the same or different individuals. For each 
subject, one individual will be designated as the “caregiver informant” (or “caregiver”), who will be 
sufficiently familiar with the subject to provide information to the site staff with respect to the 
subject’s sleep and wake patterns, behavior, mood, AEs, and quality of life.  Typically, the caregiver 
informant will need to spend at least 10 hours per week with the subject. 
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Clinical Study Protocol
(Per Amendment 06)
E2006-G000-202
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Page 5 of 123
If the caregiver informant does not reside with the patient, then the other informant(s) will be
responsible for ensuring that the sleep log is completed daily and that dosing occurs at the appropriate 
time.  There can be more than one such informant, as in the case of home health aides who stay with 
the subject during the week and change on the weekend. 
If the individual who is originally designated as the caregiver informant cannot fulfill the function, 
he/she may be replaced by a suitable alternate until the Baseline Visit, and thereafter only following 
consultation with the Sponsor.
Optional Prescreening
There may be circumstances where the subject and/or caregiver is not sure whether the subject has an 
ISWRD pattern of sleep and wake, and would benefit from reviewing a report on the subject’s 
sleep/wake pattern before agreeing to participate in the study.  In these cases, the sites can offer the 
subject an opportunity to wear a designated activity tracker before consenting to the rest of the study 
procedures.  A separate prescreening consent form would be signed by the subject and his/her legal 
representative for this purpose.  After wearing the device for approximately 4 days, the subject and 
caregiver would be scheduled to return to the clinic so that the output from the device can be 
reviewed.  At that time, the subject and caregiver would decide whether to participate in the study,
which will require the study consent forms to be completed as described above.
(revised per 
Amendment 05)
Screening Period 
The maximum duration of the Screening Period will be 42 days.  At the first visit, informed consent 
will be obtained after the study has been fully explained to each subject and caregiver and before the 
conduct of any screening procedures or assessments.  Subjects or their legal representative will sign 
informed consent; caregivers must sign a separate consent form.  A medical, psychiatric, and sleep 
history interview will be conducted, and will include confirmation that the subject meets diagnostic 
criteria for Circadian Rhythm Sleep Disorder, Irregular Sleep Wake Type.  The clinician will confirm 
that the subject meets diagnostic criteria for AD-D, based on the National Institute on 
Aging/Alzheimer’s Association Diagnostic Guidelines.  If necessary, investigators may order a 
computed tomography (CT) scan and relevant blood tests to rule out other possible causes of 
dementia. Subjects will be administered the MMSE and the electronic Columbia -Suicide Severity 
Rating Scale (eC-SSRS), and will undergo the subject component of the Cornell Scale for Depression 
in Dementia (CSDD) interview.  Additional eligibility criteria and clinical laboratory tests, ECG, vital 
signs, height, and weight will be assessed.  Caregivers will be administered the caregiver input 
component of the CSDD.  (revised per Amendments 03 and 05)
Eligible subjects will be provided with an actigraph to wear continuously throughout the study.  They 
will be asked to provide a typical (habitual) time when the subject goes to sleep at night. (revised per 
Amendments 02 and 05)
The appropriate informants will be provided with a daily log (sleep log) to note the start and end 
times of the subject’s actual time in bed each day during the night, and to log the approximate times 
that the actigraph was replaced on the subject’s wrist, if inadvertently removed.  The informants will 
be trained in the use of the actigraph and the log.  Site staff will instruct informants (1) in the evening, 
to fill in the times when the actigraph was not worn; and (2) in the morning, to fill out the bedtimes 
and morning rise times, and will emphasize the importance of doing so.  Sites will also arrange for 
the subject to undergo a diagnostic sleep study either at a sleep center or at home, to determine the 
presence or absence of sleep apnea, unless a diagnostic sleep study has been obtained within the 
previous 6 months.  Before randomization, the investigator will be required to review a report 
detailing the subject’s apnea-hypopnea index. (revised per Amendments 01, 02, 03, and 05)
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After subjects have had the actigraph for at least 14 days, caregivers will return to the clinic.  The 
actigraph data will be downloaded and transmitted to the central reader along with the sleep log of 
bedtimes, morning waketimes, and the approximate times when the actigraph was replaced on the 
subject’s wrist.  Adverse event and concomitant medication use will be recorded. The sites will keep 
the actigraph at the clinic until the Baseline visit, when the device will again be provided to the 
subjects.  The central scoring will determine whether the data from the screening period meet the 
quality standards required by the inclusion criteria. (revised per Amendments 01 and 05)
During the Screening Period, subjects who meet the eligibility criteria for ISWRD on the basis of 
actigraphy and are not excluded on the basis of the diagnostic sleep study for sleep apnea will then be 
scheduled for the Baseline visit.  Subjects who did not meet eligibility criteria based on actigraphy 
may be rescreened following consultation with the Sponsor as long as they were not excluded based 
on the apnea-hypopnea index (AHI). (revised per Amendment 05)
Baseline Period
On Day 1, the Screening Period will end and the Baseline Period will take place.  The Baseline visit 
must occur no earlier than 2 days and no later than 27 days after Visit 2 (caregiver visit), and may be 
scheduled across 2 consecutive days if necessary. Clinical laboratory tests, an ECG, vital signs, and 
weight will be assessed.  Adverse events and concomitant medications will be queried and the site on 
the arm where the actigraph is applied will be examined.  A plasma sample will be obtained from any 
subject taking one or more cognitive enhancers and will be used to measure plasma concentrations of 
the cognitive enhancer(s).  As proxy for the subject, caregivers will complete the SDI, EQ-5D-5L 
(Proxy 1 Version), and the NPI-10. The caregiver will also complete the self-version of the EQ-5D-
5L, the ZBI, and the PSQI for himself/ herself.  The subject will be administered the ADAS-cog and
the EQ-5D-5L (Self version). The CGIC-ISWRD rater will complete the baseline assessment for the 
Clinician’s Global Impression of Change -ISWRD Scale.  (revised per Amendments 01 and 03)
Treatment Period
The Treatment Period will begin on the evening of Day 1 and will continue for 4 weeks.  Subjects 
will be randomized, in a double-blind manner, to receive LEM2.5, LEM5, LEM10, LEM15, or PBO.  
Study drug will be dispensed to the caregiver.  During the Treatment Period, subjects will take study 
drug each night immediately (ie, within 5 minutes) before bedtime (defined as the median calculated 
bedtime [MCB]) calculated based on the sleep log during Screening.  Time of dosing will be 
collected on the sleep log and entered into the appropriate electronic case report form (eCRF) by the 
sites.(revised per Amendments 01 and 05)
After approximately 2 weeks of the Treatment Period, caregivers and subjects will return to the 
clinic.  The actigraph data will be downloaded and transmitted to the central reader along with the 
sleep log.  Vital signs will be assessed at this visit.  AEs, treatment compliance, and concomitant 
medication use will be recorded.
The site on the arm where the actigraph is applied will be 
examined.  
If the subject experiences an AE that results in a temporary discontinuation of study medication, a 
rechallenge is possible following consultation with the Medical Monitor. (revised per Amendment 
05)
At the end of 4 weeks, subjects will return to the clinic with their caregivers for end of Treatment 
Period assessments.  Clinical laboratory tests, an ECG, vital signs, and weight will be assessed, and 
AEs and concomitant medications will be recorded. The site on the arm where the actigraph is 
applied will be examined. Treatment compliance will be assessed.  As proxy for the subject, 
caregivers will complete the SDI, the NPI-10 and the EQ-5D-5L (Proxy 1 Version).  The caregiver 
will also complete the EQ-5D-5L (Self Version), ZBI-short, and PSQI for himself/ herself. Subjects 
will be administered the MMSE, EQ-5D-5L (Self Version), ADAS-cog, and eC-SSRS.  A PK sample 
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will be obtained.  The CGIC-ISWRD Scale rater will complete the CGIC-ISWRD Scale. The 
actigraph data will be downloaded and transmitted to the central reader along with the sleep log, and 
the actigraph will be returned to the subject for the Follow-Up Period. (revised per Amendment 01)
During the End of Treatment visit, the study staff will discuss the Extension Phase with potentially 
eligible subjects and caregivers.  (revised per Amendment 05)
Follow-Up Period
The Core Study Follow-Up Period will begin when subjects leave the clinic at the end of the 
Treatment Period. Subjects will cease taking study drug but will continue to wear the actigraph until 
the End of Study visit.  (revised per Amendment 05)
At least 14 days but no more than 18 days after the end of the Treatment Period, subjects and 
caregivers will return to the clinic for the End of Core Study Visit.  Clinical laboratory tests, an ECG, 
vital signs, and weight will be assessed, and AEs and concomitant medications will be recorded. The 
site on the arm where the actigraph is applied will be examined. Actigraphy data will be downloaded
and transmitted to the central reader along with the sleep log.  (revised per Amendment 05)
A subject who prematurely discontinues taking study drug should return to the clinic as soon as 
possible after discontinuing study drug, to complete an Early Termination Visit and a Follow-Up 
Visit after 14 days.  If the subject discontinues from the study due to an AE, the subject must 
complete an Early Termination Visit, and the AE must be followed to resolution or for 2 weeks, 
whichever comes sooner. (revised per Amendment 05)
Adjudication Committee (revised per Amendments 02 and 06)
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure. A set of preferred terms 
constituting a customized Medical Dictionary for Regulatory Activities (MedDRA) query for 
cataplexy or seizure will be used to identify events for adjudication (including cataplexy, muscle 
fatigue, muscular weakness, muscle tone disorder, hypotonia, drop attacks, slurred speech, diplopia, 
falls, convulsions [standardized MedDRA query (SMQ) narrow and broad], atypical migraine, loss of 
consciousness, decreased consciousness, myoclonus, syncope, transient global amnesia, lipothymia, 
[faintness] and transient ischemic attack). To assist in the preparation of narratives about such events 
and to support the committee’s adjudication process, investigators and site staff will be instructed to 
query subjects who report any of the above events for supplemental information using a questionnaire 
for events potentially related to cataplexy and the serious adverse event (SAE) form for any of the 
above events considered serious.  (revised per Amendments 02 and 06)
End of Core Study  (revised per Amendment 05)
Estimates for end of study are as follows: 

The study will begin in approximately December 2016.

The end of the study will be the date of the last study visit for the last subject in the study.

Approximately 60 subjects (60 to 90 years) with ISWRD will be randomized to lemborexant 
or PBO for 4 weeks (revised per Amendments 01 and 06)

The estimated duration for each subject in the Core Study is anticipated to be a maximum of
93 days/13.3 weeks (Screening Period maximum of 42 days plus Treatment Period [maximum 
33 days] plus Follow-Up Period [maximum 18 days including End of Study visit]).  (revised 
per Amendments 03 and 05)
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Extension Phase (revised per Amendment 05)
The Extension Phase comprises a 30-month Maintenance Period and a 14-day Follow-Up Period.
Design and Plan
Subjects who complete the Core Study End of Study (EOS) Visit within 30 days prior to enrollment 
in the Extension Phase will be eligible for participation.  Subjects who complete the Core Study, but 
who do not elect to immediately continue into the Extension Phase, have up to 30 days after the End 
of Study Visit to enroll.  Such subjects will be required to return to the site within 30 days of 
completion of the Core Study, and will repeat selected assessments before being dispensed drug for 
the Extension Phase.
Maintenance Period
During the Maintenance Period, all subjects initially will receive lemborexant 10 mg/day (LEM10).  
At the discretion of the investigator, subjects will have the option of increasing the dose to 
lemborexant 15 mg/day (LEM15) or decreasing the dose to lemborexant 5 mg/day (LEM5).  All dose 
adjustments will be performed at an Unscheduled Visit or at the next scheduled visit.  The dose can 
be adjusted more than once during the Extension Phase.
All doses will be taken orally in tablet form each night for the duration of the Extension Phase 
immediately (ie, within 5 minutes) before the time the subject intends to sleep.  Subjects will receive 
1 or 2 tablets as described below:

LEM5:  one lemborexant 5-mg tablet

LEM10:  one lemborexant 10-mg tablet

LEM15:  one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
Study visits, either in person or by telephone, will be conducted according to the Schedule of 
Procedures and Assessments for the Extension Phase.  If the phone visit indicates an ongoing AE, the 
subject should be brought to the clinic for an Unscheduled Visit.  Subjects may discontinue from 
study drug for any reasons.  A subject who prematurely discontinues taking study drug should return 
to the clinic within 2 weeks of discontinuation to complete an Early Termination Visit.  The 
assessments of the Early Termination Visit are the same as those for the EOS Visit of the Core Study.  
If the subject discontinues from the study due to an AE, the subject must complete an Early 
Termination Visit, and the AE must be followed to resolution or for a period of 4 weeks, whichever 
comes sooner.
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Follow-up Period
The Follow-Up Period will be 14 to 18 days in duration, and begins when subjects leave the clinic at 
the end of the Maintenance Period.  At least 14 days but no more than 18 days after the end of the 
Maintenance Period, subjects and caregivers will return to the clinic for the End of Study Visit, 
including the recording of AEs and concomitant medications, and assessment of clinical laboratory 
tests, vital signs and weight, suicidality, and will undergo an ECG.  
Treatment in the Extension Phase will last for a maximum duration of 30 months, until lemborexant 
is commercially available, or until the lemborexant clinical development program for ISWRD is 
discontinued.
Number of Subjects
It is expected that approximately 230 subjects will be screened to provide 60 randomized subjects. 
(revised per Amendment 06)
Subjects will be randomized to one of the following treatment arms: PBO, LEM2.5, LEM5, LEM10, 
or LEM15, in an approximate 1:1:1:1:1 ratio, stratified by country.  (revised per Amendment 05)
Inclusion Criteria for Subjects (Core Study) (revised per Amendment 05)
1.
Male or female, age 60 to 90 years at the time of informed consent (revised per 
Amendment 01)
2.
Able to provide informed consent.  If a subject lacks capacity to consent in the investigator's 
opinion, the subject's assent should be obtained, if required in accordance with local laws, 
regulations and customs, and the written informed consent of a legal representative should be 
obtained (capacity to consent and definition of legal representative should be determined in 
accordance with applicable local laws and regulations).
3.
Documentation of diagnosis with AD-D on the basis of the National Institute on 
Aging/Alzheimer’s Association Diagnostic Guidelines
4.
MMSE 10 to 26 at Screening (revised per Amendments 01 and 03)
5.
Meets criteria for Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type (Diagnostic 
and Statistical Manual of Mental Disorders – 5th edition [DSM-5]) and the 10th revision of 
the International Classification of Diseases (ICD-10), as follows: Complaint by the subject or 
caregiver of difficulty sleeping during the night and/or excessive daytime sleepiness 
associated with multiple irregular sleep bouts during a 24-hour period (revised per 
Amendment 03)
6.
Frequency of complaint of sleep and wake fragmentation ≥3 days per week
7.
Duration of complaint of sleep and wake fragmentation ≥3 months
8.
During the Screening Period, mean aSE <87.5% within the defined nocturnal sleep period 
and mean aWE <87.5% during the defined wake period (revised per Amendments 02 and 05)
9.
Confirmation by actigraphy of a combination of sleep bouts of >10 minutes during the wake 
period plus wake bouts of >10 minutes during the sleep period, totaling at least 4 bouts per 
24 hours period, ≥ 3 days per week
10. Ambulatory and living in the community or in a residence not classified as a skilled nursing 
facility (an assisted living facility with separate living quarters where subjects and their 
caregivers reside is acceptable) (revised per Amendment 01)
11. Willing not to start a behavioral or other treatment program for sleep or wake difficulties and 
not to start a new treatment for other symptoms of AD-D during participation in the study
12. Has a reliable and competent caregiver (or caregiver and informants) who can accompany the 
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subject to study visits, administer study medication on a nightly basis and provide 
information on the status of the subject (revised per Amendment 01)
13. For subjects taking a cholinesterase inhibitor and/or memantine, dosing regimen must have 
been stable for at least 3 months
Inclusion Criteria for Caregivers 
14. Able to provide informed consent
15. Spends at least 10 hours per week with the subject (revised per Amendment 01)
16. Able to meet caregiver requirements (Subject inclusion criterion #13)
17. Willing to provide information on himself/herself regarding sleep quality and caregiver 
burden
Inclusion Criteria for Subjects (Extension Phase) (revised per Amendment 05)
1.
Completed the Core Study (EOS Visit).  Subjects who participated in the Core Study and 
completed the EOS Visit within 30 days may return to participate in the Extension Phase as 
long as there are no contraindications due to ongoing adverse events or prohibited 
medications.  (revised per Amendment 05)
Exclusion Criteria for Subjects 
1.
A diagnosis of vascular dementia, dementia following multiple strokes,
or any 
synucleinopathy / Lewy body disorder. This includes Dementia with Lewy Bodies and 
Parkinson’s disease with or without dementia.
2.
A current diagnosis of moderate to severe obstructive sleep apnea (OSA) or central sleep 
apnea, or current use of continuous positive airways pressure even if mild severity of OSA, 
restless legs syndrome, periodic limb movement disorder (with awakenings), or narcolepsy
3.
An Apnea-Hypopnea Index or equivalent ≥15 events/hour on diagnostic sleep study 
conducted prior to Baseline or within 6 months of Screening 
4.
A clinically significant movement disorder that would affect the differentiation of sleep and 
wake by the actigraphy analytic algorithm
5.
Current symptoms or history during the past year of Rapid Eye Movement (REM) Behavior 
Disorder or sleep-related violent behavior 
6.
Probable Major Depression, as evidenced by score >10 on the CSDD at Screening
7.
Unable to tolerate wearing the actigraph.  At a minimum, subjects must be able to wear the 
actigraph for 5 complete days out of 7 days’ data.  A day will be considered complete as long 
as data from 90% of the 24-hour period are able to be scored.
8.
Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
ISWRD
9.
History of drug or alcohol dependency or abuse within approximately the previous 2 years
10. Reports habitually consuming more than 14 drinks containing alcohol per week or habitually 
consumes alcohol within 3 hours before bedtime and unwilling to limit alcohol intake to 2 or 
fewer drinks per day or forego having alcohol within 3 hours before bedtime for the duration 
of his/her participation in the study
11. Known to be human immunodeficiency virus positive
12. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
13. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at 
Screening (repeated only if initial ECG indicates a QTcF interval >450 ms) (subjects with 
evidence of bundle branch block are not excluded if the block is not clinically significant, as 
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documented by the investigator in the source document) (revised per Amendment 01)
14. Current evidence of clinically significant disease that in the opinion of the investigator(s) 
could affect the subject’s safety or interfere with the study assessments
15. Any history of a medical or psychiatric condition other than Alzheimer’s Disease dementia 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments
16. History of  malignancy within the previous 5 years except for adequately treated basal cell or 
squamous cell skin cancer or cervical carcinoma in situ
17. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of 
Screening, as indicated by answering “Yes” to questions 4 and 5 on the Suicidal Ideation 
section of the eC-SSRS
18. Any suicidal behavior within the past 10 years based on the eC-SSRS (revised per 
Amendment 01)
19. History of violence toward the caregiver or others
20. Scheduled for surgery using general anesthesia during the study (revised per Amendment 03)
21. Used any prohibited prescription or over-the-counter concomitant medications within 1 week 
or 5 half-lives, whichever is longer, before starting actigraphy during Screening.  (A list of 
prohibited concomitant medications is presented in Appendix 3 of the protocol.)
22. Used any modality of treatment for ISWRD between Screening and Randomization based on 
approaches related to circadian rhythms, including phototherapy (light therapy), melatonin 
and melatonin agonists  (revised per Amendment 03)
23. Failed treatment with Belsomra® (efficacy and/or safety) following treatment with an 
appropriate dose and of adequate duration in the opinion of the investigator
24. Transmeridian travel across more than 3 time zones between Screening and Randomization, 
or plans to travel across more than 3 time zones during the study
25. Hypersensitivity to lemborexant or to its excipients
26. Currently enrolled in another clinical trial, except for observational studies with no treatment 
component (revised per Amendment 01)
27. Used any investigational drug or device before informed consent (ie, within 30 days or 5× the 
investigational drug half-life whichever is longer or 6 months for potential disease-modifying 
drugs)
28. Previously participated in any clinical trial of lemborexant 
Study Treatment(s)
Lemborexant 2.5 mg, 5 mg, 10 mg, 15 mg, or lemborexant-matched PBO treatments will be taken 
orally in tablet form each night for 28 consecutive nights immediately (ie, within 5 minutes) before 
the time the subject intends to try to sleep.  All subjects will receive 2 tablets as described below, 
according to the treatment arm to which the subject has been randomized:
LEM2.5: one lemborexant 2.5-mg tablet and one lemborexant-matched placebo tablet 
LEM5: one lemborexant 5-mg tablet and one lemborexant-matched placebo tablet
LEM10: one lemborexant 10-mg tablet and one lemborexant-matched placebo tablet
LEM15: one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
PBO: two lemborexant-matched placebo tablets
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Extension Phase (revised per Amendment 05)
During the Maintenance Period, all subjects initially will receive lemborexant 10 mg per day 
(LEM10).  At the discretion of the investigator, subjects will have the option of increasing the dose to 
lemborexant 15 mg per day (LEM15) or decreasing to lemborexant 5 mg per day.  All dose 
adjustments will be performed at an unscheduled visit or at the next scheduled visit.  The dose can be 
adjusted more than once during the Extension Period.
All doses will be taken orally in tablet form each night for the duration of the Extension Phase, 
immediately (ie, within 5 minutes) before the time the subject intends to sleep.  Subjects will receive 
1 or 2 tablets as described below:
• LEM5: one lemborexant 5-mg tablet
• LEM10: one lemborexant 10-mg tablet
• LEM15: one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
Duration of Treatment (revised per Amendment 05)
Core Study:  A maximum of approximately 4 weeks
Extension Phase:  Up to 30 months, or until lemborexant is commercially available, or until the 
lemborexant clinical development program for ISWRD is discontinued.
Concomitant Drug/Therapy
Potential subjects who are taking a cholinesterase inhibitor and/or memantine will be allowed in the 
study provided that the treatment regimen has been stable for at least 3 months. 
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a maximum 
of 2 alcohol-containing drinks on a given day while in the study, and will be instructed not to 
consume any alcohol within 3 hours before bedtime.  Because the definition of a standard drink 
varies among countries and regions, no definition of the volume or alcohol content of a standard 
drink is provided, with the exception of Japan.  For sites and subjects in Japan, a drink will be defined 
as 360 mL of beer, 150 mL of wine, or 50 mL of liquor.
Prohibited medications include anticholinergic drugs, moderate and strong CYP3A inhibitors and all 
CYP3A inducers.  Prohibited therapies include any treatment for ISWRD that is based on modifying 
circadian rhythms, including bright light therapy, melatonin and melatonin agonists. In this context, 
phototherapy refers specifically to the use of timed bright light as a therapeutic intervention. The 
prohibition applies even if the entire class to which that medication belongs is not prohibited (eg, 
anticonvulsants).  (revised per Amendments 03 and 06)
Medications that are used to treat behaviors associated with ISWRD, such as antipsychotic 
medications or trazodone, are permitted provided that the subject has been taking a stable dose for at 
least 1 month.  (revised per Amendment 03)
If a medication is not on the list of prohibited medications but, in the opinion of the investigator, 
causes or exacerbates the subject’s ISWRD, it must not be used throughout the study.  If a medication 
is not specified as prohibited but is in the same class as a medication that is listed in Appendix 3 of 
the study protocol, and if the investigator is uncertain whether the medication has known sedating or 
alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy that would compromise the safety of the 
subject, he/she must discontinue from the study, with the exception that certain prohibited 
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medications may be used for a short duration (not to exceed 2 weeks) to treat an acute condition if 
this is agreed with the Medical Monitor.  Note that moderate and strong CYP3A inhibitors and 
CYP3A4 inducers will not be permitted at any time for any duration during the study. (revised per 
Amendment 06)
If not used daily, benzodiazepines and non-benzodiazepine hypnotics and antipsychotics may be used 
as rescue medications to treat significant agitation or anxiety. The lowest effective dose should be 
used, for the shortest effective period of time, and for no more than 3 days per week. Before 
prescribing, whenever practicable, the investigator should discuss the proposed rescue medication 
with the Medical Monitor. If a rescue medication has been taken within 24 hours of a scheduled study 
visit, the timing of this visit should be adjusted.  (revised per Amendment 03)
Phototherapy is prohibited during the study.  In this context, phototherapy refers specifically to the 
use of timed bright light as a therapeutic intervention.
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Assessments
Efficacy Assessments (revised per Amendment 05)
Actigraphy
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity monitor 
which looks like a wrist watch. This device incorporates a multidirectional accelerometer to monitor 
degree and intensity of motion.  Data from an actigraph are collected at a sampling rate of 30 seconds 
and are scored as sleep or wake with a validated algorithm. Sleep/wake parameters are calculated 
from the scored data. 
A central actigraphy reader will score daily actigraphy records using a customized algorithm.  The 
in-bed intervals will be provided to the central reader based on the sleep logs completed by the 
caregivers.  The actigraphy data obtained during the Screening Period will be used to a) determine 
eligibility and b) derive baseline actigraphy parameters for those subjects who are randomized.  The 
nocturnal sleep period will be defined for each subject as the 8 hours starting with the subject’s MCB, 
calculated from the sleep log completed during screening. (revised per Amendment 05)
Also note that the calculated MCB will determine time of dosing for a given subject such that the 
dose each night should be taken within 5 minutes before bedtime.  (revised per Amendment 05)  

Sleep efficiency (aSE): 100% × the total duration of sleep epochs during the predefined 8-
hour nocturnal sleep period, divided by 8 hours (revised per Amendment 05)

SFI from actigraphy: The SFI will be calculated as the sum of a Movement Index (MI) and a 
Fragmentation Index (FI), with MI = (epochs of wake per TIB)*100 and FI = (number of
≤1 minute periods of immobility/total number of periods of immobility of all durations
during the defined nocturnal sleep period)*100 (revised per Amendments 01 and 05)

WFI from actigraphy:  The WFI will be calculated as the sum of an Immobility Index (II) and 
a FI, with II = (epochs of immobility per the 16 hours outside of the defined sleep 
period)*100 and FI = (number of ≤1-minute periods of mobility/total number of periods of 
mobility of all durations during the 16 hours outside of the defined sleep period)*100 
(revised per Amendments 01 and 05)

aWE: 100% × the total duration of wake epochs during the defined wake period (ie, the 16 
hours outside of the predefined sleep period) divided by 16 hours (revised per Amendment 
05)

Mean Duration of Wake Bouts (aMeanDurWB): average duration of all wake bouts (with 
wake bout defined as continuous wake of 10 minutes or longer) that occur during the 
predefined nocturnal sleep period  (revised per Amendment 05)

Mean Duration of Sleep Bouts (aMeanDurSB):
average duration of all sleep bouts (with 
sleep bout defined as continuous sleep of 10 minutes or longer) that occur during the 16 
hours outside of the predefined nocturnal sleep period (revised per Amendments 01 and 05, 
and Administrative Change)

Intradaily Variability (IV): gives an indication of ISWRD by quantifying the number and 
strength of transitions between rest and activity bouts, with a higher number indicating more 
fragmentation; derived by the ratio of the mean squares of the difference between all 
successive hours (first derivative) and the mean squares around the grand mean (overall 
variance)

Interdaily Stability (IS): gives an indication of the stability of the sleep-wake rhythm across 
days, and varies from zero (low stability) to 1 (high stability); derived by the ratio between 
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the variance of the average 24-hour pattern around the mean and the overall variance

L5: the average activity across the least active 5-hour period per 24 hour period with high 
values indicating restlessness  

M10: the average activity during the most active 10-hour period per 24 hour period, with 
low levels indicating inactivity

AMP: amplitude of the rest-activity rhythm calculated as the difference between M10 and 
L5

RA: relative amplitude of the rest-activity rhythm calculated as the difference between M10 
and L5 divided by M10 plus L5.
CGIC-ISWRD Scale (revised per Amendment 01)
The CGIC-ISWRD Scale uses the standardized methodology for obtaining global clinical ratings, 
and is an assessment conducted at the end of the treatment period by an independent rater who has no 
access to the source data or other psychometric test scores conducted as part of the given protocol.  
The instrument consists of 3 parts: a guided baseline interview administered to the subject and an 
informant, a follow-up interview administered to the subject and an informant, and a clinician’s rating 
review.  The informant must be a person who knows the subject well.  The baseline interview serves 
as a reference for future ratings.  During the baseline interview, the rater will evaluate subjects 
regarding domains of (1) sleep and wake symptoms; (2) mood and behavioral symptoms; (3) 
attention/arousal; and (4) social functioning.  In the follow-up interview, a 7-point scale is used, from 
1 = marked improvement, 4 = no change, to 7 = marked worsening, to score each of the four domains 
and to provide an overall score.  The overall score is used to address the secondary objective; the 
domain scores are exploratory.  In this study, the assessment will focus on the symptoms of ISWRD, 
not the general condition of dementia. (revised per Amendment 01)
Neuropsychiatric Inventory (NPI-10)
The NPI-10 assesses a wide range of behaviors seen in dementia for both frequency and severity. 
These include delusions, agitation, depression, irritability and apathy. The scale takes approximately 
10 minutes for a clinician to administer. This scale will be administered with the caregiver as proxy 
for the subject.  The NPI-10 has good psychometric properties and is widely used in drug trials. 
(revised per Amendment 01; revised to be an efficacy assessment in Amendment 05)
Mini Mental State Examination
The MMSE is a cognitive instrument commonly used for screening purposes. It is a 30-point scale 
with higher scores indicating less impairment and lower scores indicating more impairment.  Seven 
items are assessed that measure orientation to time and place, registration, recall, attention, language,
and drawing. The MMSE will be administered to the subject by site staff. (Revised to be an efficacy 
assessment in Amendment 05)
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog) 
The ADAS-cog is the most widely used cognitive scale in Alzheimer's disease trials.  It is a 
structured scale that evaluates memory (word recall, delayed word recall, and word recognition), 
reasoning (following commands), language (naming, comprehension), orientation, ideational praxis 
(placing letter in envelope) and constructional praxis (copying geometric designs).  Ratings of spoken 
language, language comprehension, word finding difficulty, ability to remember test instructions, 
maze, and number cancellation are also obtained.  The modified version (ADAS-cog-13) used in this 
study is scored from 0 to 90 points with a score of 0 indicating no impairment, and a score of 90 
indicating maximum impairment. (Revised to be an efficacy assessment in Amendment 05)
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Sleep Disorders Inventory (SDI)
The SDI is an expanded version of one item of the NPI. It describes the frequency, severity, and 
caregiver burden of sleep-disturbed behaviors during a period prior to its administration. The SDI 
consists of the seven subquestions from the NPI sleep disturbance item. Each of the subquestions is a 
separate question with frequency, severity, and caregiver distress rated by the caregiver with respect 
to the patient-participant for the 2 weeks prior to the visit. (Revised to be an efficacy assessment in 
Amendment 05)
Pharmacokinetic Assessments (Core Study only) (revised per Amendment 05)
A blood sample for plasma concentrations of lemborexant and its metabolites M4, M9 and M10 will 
be taken at the end of treatment visit.  The time and date of the 2 most recent doses before this sample 
and the time and date of the sample will be documented.  
One blood sample (approximately 4 mL) will be obtained at  Baseline (Visit 3) for only those 
subjects taking specific cognitive enhancers (ie, donepezil or galantamine or memantine alone or both 
donepezil and memantine or both galantamine and memantine).  Another blood sample 
(approximately 4 mL) will be obtained at Visit 5 or ET for all subjects to measure lemborexant and 
its metabolites, as well as cognitive enhancers, as appropriate. (revised per Amendments 03 and 05)
For those subjects taking donepezil, the date and time of the 2 most recent doses of donepezil will be 
documented. For all subjects taking lemborexant, the date and time of the 2 most recent doses of 
lemborexant will also be documented. (revised per Amendment 03)
In case of early termination due to safety or any other reasons, a plasma sample for lemborexant (and
its metabolites), and for any cognitive enhancer (as applicable) will be taken from the subject.
Pharmacodynamic Assessments
For modeling purposes, the change from baseline at the last week of treatment for the following 
efficacy variables aSE, aWE, SFI, WFI, IV, IS, AMP, and RA will be treated as PD variables.
Pharmacokinetic/Pharmacodynamic Assessments
For PK/PD assessments, the following efficacy variables aSE, aWE, SFI, WFI, IV, IS, AMP, and RA
will be treated as PD variables.
Pharmacogenomic/Pharmacogenetic Assessments
Blood samples for genotyping and for additional exploratory analyses will be obtained at Baseline
from consenting subjects.  
Safety Assessments (revised per Amendment 05)
All subjects will undergo routine safety assessments at specified visits, including queries for AEs, 
ECGs, vital signs, weight, clinical hematology and chemistry analysis and urinalysis, and suicidality 
assessed using the eC-SSRS.  
Safety assessments as listed above will be the only assessments conducted during the Extension 
Phase. (revised per Amendment 05)
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) assesses an individual’s degree of suicidality, 
including both suicidal ideation and suicidal behavior.  The electronic version of the questionnaire 
(ie, the eC-SSRS) will be completed by the subject with caregiver input. (revised per Amendment 
05)
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Morning Residual Effects
To assess morning residual effects, activity levels from the first 3 hours after waketime during the 
first 3 days of the first week of treatment and the same time interval during the last 3 days of 
treatment will be compared with the mean activity levels from the first 3 hours after waketime during 
the actigraphy baseline period.  (revised per Amendment 05)
Other Assessments (revised per Amendment 05)
Cornell Scale for Depression in Dementia (CSDD)
The CSDD derives information from the patient and the informant (caregiver) to assess signs and 
symptoms of major depression in patients with dementia.  Information is elicited through two 
semi-structured interviews; an interview with an informant and an interview with the patient, both of 
which focus on depressive symptoms and signs that occurred during the week preceding the 
interview.  The final ratings of the CSDD items represent the rater’s clinical impression rather than
the responses of the informant or the patient.  The CSDD, which takes approximately 20 minutes to 
administer, assesses a total of 19 items in the following 5 categories: mood-related signs, behavioral 
disturbance, physical signs, cyclic functions, and ideational disturbance.  Each item within each 
category is rated for severity on a scale of 0-2 (0=absent, 1=mild or intermittent, 2=severe).  The item 
scores are added. Scores above 18 indicate a definite major depression, scores above 10 indicate a 
probable major depression, and scores below 6 are associated with absence of significant depressive 
symptoms.
EuroQol 5 Dimensions – 5 Levels (EQ-5D-5L)
The EQ-5D-5L is a generic instrument that can be used in the clinical and economic evaluation of 
health care, and to collect data on the patient’s health status and preferences/utility.  The instrument 
comprises questions on mobility, self-care, usual activities, pain/discomfort and anxiety/depression, 
and a visual analogue scale from 0 (“Worst imaginable health state”) to 100 (“Best imaginable health 
state”). 

The subject will self-complete the standard version of the EQ-5D-5L regarding his/her own 
status.  The standard version is worded for self-completion, but is not labeled by EuroQol as 
the Self Version.  For the purposes of this protocol and to differentiate from the Proxy 
version of the EQ-5D-5L, the standard version will be referred to as the Self Version. 
o
For subjects with physical disabilities that impair self-completion (eg, arthritis or severe 
vision-impairment), caregivers or study coordinators may engage in assisted self-
completion by reading questions and responses verbatim (without any interpretation)
and/or recording responses for subjects as long as the responses are those of the subject.

During the Core Study only, the caregiver will complete both the Self Version (regarding the 
caregiver) and the Proxy 1 Version (regarding the caregiver’s perception of the subject).  
(revised per Amendment 05)

Thus, 3 EQ-5D-5L forms per subject per visit should be completed: 1) subject Self Version, 
2) caregiver Self Version, 3) caregiver Proxy 1 Version.
Zarit Burden Interview – short form (ZBI-short)
The ZBI-short was developed from the full ZBI, to be suitable for caregivers of cognitively impaired 
older adults across diagnostic groups. The ZBI-short can be used for cross-sectional, longitudinal, and 
intervention studies. It has been designed to reflect the stresses experienced by caregivers of dementia 
patients. The ZBI-short can be completed by caregivers directly or as part of an interview (eg, study 
coordinator interviews caregiver and completes based on caregiver response). Caregivers are asked 
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to respond to a series of 12 questions in 2 domains: personal strain and role strain. Each question is 
scored on a 5-point Likert scale from 0 to 4 (never to almost always).  The range of summed scores is 
0 to 48. Higher scores reflect a higher feeling of burden.
Pittsburgh Sleep Quality Index (PSQI)
The PSQI will be used to assess the caregiver’s quality of sleep.  It is an instrument used to measure 
the quality and patterns of sleep in adults by measuring seven components: subjective sleep quality, 
sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medications, and daytime dysfunction, over the previous month. 
In scoring the PSQI, seven 
component scores are derived, each scored from 0 (no difficulty) to 3 (severe difficulty). The 
component scores are summed to produce a global score (range 0 to 21). Higher scores indicate 
worse sleep quality. The PSQI will be administered to the caregiver, to assess his/her quality of 
sleep.
Bioanalytical Methods
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10), donepezil, 
memantine, and galantamine will be measured using validated liquid chromatography-tandem mass 
spectrometry assay methods. (revised per Amendment 03)
Statistical Methods
All statistical tests will be based on the 5% level of significance (two-sided), unless otherwise stated.  
No multiplicity adjustments will be made.
Study Endpoints (revised per Amendment 06)
Sleep-Related Endpoints (revised per Amendments 05 and 06)
The sleep-related endpoints are: 

The change from baseline of mean aSE during the last week of treatment with LEM 
compared to PBO (revised per Amendment 01)

The change from baseline of aSE during each week of treatment with LEM compared to 
PBO.  (revised per Amendment 06) 

Change from baseline in mean SFI during each week of treatment (revised per Amendments
01 and 06)

Change from baseline of the mean duration of wake bouts (aMeanDurWB) over each week of 
treatment (revised per Amendments 01 and 06)
Wake-Related Endpoints (revised per Amendments 05 and 06)

The change from baseline of mean aWE during each week of treatment with LEM compared 
to PBO (revised per Amendment 01)

Change from baseline of the mean duration of sleep bouts (aMeanDurSB) over each week of 
treatment (revised per Amendments 01 and 06)

Change from baseline of mean WFI during each week of treatment (revised per Amendments
01 and 06)
Circardian Rhythm-Related Endpoints (revised per Amendment 05 and 06)

Change from baseline of IV, IS, L5, M10, AMP, and RA over each week of treatment 
(revised per Amendment 01) 
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Additional Endpoints (revised per Amendments 05 and 06)
The following endpoints will be analyzed for LEM2.5, LEM5, LEM10 and LEM15 compared to 
PBO:  

Safety and tolerability of LEM, including AEs and SAEs

Change from baseline in CGIC-ISWRD Scale on symptoms of ISWRD total score and 
domains at Day 29 (revised per Amendments 01 and 06)

Change from baseline of the sum of activity counts and change from baseline of the number 
of bouts >10 minutes of sleep in the first 3 hours after morning waketime on the first 3 days 
and last 3 days of treatment 

Rebound sleep and wake fragmentation endpoints as assessed from actigraphy during the 
Follow-Up Period
o
Change from baseline in mean aSE of the first 7 nights, and aSE of the second 7 nights of 
the Follow-up Period
o
Change from baseline in mean aWE of the first 7 days and mean aWE of the second 
7 days of the Follow-Up Period
o
Proportion of subjects whose mean aSE is higher than at baseline for the first 7 nights or 
the second 7 nights of the Follow-Up Period
o
Proportion of subjects whose mean aWE is longer than at baseline for the first 7 days or 
the second 7 days of the Follow-Up Period (revised per Amendment 03)

Change from baseline on ADAS-cog at Day 29

Change from baseline on MMSE at Day 29

Change from baseline sleep quality in caregivers as measured by the  PSQI at Day 29 

Change from baseline of caregiver burden on on all scores of the ZBI-short form at Day 29.  
(revised per Amendment 06)

Change from baseline on the EQ-5D-5L utility and Visual Analogue Scale (VAS) scores at 
Day 29 for both subject and caregiver

Change from baseline of the total score of NPI-10 at Day 29 

Change from baseline on SDI at Day 29

Characterize the PK of lemborexant using the population approach and descriptive statistics 
for the plasma concentrations of its metabolites M4, M9, and M10.  (revised per Amendment 
06)

Relationships between exposure to lemborexant, efficacy, and/or safety variables using 
PK/PD modeling

Plasma concentration of lemborexant and any cognitive enhancer(s) in subjects taking both 
drugs

Evaluate the long-term safety and tolerability of flexible doses of LEM5, LEM10, and 
LEM15 per day over a period of 30 months in subjects with ISWRD who have completed the 
Core Study.  (revised per Amendments 05 and 06)
Analysis Sets
The Safety Analysis Set is the group of randomized subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
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randomized study drug and had at least 1 postdose efficacy measurement.
The PK Analysis Set is the group of subjects who have at least 1 quantifiable plasma concentration of 
lemborexant, with adequately documented dosing history.
The PK/PD Analysis Set is the group of subjects receiving either lemborexant or placebo who have 
efficacy or safety data with documented dosing history.  In addition, subjects receiving lemborexant
should have at least 1 quantifiable lemborexant concentration data point as per the PK Analysis Set.
Core Study (revised per Amendment 05)
Efficacy Analyses
Analysis for the Sleep-Related, Wake-Related, and Circadian Rhythm-Related Endpoints (revised per 
Amendment 06)
The change from baseline of the mean aSE for the last week and for each week on treatment, and the 
change from baseline of mean aWE  for the last week on treatment will be analyzed using MCP-
MOD (Multiple Comparisons & Modelling) approach. Dose response models that will be evaluated 
are linear, linear log, quadratic, exponential, emax, sigmoid emax, beta and logistic. (revised per 
Amendments 05 and 06)
Analysis stage – MCP-step: Establish a dose-response signal (the dose-response curve is not flat) 
using multiple comparison procedure. Based on the observed data, the model that shows statistically 
significant trend test will be selected (at one-sided 5% significance). If more than one is statistically 
significant, then the most optimal model using Akaike Information Criteria will be selected. This 
method prospectively controls the type I error at 5%.
Analysis Stage – Mod-step: Dose response and target dose estimation will be based on dose response 
modelling. MCP-MOD approach allows for interpolation between doses. 
As a sensitivity analysis to the aSE and aWE endpoints, the mean aSE and mean aWE for Week 4 
will be analyzed using the longitudinal data analysis (LDA). (revised per Amendments 01 and 06)
The change from baseline of the following endpoints will be analyzed using LDA on the FAS for 
LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, as appropriate:  mean SFI, mean WFI, 
mean aMeanDurWB, mean aMeanDurSB, IV, IS, L5, M10, AMP, and RA . (revised per Amendment 
06)  The model will include all data and will be adjusted for the corresponding baseline value, 
country, treatment, time (Week 1, Week 2, Week 3 and Week 4) and the interaction of treatment by 
time. Treatment by time interaction will be used to construct the treatment comparisons at a specific 
time.  The LDA model accounts for any missing data, and assumes that the missing data are missing 
at random.  An unstructured covariance matrix will be used, and if the model fails to converge, then 
an autoregressive matrix will be used.  Where data are normally distributed, least square (LS) means, 
difference in LS means of each lemborexant dose compared to PBO, 95% confidence intervals (CIs)
and P values at the appropriate time point will be presented. (revised per Amendment 01)
Additional analyses as deemed necessary, may include the investigation of subgroup analyses and/or 
addition of covariates to the model of age, sex, race, body mass index (BMI), severity of aSE, 
severity of aWE, wake fragmentation, severity of AD-D based on MMSE and/or other subgroups.
(revised per Amendment 06)
Analyses for Additional Endpoints (revised per Amendment 06)
The overall score of CGIC-ISWRD Scale at Day 29 will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test, adjusted for country.  (revised per Amendment 01)
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To assess residual morning sleepiness levels, change from baseline in the sum of activity counts in 
the 3 hour interval after morning waketime will be compared for each treatment group relative to 
placebo for each of the 6 mornings comprising the first 3 days and last 3 days of treatment.  The 
change from baseline will be analyzed using analysis of covariance (ANCOVA), with treatment and 
baseline as fixed effects. Provided that the data are normally distributed, LS means, difference in LS 
means of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, 95% CIs, and p--values will be 
presented.  In addition, the change from baseline of the number of bouts >10 min scored as sleep will 
be determined. The change from baseline will be analyzed using ANCOVA, as above.
Rebound sleep and wake fragmentation are defined as worsened aSE or aWE compared to baseline 
after study drug treatment is completed.  Actigraphy data from the Follow-Up Period will be 
compared to actigraphy data from the baseline to assess whether subjects experience rebound sleep or 
wake fragmentation.  Specifically, a lower value for aSE or aWE during the Follow-Up Period 
compared to the mean aSE or aWE value during baseline will be considered worsened sleep or wake 
fragmentation.  
To assess rebound sleep and wake fragmentation, both categorical analysis at the subject level and 
continuous analysis at the group mean level will be performed.  For each of the 2 weeks of the 
Follow-Up Period the proportion of subjects whose corresponding value for aSE or aWE exceeds the 
corresponding baseline value by 1% for aSE and 0.5% for aWE (which is approximately 5 minutes
based on the total length of each assessment period) will be summarized by treatment group and 
compared to placebo. The percentage of ‘rebounders’ between each treatment and placebo group will 
be analyzed using a Cochran-Mantel-Haenszel test, adjusted for country.  
To assess statistical significance using the continuous data at the group mean level, the data will be 
analyzed using ANCOVA, adjusted for country and treatment.  The LS mean of each week of the 
Follow-Up Period will be compared to the baseline between each treatment group and placebo.  If the 
upper bound of the 95% CI of aSE or aWE for the mean of each week of the Follow-Up Period is less 
than the lower bound of a 95% CI for the values during the baseline in the given treatment group, it 
will be considered strong evidence for rebound sleep or wake fragmentation. If the LS means for aSE 
and aWE for the Follow-Up Period are all higher than for the baseline, then no rebound sleep or wake 
fragmentation is suggested.  Otherwise, the degree to which the parameters worsen, and the time 
point(s) at which they worsen will be considered to evaluate whether clinically meaningful rebound 
sleep and/or wake fragmentation is present.
Each domain of CGIC-ISWRD Scale at Day 29 will be analyzed using the Cochran–Mantel–
Haenszel test, adjusted for country.  (revised per Amendment 01)
The change from baseline of total score from the NPI-10, SDI, ADAS-Cog and MMSE at Day 29 
will be analyzed with ANCOVA, with treatment and baseline as fixed effects on the Efficacy
Analysis Set.  The difference in LS means of LEM2.5, LEM5, LEM10 and LEM15 compared to 
PBO, 95% CIs and P-values will be presented. (revised per Amendment 05)
Pharmacokinetic Analysis 
The Safety Analysis Set will be used for individual plasma concentration listings of lemborexant and 
its metabolites M4, M9, and M10.  The PK Analysis Set will be used for summaries of plasma 
concentrations of lemborexant and its metabolites M4, M9, and M10, by dose and day.
A population PK approach will be used to characterize the PK of lemborexant.  For this approach, PK 
data from this study will be pooled with relevant data from existing Phase 1 and 2 studies, and other 
Phase 3 studies if available.  The effect of intrinsic and extrinsic factors (ie, demographics, 
concomitant medications) on the PK of lemborexant will be evaluated.  The PK model will be 
parameterized for oral clearance (CL/F) and volume of distribution (V/F).  Derived exposure 
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parameters such as area under the concentration-time curve (AUC), maximum observed plasma 
concentration (Cmax) and any other relevant parameters will be calculated from the model using the 
individual posterior estimate of CL/F and dosing history. (revised per Amendment 05)
Baseline plasma concentrations of cognitive enhancer(s) from appropriate subjects will be compared 
to those at end of treatment.  Plasma concentrations taken at the end of study will be compared to 
corresponding baseline concentrations to assess for evidence of potential drug-drug interaction.  
(revised per Amendment 03)
Pharmacodynamic Analysis
All of the PD variables are considered efficacy variables for the purposes of analysis.  (revised per 
Amendment 01)
Pharmacogenomic Analyses
DNA samples will be collected and stored, and may be used to examine the role of genetic variability 
in absorption, distribution, metabolism, and excretion, or development of AEs. Variation in 
lemborexant exposure or AEs may be explored by correlation of single-nucleotide polymorphisms 
with PK, safety, or efficacy data.  Efficacy will be explored in relation to APOɛ4 genotype.
Pharmacokinetic/Efficacy Analyses
The PK/Efficacy relationship between exposure to lemborexant and efficacy variables including but 
not limited to SFI and WFI, and the most frequently occurring TEAEs, will be explored graphically.  
Any emergent PK/Efficacy relationships will be evaluated by population PK/Efficacy modeling.  The 
population PK/Efficacy analysis plan will be described and results will be reported in a separate 
document. 
Population PK and PK/Efficacy analyses will be performed using NONMEM version 7.2 or later.
Safety Analyses
Evaluations of safety will be performed on the relevant Safety Analysis Set.  The incidence of AEs 
and suicidality (eC-SSRS), along with change from baseline in laboratory safety test variables, ECGs, 
vital sign and weight measurements, will be summarized by treatment group using descriptive 
statistics.
In addition to typical events associated with special situations (EASSs), designated 
compound-specific EASSs will be summarized separately.  These will include Customized MedDRA 
Queries for AEs that could potentially be considered cataplexy or seizure.  (revised per 
Amendment 02)
Other Analyses
Endpoints may also be presented graphically or analyzed by modeling methods if warranted.  (revised 
per Amendment 06)
The change from baseline of the EQ-5D-5L utility and VAS scores, the global score of PSQI, all 
scores of the ZBI-short and the SDI at Day 29 will be analyzed using ANCOVA, with treatment and 
baseline as fixed effects. Provided that the data are normally distributed, LS means, difference in LS 
means of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, 95% confidence intervals (CIs) 
and p-values will be presented.  The analyses for the EQ-5D-5L (caregiver self-version), PSQI, and 
ZBI will be conducted for a) caregivers who reside in the same residence as the subjects, b) caregiver 
informants who do not, reside in the same residence as the subjects, and c) all types of 
caregivers/informants combined.  (revised per Amendment 01)
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Extension Phase  (revised per Amendment 05)
Efficacy
The change from baseline of scale domains, as well as total score from the efficacy endpoint SDI will 
be summarized by time point and by modal dose.  
Other comparisons may be performed as deemed appropriate in the future (subjects who remain on 
LEM10 and never switch vs subjects who switched from LEM10), and these will be included in the 
Extension Phase SAP.
Safety Analysis
The analysis of safety data will be performed by time point and modal dose.  Other comparisons may 
be performed if appropriate; these will be included in the SAP.
The safety endpoints of adverse events (TEAEs, SAEs, and AEs leading to discontinuation) will be 
summarized by System Organ Class (SOC) and Preferred Term (PT), and the incidence of AEs will 
be summarized by maximum severity and relationship to study drug.  Change from baseline analyses 
will be presented for clinical laboratory values, vital signs and weight, ECGs, and physical 
examination results. The results of eC-SSRS assessments will be listed for each subject, and the 
incidence of treatment-emergent suicidal ideation or suicidal behavior will be summarized by 
treatment group using descriptive statistics.
Interim Analyses
A database lock will occur after all of the subjects have completed the Core Study, including the End 
of Study visit.  The Core Study data will be analyzed according to the Core Study statistical analysis 
plan (SAP).  A second database lock will occur after the End of Study visits have been completed for 
the Extension Phase.  Analyses for the Extension Phase will be based on the Extension Phase SAP.
An interim analysis will be conducted with only the subjects from the US and Japan; details will be 
provided in the SAP.  (revised per Amendments 05 and 06)
Sample Size Rationale
Approximately 60 subjects will enroll in this proof-of-concept study.  (revised per Amendment 06)
Some supporting exploratory power estimation is based on testing the dose response using the MCP-
Mod package in R; several dose response curves were explored at one-sided 0.05 level of significance 
with different values of n (12, 13, and 14 subjects) per treatment group. (revised per Amendment 06)
Conservative scenarios based on 10 percentage point difference between the active drug and placebo
will be presented.  (revised per Amendment 06)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................30
5
ETHICS............................................................................................................................33
5.1
Institutional Review Boards/Independent Ethics Committees ..............................33
5.2
Ethical Conduct of the Study.................................................................................34
5.3
Subject Information and Informed Consent...........................................................34
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................35
7
INTRODUCTION ...........................................................................................................36
7.1
Indication ...............................................................................................................36
7.1.1
Irregular Sleep-Wake Rhythm Disorder in Alzheimer’s Disease 
Dementia......................................................................................................36
7.1.2
Unmet Medical Need...................................................................................39
7.1.3
Rationale for a Dual Orexin Receptor Antagonist to Treat Irregular 
Sleep-Wake Rhythm Disorder.....................................................................39
7.1.4
Clinical Experience with Lemborexant .......................................................39
7.1.4.1
Phase 1 ...............................................................................................39
7.1.4.2
Phase 2 ...............................................................................................41
7.1.4.3
Summary of Clinical Experience.......................................................42
7.1.5
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..........................42
7.2
Study Rationale......................................................................................................43
8
STUDY OBJECTIVES....................................................................................................43
8.1
Sleep-Related Objectives  (Revised per Amendments 05 and 06) ........................43
8.2
Wake-Related Objectives (revised per Amendments 05 and 06)..........................43
8.3
Circadian Rhythm-Related Objectives  (revised per Amendments 05 and 06).....44
8.4
Additional Objectives  (revised per Amendment 05 and 06) ................................44
9
INVESTIGATIONAL PLAN..........................................................................................46
9.1
Overall Study Design and Plan..............................................................................46
9.1.1
Caregivers and Informants (revised per Amendment 01)............................46
9.1.2
Prerandomization Phase...............................................................................50
9.1.2.1
Optional Prescreening........................................................................50
9.1.2.2
Screening Period................................................................................50
9.1.2.3
Baseline Period ..................................................................................51
9.1.3
Randomization Phase...................................................................................51
9.1.3.1
Treatment Period................................................................................51
9.1.3.2
Follow-Up Period...............................................................................52
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9.1.4
Extension Phase ...........................................................................................52
9.2
Discussion of Study Design, Including Choice of Control Groups.......................53
9.2.1
Rationale for Efficacy Assessments.............................................................53
9.2.2
Rationale for Subject Population .................................................................53
9.2.3
Rationale for Dose Selection .......................................................................53
9.2.4
Rationale for Duration of Treatment............................................................53
9.2.5
Rationale for Study Endpoints.....................................................................54
9.2.6
Randomization.............................................................................................54
9.2.7
Study Controls .............................................................................................54
9.2.8
Adjudication Committee (revised per Amendment 02)...............................54
9.3
Selection of Study Population................................................................................54
9.3.1
Inclusion Criteria for Subjects (revised per Amendment 05)......................55
9.3.2
Exclusion Criteria for Subjects (revised per Amendment 05).....................56
9.3.3
Removal of Subjects from Therapy or Assessment.....................................57
9.4
Treatments..............................................................................................................58
9.4.1
Treatments Administered (revised per Amendment 05)..............................58
9.4.2
Identity of Investigational Products.............................................................58
9.4.2.1
Chemical Name, Structural Formula of E2006..................................58
9.4.2.2
Comparator Drug ...............................................................................59
9.4.2.3
Labeling for Study Drug....................................................................59
9.4.2.4
Storage Conditions.............................................................................59
9.4.3
Method of Assigning Subjects to Treatment Groups...................................59
9.4.4
Selection of Doses in the Study...................................................................60
9.4.5
Selection and Timing of Dose for Each Subject..........................................60
9.4.6
Blinding........................................................................................................60
9.4.7
Prior and Concomitant Therapy...................................................................60
9.4.7.1
Drug-Drug Interactions......................................................................61
9.4.7.2
Prohibited Concomitant Therapies and Drugs...................................61
9.4.8
Treatment Compliance.................................................................................61
9.4.9
Drug Supplies and Accountability...............................................................62
9.5
Study Assessments.................................................................................................63
9.5.1
Assessments.................................................................................................63
9.5.1.1
Demography.......................................................................................63
9.5.1.2
Screening Assessments ......................................................................63
9.5.1.2.1
Medical History and Physical Examinations...........................63
9.5.1.2.2
Cornell Scale for Depression in Dementia...............................64
9.5.1.2.3
Viral Test .................................................................................64
9.5.1.3
Efficacy Assessments.........................................................................64
9.5.1.3.1
Actigraphy (revised per Amendment 05) ................................64
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9.5.1.3.2
Clinician’s Global Impression of Change Irregular Sleep-
Wake Rhythm Disorder (CGIC-ISWRD) Scale (revised per 
Amendment 01) .......................................................................66
9.5.1.3.3
Neuropsychiatric Inventory (NPI-10) (Revised to be an 
efficacy assessment per Amendment 05).................................66
9.5.1.3.4
Mini Mental State Examination (Revised to be an efficacy 
assessment per Amendment 05)...............................................66
9.5.1.3.5
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-
cog)  (Revised to be an efficacy assessment per 
Amendment 05) .......................................................................67
9.5.1.3.6
Sleep Disorders Inventory (SDI)  (Revised to be an efficacy 
assessment per Amendment 05)...............................................67
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments...........................................................67
9.5.1.4.1
Pharmacokinetic Assessments .................................................67
9.5.1.4.2
Pharmacodynamic Assessments ..............................................68
9.5.1.4.3
Pharmacokinetic/Pharmacodynamic Assessments ..................68
9.5.1.4.4
Pharmacogenomic/Pharmacogenetic Assessments..................68
9.5.1.5
Safety Assessments............................................................................68
9.5.1.5.1
Adverse Events ........................................................................68
9.5.1.5.2
Classification of Causality.......................................................70
9.5.1.5.3
Serious Adverse Events ...........................................................70
9.5.1.5.4
Laboratory Measurements .......................................................71
9.5.1.5.5
Vital Signs and Weight Measurements....................................73
9.5.1.5.6
Physical Examinations.............................................................73
9.5.1.5.7
Electrocardiograms ..................................................................73
9.5.1.5.8
Other Safety Assessments (revised per Amendment 05).........74
9.5.1.6
Other Assessments.............................................................................74
9.5.1.6.1
EQ-5D-5L ................................................................................74
9.5.1.6.2
Zarit Burden Interview – short form........................................75
9.5.1.6.3
Pittsburgh Sleep Quality Index ................................................75
9.5.2
Schedule of Procedures/Assessments ..........................................................75
9.5.2.1
Schedule of Procedures/Assessments ................................................75
9.5.2.2
Description of Procedures/Assessments Schedule.............................80
9.5.3
Appropriateness of Measurements...............................................................80
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................80
9.5.4.1
Reporting of Serious Adverse Events................................................80
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................81
9.5.4.3
Reporting of Events Associated with Special Situations...................81
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9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ......................81
9.5.4.3.2
Reporting of Study-Specific Events.........................................81
9.5.4.4
Expedited Reporting ..........................................................................82
9.5.4.5
Breaking the Blind.............................................................................82
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................82
9.5.5
Completion/Discontinuation of Subjects.....................................................82
9.5.6
Abuse or Diversion of Study Drug ..............................................................83
9.5.7
Confirmation of Medical Care by Another Physician .................................83
9.6
Data Quality Assurance .........................................................................................83
9.6.1
Data Collection ............................................................................................83
9.6.2
Clinical Data Management ..........................................................................83
9.7
Statistical Methods.................................................................................................84
9.7.1
Statistical and Analytical Plans....................................................................84
9.7.1.1
Study Endpoints.................................................................................84
9.7.1.1.1
Sleep-Related Endpoints (revised per Amendments 05 and 
06) ............................................................................................84
9.7.1.1.2
Wake-Related Endpoints (revised per Amendments 05 and 
06) ............................................................................................84
9.7.1.1.3
Circadian Rhythm-Related Endpoints (revised per 
Amendments 05 and 06)..........................................................84
9.7.1.1.4
Additional Endpoints  (revised per Amendment 06)...............85
9.7.1.2
Definitions of Analysis Sets...............................................................86
9.7.1.3
Subject Disposition............................................................................86
9.7.1.4
Demographic and other Baseline Characteristics ..............................86
9.7.1.5
Prior and Concomitant Therapy.........................................................87
9.7.1.6
Efficacy Analyses ..............................................................................87
9.7.1.6.1
Analysis for the Sleep-Related, Wake-Related, and 
Circadian Rhythm-Related Endpoints (revised per 
Amendment 06) .......................................................................87
9.7.1.6.2
Analyses for Additional Endpoints (revised per 
Amendment 06) .......................................................................88
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................89
9.7.1.7.1
Pharmacokinetic Analyses.......................................................89
9.7.1.7.2
Pharmacokinetic/Pharmacodynamic Analyses ........................89
9.7.1.7.3
Pharmacokinetic/Efficacy Analyses ........................................89
9.7.1.7.4
Pharmacogenomic Analyses....................................................90
9.7.1.8
Safety Analyses..................................................................................90
9.7.1.8.1
Extent of Exposure...................................................................90
9.7.1.8.2
Adverse Events ........................................................................90
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9.7.1.8.3
Clinical Laboratory Values......................................................91
9.7.1.8.4
Vital Signs and Weight ............................................................92
9.7.1.8.5
Electrocardiograms ..................................................................92
9.7.1.8.6
Other Safety Analyses (Revised per Amendment 05).............93
9.7.1.9
Other Analyses...................................................................................93
9.7.2
Determination of Sample Size (revised per Amendment 06)......................93
9.7.3
Interim Analysis...........................................................................................97
9.7.4
Other Statistical/Analytical Issues ...............................................................97
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................97
10
REFERENCE LIST .........................................................................................................98
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....101
11.1
Changes to the Protocol .......................................................................................101
11.2
Adherence to the Protocol....................................................................................101
11.3
Monitoring Procedures.........................................................................................101
11.4
Recording of Data................................................................................................102
11.5
Identification of Source Data...............................................................................102
11.6
Retention of Records............................................................................................102
11.7
Auditing Procedures and Inspection....................................................................103
11.8
Handling of Study Drug.......................................................................................103
11.9
Publication of Results ..........................................................................................103
11.10 Disclosure and Confidentiality ............................................................................104
11.11 Discontinuation of Study .....................................................................................104
11.12 Subject Insurance and Indemnity.........................................................................104
12
APPENDICES ...............................................................................................................105
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests...........................................................................71
Table 2
Blood Sampling Volumes for Laboratory and Pharmacokinetic 
Assessments (revised per Amendments 03 and 05).....................................................72
Table 3
Schedule of Procedures/Assessments in Study E2006-G000-202 
(revised per Amendments 01, 02, 05, and 06) (Core Study) .......................................76
Table 4
Vital Sign Criteria......................................................................................92
Table 5
Power Calculations for Actigraph Sleep Efficiency Under Different 
Dose Response Curves (n=12 and sigma=12) (revised per Amendment 06)..............94
Table 6
Power Calculations for Actigraph Sleep Efficiency Under Different 
Dose-Response Curves (n=13 and sigma=12) (revised per Amendment 06)..............95
Table 7
Power Calculations for Actigraph Sleep Efficiency Under Different 
Dose Response Curves (n=14 and sigma=12) (revised per Amendment 06)..............96
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Table 8
Schedule of Procedures and Assessments for Study E2006-G000-202 
Extension Phase (revised per Amendment 06) ..........................................................117
LIST OF IN-TEXT FIGURES
Figure 1
Representative Activity Data Graphs for a Normal Control and a 
Subject with Alzheimer’s Disease (AD)......................................................................37
Figure 2
Schematic Activity Data Graphs for Normal Sleep and Fragmented 
Sleep (revised per Amendment 01)..............................................................................38
Figure 3
Study Design (revised per Amendments 03 and 05) .................................48
LIST OF APPENDICES
Appendix 1
Sponsor's Grading for Laboratory Values (revised per Amendment 03) 106
Appendix 2
Pharmacogenomic Research....................................................................108
Appendix 3
Prohibited Concomitant Medications ......................................................111
Appendix 4
Extension Phase .......................................................................................114
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADAS-cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
AD
Alzheimer’s Disease
AD-D
Alzheimer’s Disease -- Dementia
AE
adverse event
AHI
apnea-hypopnea index
aMeanDurSB
Mean duration of sleep bouts > 10 min during the defined wake period
aMeanDurWB
Mean duration of wake bouts > 10 min during the defined sleep period
AMP
amplitude of the rest-activity rhythm
ANCOVA
analysis of covariance
aSE
actigraphy sleep efficiency
AUC
area under the concentration-time curve
aWE
actigraphy wake efficiency
BMI
body mass index
BP
blood pressure
CA
Competent Authority
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
apparent oral clearance
Cmax
maximum observed concentration
CRA
clinical research associate
CRF
case report form
CRO
Contract Research Organization
CSDD
Cornell Scale for Depression in Dementia
CSF
cerebrospinal fluid
CT
computed tomography
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders – 5th edition
EASS
events associated with special situations
ECG
electrocardiogram
eCRF
electronic case report form
eC-SSRS
electronic Columbia–Suicide Severity Rating Scale
EOS
end of study
EQ-5D-5L
Euro-QOL version 5 dimensions, 5 levels 
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Abbreviation
Term
ET
Early Termination
EU
European Union
FAS
full analysis set
FI
fragmentation index
FDA
Food and Drug Administration
GCP
Good Clinical Practice
H
high
CGIC-ISWRD Scale
Clinician’s Global Impression of Change -Irregular Sleep-Wake Rhythm 
Disorder Clinical Assessment Scale
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
ICD
International Classification of Diseases
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IV
intradaily variability
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IS
interdaily stability
ISWRD
Irregular Sleep-Wake Rhythm Disorder
KSS
Karolinska Sleepiness Scale
L
low
LDA
longitudinal data analysis
LEM
lemborexant
LEM2.5
lemborexant, 2.5 mg dose
LEM5
lemborexant 5 mg dose
LEM10
lemborexant, 10 mg dose
LEM15
lemborexant, 15 mg dose
LNH
low-normal-high
LS
least square
MCB
median calculated bedtime
MedDRA
Medical Dictionary for Regulatory Activities
MI
movement index
MMSE
Mini Mental State Examination
M-MSLT
Modified Multiple Sleep Latency Test
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Abbreviation
Term
N
normal
NPI-10
Neuropsychiatric Inventory – 10 item version
OSA
obstructive sleep apnea
PBO
placebo
PD
pharmacodynamics
PI
principal investigator
PK
pharmacokinetics
PSG
polysomnography
PSG SE
polysomnography sleep efficiency
PSQI
Pittsburgh Sleep Quality Index
PT
Preferred Term
QT
period from the beginning of the QRS complex to the end of the T wave on an 
electrocardiogram. 
QTcF
QT corrected for heart rate using Fridericia’s formula
RA
relative amplitude
REM
rapid eye movement
SAE
serious adverse event
SAP
Statistical Analysis Plan
SDI
Sleep Disorders Inventory
SDLP
standard deviation of lateral position
SE
Sleep Efficiency
SFI
Sleep Fragmentation Index
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse events
TIB
time in bed
TOB
time out of bed
US
United States
VAS
Visual Analogue Scale
V/F
apparent volume of distribution
WFI
Wake Fragmentation Index
ZBI
Zarit Burden Inventory
ZOP
Zopiclone
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent forms (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice), Section 3, and any local regulations including 
Federal Regulations, Title 21, Code of Federal Regulations (CFR) Part 56. Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associates (CRA[s]), change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
At the end of the study, the sponsor should notify the IRB/IEC 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/IEC 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/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
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5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following:
•
Principles of the World Medical Association Declaration of Helsinki 
•
ICH E6 Guideline for GCP (Committee for Medicinal Products for Human 
Use/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
Committee for Proprietary Medicinal Products, International Council for Harmonisation 
of Pharmaceuticals for Human Use
•
Title 21 of the United States CFR regarding clinical studies, including Part 50 and Part 56 
concerning informed subject consent and IRB regulations and applicable sections of 
United States 21 CFR Part 312
•
European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union (EU) country. All suspected unexpected serious 
adverse reactions (SUSARs) will be reported, as required, to the Competent Authorities 
of all involved EU member states (revised per Amendment 04)
•
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) for studies conducted in Japan, in addition to Japan’s GCP
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator or his/her designee 
must explain to each subject and caregiver (and legally authorized representative if the 
caregiver does not have this status) 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 
and caregiver must be informed that participation in the study is voluntary, that the subject or 
caregiver may withdraw from the study at any time, and that withdrawal of consent will not 
affect the subject’s subsequent medical treatment or relationship with the treating physician.
At the Screening Visit, this informed consent should be given by means of a standard written 
statement, written in nontechnical language.  The subject or caregiver (or, if applicable, the 
legally authorized representative) should understand the statements before signing and dating 
it and will be given a copy of the signed document.  If a subject is unable to read or if the 
caregiver (or, if applicable, the legally authorized representative) is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICFs and any other written information to be provided to subjects are read and explained to 
the subject or the caregiver (or, if applicable, the legally authorized representative), and after 
the subject or the caregiver (or, if applicable, the legally authorized representative) has orally 
consented to the subject’s participation in the study and, if capable of doing so, has signed 
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and personally dated the ICFs, the witness should sign and personally date the consent forms.  
The subject will be asked to sign the ICFs before any study-specific procedures are 
performed.  No subject can enter the study before his/her informed consents have been 
obtained.
Unsigned copies of IRB/IEC-approved ICFs must be prepared in accordance with ICH E6, 
Section 4, and Federal Regulations, Title 21 CFR Part 50.  Each subject and caregiver must 
sign the approved ICFs before study participation.  The forms must be signed and dated by 
the appropriate parties.  The original, signed ICFs for each subject and caregiver (and, if 
applicable, the legally authorized representative) will be verified by the sponsor and kept on 
file according to local procedures at the site.  
The subject and caregiver (and, if applicable, the legally authorized representative) should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject's and caregiver's willingness to continue participation in the study. 
The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 60 investigational sites in the United States (US), European Union 
(EU), and Japan. (revised per Amendments 01 and 04)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in the Investigator 
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
7.1.1
Irregular Sleep-Wake Rhythm Disorder in Alzheimer’s Disease Dementia
Sleep disturbances appear early in the course of Alzheimer’s Disease – Dementia (AD-D)
and other dementias and are associated generally with a loss of circadian rhythmicity 
(Guarnieri and Sorbi, 2015; Musiek et al., 2015).  Patients with AD-D and other dementias 
can spend much of the night awake, and much of the daytime hours asleep.  When sleep is 
not consolidated at night but rather distributed in sleep bouts across the 24-hour day, this 
pattern is referred to as Irregular Sleep-Wake Rhythm Disorder (ISWRD) (Figure 1).  This 
disorder is characterized by decreased amplitudes of the sleep-wake and alertness rhythms, 
with less predictability of the sleep-wake pattern from day to day (Satlin et al., 1995; 
Peter-Derex et al., 2015).
The ISWRD pattern can be visualized in Figure 1 this irregular sleep-wake rhythm is 
frequently seen in association with neurologic dysfunction, including AD-D (Abbott and Zee, 
2015).  Since actigraphy can capture the full 24-hour pattern of sleep and wake in treatment 
trials, actigraphy has been a common choice (Camargos et al., 2013). Using data on activity 
counts collected with an accelerometer device, with support from sleep log data, algorithms 
can be applied to define intervals of sleep and wake across the 24-hour day, as well as within 
the sleep log-defined night/in-bed interval and day/out-of-bed interval.  This noninvasive 
methodology allows for continuous observation from which objective efficacy variables may 
be derived (Goncalves et al., 2014).  In the top panel of Figure 1, the healthy control subject 
shows high levels of activity across the day, quiescent nighttime sleep periods, and interdaily 
stability.  By contrast, the data in the lower panel of Figure 1 show the reduced amplitude 
and irregularity of the sleep-wake pattern in a subject with AD-D (Satlin et al., 1992).
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Figure 1
Representative Activity Data Graphs for a Normal Control and a Subject with Alzheimer’s Disease (AD)
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Sleepiness during the day can substantially impact quality of life for the patient with 
dementia (Carvalho-Bos et al., 2007).
While the importance of sleep problems in the 
development, progression, management, and treatment of dementia is still not fully 
recognized, sleep-wake disturbances are a highly prevalent and often disabling feature of 
AD-D (Miller, 2015).  Research has shown that the inability to sleep at night is among the 
leading causes of institutionalization (Pollak and Perlik, 1991), since wakefulness during the 
night not only poses a safety risk to the patient, eg, by increasing the risk of wandering or 
falling in the dark, but also increases the burden on caregivers whose sleep is also disrupted.
ISWRD, (International Classification of Diseases [ICD]-10 code G47.23) is also listed in 
Diagnostic and Statistical Manual of Mental Disorders – 5th edition (DSM-5), and is diagnostically 
distinct from insomnia.  Relative to healthy, age-matched subjects, nocturnal sleep in patients 
with AD-D is disrupted by fragmentation.  With many awakenings shorter than 10 minutes 
and a few longer bouts of wakefulness, this results in substantially lower sleep efficiency and 
unrefreshing sleep (Liguori et al., 2016). Patients with AD-D also have difficulty maintaining 
wakefulness throughout the daytime hours, and report excessive daytime sleepiness.  This 
contrasts with insomnia disorder, in which patients may have difficulties with initiating 
and/or maintaining sleep during the nocturnal sleep period, but do not exhibit symptoms of 
excessive daytime sleepiness and have difficulty napping during the day (Pillai et al., 2016).  
In addition, when patients with AD-D awaken at night, they are at risk for confusion and falls 
in association with the awakenings whereas aberrant nocturnal behaviors are generally not 
associated with middle-of-the-night awakenings in insomnia disorder, except in association 
with the uses of some types of hypnotic medications.
Figure 2 is a schematic of ISWRD as defined by actigraphy, demonstrating a typical pattern 
of fragmentation (Campbell et al., 1999).
Figure 2
Schematic Activity Data Graphs for Normal Sleep and Fragmented Sleep 
(revised per Amendment 01)
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7.1.2
Unmet Medical Need
While medications are often prescribed to treat sleep difficulties in this patient population, 
there are currently no treatments approved to treat ISWRD.  Benzodiazepine and 
non-benzodiazepine sedative hypnotics can cause confusion, increase cognitive impairment, 
slow reaction, and worsen balance, leading to falls (National Institute of Aging AD treatment 
guide).  Drugs in this class can especially predispose to confusion and falls during middle-of-
the-night awakening (FDA Questions and Answers: Risk of next-morning impairment after 
use of insomnia drugs, 2014). 
Sedating antidepressants such as trazodone, and 
antihistamines with anticholinergic properties, can potentially exacerbate cognitive 
difficulties, sleepiness, and confusion (Peron et al., 2011).  Typical and atypical 
antipsychotics are associated with increased risk of death in elderly dementia patients, which 
resulted in a black-box warning for these drugs, and can also cause sedation, confusion, and 
Parkinsonian symptoms  (FDA Information for Healthcare Professionals: Conventional 
Antipsychotics, 2008).  A recent guideline (Auger et al., 2015) recommends the avoidance of 
currently available sleep aids including melatonin to treat sleep disturbances in patients with 
dementia.  Thus, there is an unmet medical need for an effective and safe alternative to drugs 
that are currently used off-label and carry risks (Salami et al., 2011).
7.1.3
Rationale for a Dual Orexin Receptor Antagonist to Treat Irregular Sleep-
Wake Rhythm Disorder
The orexin neurotransmitter system is directly involved in modulation of the circadian sleep-
wake rhythm, with orexins promoting wakefulness.  In populations with Mild Cognitive 
Impairment (Liguori et al., 2016) and mild to severe AD (Liguori et al., 2014), elevated 
orexin levels have been associated with both disturbed sleep and impaired cognition.  In 
human studies, disrupted sleep was associated with more severe cognitive impairment (lower 
scores on the Mini Mental State Examination [MMSE]) and with higher orexin levels in 
cerebrospinal fluid (CSF).  These higher CSF orexin levels were correlated with higher tau 
protein levels in CSF.  In addition, in these studies, rapid eye movement (REM) sleep was 
shown to be decreased in subjects with higher orexin levels.  As noted, REM sleep is 
involved in memory function.
Thus, lemborexant, a DORA that will block an over-active orexin system, has the potential 
not only to improve sleep, but to impact the underlying neuropathology.
7.1.4
Clinical Experience with Lemborexant
7.1.4.1
Phase 1
E2006-A001-001 (Study 001):  Single ascending dose study.  This study included healthy 
subjects and otherwise healthy subjects with primary insomnia.  In addition to determining 
the safety and tolerability of single doses, the study provided preliminary evidence of 
efficacy in the target patient population.
E2006-A001-002 (Study 002):  Multiple ascending dose study.  This study enrolled healthy 
adult and elderly subjects, each of whom was dosed with lemborexant or placebo at night.  In 
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addition to determining the safety and tolerability of multiple doses, the study also provided 
preliminary evidence of a lack of important differences in exposure between adult and 
elderly subjects.  
E2006-A001-003 (Study 003):  A multiple dose study to bridge pharmacokinetics (PK), 
pharmacodynamics (PD), safety and tolerability between Japanese and white healthy 
subjects.  This study provided evidence of a lack of important differences in exposure and 
safety between Japanese and white subjects.
E2006-A001-004 (Study 004):  Metabolism-based inducer/inhibitor study.  This study 
provided data demonstrating (1) strong inhibitors of CYP3A lead to higher plasma 
concentrations of lemborexant; and (2) strong inducers of CYP3A lead to notably lower 
plasma concentrations of lemborexant. The study also demonstrated a weak effect of 
lemborexant on CYP2B6 activity and no effect on CYP3A activity.
E2006-A001-005 (Study 005):  Relative bioavailability study of capsules vs tablet 
formulations.  This study demonstrated that the capsules and tablets provided similar 
exposure (maximum observed concentration [Cmax] and area under the concentration-time 
curve [AUC]), thus allowing the tablet formulation to be used in future clinical trials.
E2006-A001-007 (Study 007):  Human mass balance absorption, distribution, metabolism, 
and excretion study to characterize the route and extent of excretion of lemborexant. This 
study demonstrated that elimination takes place by fecal (57%) and urinary excretion (29%) 
based on total recovery (86.5%) of radioactivity following a single dose of radiolabeled 
lemborexant. In addition, there were no human-specific metabolites and the only major 
(12%) metabolite was M10.  The blood-to-plasma ratio was approximately 0.65.
E2006-A001-008 (Study 008):  Food effect study.  This study demonstrated a mild food 
effect.  The Cmax was decreased by 23% and the AUC from zero time zero to infinity (AUC[0-
inf]) was increased by 18% following consumption of a high fat meal.
E2006-A001-012 (Study 012):  Drug-drug interaction study.  These study results 
demonstrated that:  (1) coadministration of a moderate CYP3A inhibitor (fluconazole) 
showed a moderate interaction as demonstrated by a 1.63-fold increase in Cmax and 4.2-fold 
increase in AUC of lemborexant; (2) coadministration of lemborexant had no statistically 
significant effect on oral contraceptives (ethinyl estradiol and norethindrone), which also did 
not alter the PK of lemborexant; and (3) concomitant administration of a gastric acid 
suppressant agent had a weak interaction as shown by a 27% decrease in Cmax and no impact 
on AUC of lemborexant.  (revised per Amendment 06)
E2006-E044-106 (Study 106) was a randomized, double-blind, placebo-controlled, 4-way 
incomplete block crossover study in healthy volunteers to evaluate on-road driving safety. 
The primary objective was to demonstrate that lemborexant 2.5, 5, and 10 mg compared to 
placebo (PBO) does not impair driving as assessed by standard deviation of lateral position 
(SDLP) during an on-road driving test in the morning following a single dose (Day 2) and 
multiple doses (Day 9) of lemborexant administered at bedtime.  An active comparator, 
zopiclone 7.5 mg (ZOP) was included for assay sensitivity. All subjects received placebo and 
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zopiclone, and 2 of the 3 lemborexant doses.  A total of 48 subjects were randomized and 
completed all 4 treatment periods; no subject discontinued from the study.  No drives were 
stopped or never started while subjects were taking lemborexant; 3 drives from 2 subjects 
were stopped when subjects were taking ZOP.  The primary objective was met, ie, for drives 
on both Day 2 and Day 9, for all lemborexant doses, the upper bound of the 95% CI for 
SDLP treatment difference from PBO did not exceed the prespecified clinically meaningful 
threshold of 2.4 cm.  Symmetry analyses were not statistically significant for any 
lemborexant dose at either Day 2 or Day 9, indicating that the frequency of subjects with 
SDLP treatment difference from PBO ≥2.4 cm (impaired) was similar to the frequency of 
subjects with SDLP treatment difference from PBO ≤–2.4 cm (improved).  Assay sensitivity 
was demonstrated:  for ZOP, the upper bound of the 95% CI of SDLP treatment difference 
from PBO exceeded 2.4 cm (Days 2 and 9), and the symmetry analyses for ZOP were 
statistically significant (Days 2 and 9). (revised per Amendment 05)
E2006-A001-107 (Study 107):  This Phase 1 study was conducted to evaluate the effects of 
the 5 and 10 mg doses on next-morning residual sleepiness in subjects with insomnia 
disorder.  The study design was randomized, double-blind, and PBO-controlled with a 3-way 
crossover.  Next-morning residual sleepiness was measured on a modified multiple sleep 
onset latency test (M-MSLT).  An active comparator, flurazepam 30 mg, was included to 
confirm assay sensitivity.  Results showed that for neither 5 mg nor 10 mg was the lower 
bound of the 95% CI of the treatment difference in change from baseline of average sleep 
onset latency on the M-MSLT more than -6 minutes, which was the prespecified criterion 
defining clinically meaningful next-morning residual sleepiness.  That is, neither dose level 
of E2006 resulted in a clinically meaningful reduction in average time to sleep onset in the 
morning hours, supporting the safety of these doses and their use in Phase 3 studies.
7.1.4.2
Phase 2
A dose-finding study (E2006-G000-201; Study 201) was conducted in subjects who had 
insomnia disorder, with the primary objectives of identifying doses that resulted in efficacy 
but did not result in significant next-day residual sleepiness. The doses evaluated were 
1, 2.5, 5, 10, 15, and 25 mg, administered once daily for 15 days.  The study was stopped 
early for efficacy after the prespecified success criterion for sleep efficiency (SE) was 
achieved without unacceptable next-day residual sleepiness as evaluated by the Karolinska 
Sleepiness Scale (KSS).
As measured by polysomnography (PSG), improvements in sleep were also demonstrated by 
statistically significant increases from baseline in SE, and by decreases from baseline in 
mean latency to persistent sleep and wake after sleep onset.  These changes were largely 
maintained over 15 days of treatment with lemborexant as compared with placebo.  
Subjective measures derived from sleep diary entries yielded results largely comparable to 
PSG-derived results.  Further, there was no evidence of rebound insomnia after treatment 
was completed, as measured either by PSG or sleep diary.
At doses up to 10 mg, changes from baseline in next-day sleepiness, as measured by the 
KSS, did not differ from those after placebo.  At the highest doses of 15 and 25 mg, the 
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increase in KSS from baseline was statistically significantly different from placebo at some 
time points, but the increases in KSS were of small magnitude (ie, less than 1 unit on 
average).  Although there was approximately a one- to two-fold accumulation of lemborexant 
in plasma over the 15-day Treatment Period across the dose range, next-day sleepiness did 
not increase from the beginning to the end of treatment.
7.1.4.3
Summary of Clinical Experience
Overall, data from the clinical program to date have shown an acceptable safety and 
tolerability profile of lemborexant, and efficacy on both objective and subjective measures of 
sleep onset and sleep maintenance.
At the doses (2.5/5/10 mg) currently being studied for the treatment of insomnia disorder, 
lemborexant has been well-tolerated. In the Phase 2 study (E2006-G000-201 [Study 201]), 
lemborexant had no significant impact on morning cognitive performance tasks.  
Lemborexant was shown to improve sleep latency and sleep maintenance, both objectively 
by PSG and subjectively via daily sleep diaries.   In addition, lemborexant increases total 
sleep time, including REM sleep, which may help to improve or stabilize memory function.
Safety and efficacy findings in elderly subjects with insomnia were not different from those 
in younger subjects.  There are no important exposure differences between males and females 
or between older and younger individuals.  Lemborexant is metabolized by CYP3A4. 
Although donepezil and galantamine are also metabolized by CYP3A4, the likelihood of 
interaction with lemborexant is low as lemborexant is not a CYP3A inhibitor. Memantine is 
metabolized by pathways not involving CYP3A4.  Therefore, the drugs typically
administered for amelioration of dementia are not expected to have any clinically relevant 
metabolic interactions with lemborexant. However, an analysis will be conducted to identify 
any potential PK interactions between lemborexant and these drugs.  (revised per 
Amendment 03)
In general, E2006 does not impact CYP3A substrates but has a mild effect on CYP2B6 
substrates. Co-administration with a moderate inhibitor of CYP3A (fluconazole) and a
strong inhibitor of CYP3A (itraconazole) increased plasma concentration whereas the 
exposure was greatly reduced by a strong CYP3A inducer (rifampin).  Therefore, moderate 
and strong inhibitors and strong inducers are prohibited.  Following the ingestion of a high-
fat breakfast, a mild food effect was noted in the fed condition of a standard food effect study. 
Lemborexant should not be consumed within a few hours of a meal.  (revised per 
Amendment 06)
7.1.5
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure
Not applicable.
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7.2
Study Rationale
The present study will evaluate the effects of daily lemborexant doses for 4 weeks in subjects
with mild or moderate AD-D who complain of disrupted sleep or multiple awakenings at 
night along with frequent periods of falling asleep during the day that impacts the quality of 
life of the subject. In addition to actigraphy, a battery of psychometric assessments will be 
administered to evaluate effects on well-being of both the subject and the caregiver.  The use 
of these measures in this subject population during administration of lemborexant should lead 
to a better understanding of the therapeutic potential of lemborexant in ISWRD.
8
STUDY OBJECTIVES
8.1
Sleep-Related Objectives  (Revised per Amendments 05 and 06)

To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 10 mg 
(LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change from baseline 
in actigraphy-derived Sleep Efficiency (aSE)  during the last week of treatment in 
subjects with Alzheimer’s disease dementia (AD-D) who have ISWRD. (revised per 
Amendments 01, 05, and 06)

To determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO on 
the change from baseline aSE during each week of treatment.  (revised per 
Amendment 06) 

To determine the efficacy of lemborexant LEM2.5, LEM5, LEM10 and LEM15 
compared to PBO on the change from baseline on the Sleep Fragmentation Index (SFI)
during each week of treatment. (revised per Amendment 06)To determine the change 
from baseline of the mean duration of wake bouts (aMeanDurWB) over each week of 
treatment.  (revised per Amendment 06)
8.2
Wake-Related Objectives (revised per Amendments 05 and 06)

To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 10 mg 
(LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change from baseline 
in actigraphy-derived Wake Efficiency (aWE)  during the last week of treatment in 
subjects with Alzheimer’s disease dementia (AD-D) who have ISWRD. (revised per 
Amendments 01, 05, and 06)

To determine the efficacy of lemborexant LEM2.5, (LEM5, LEM10, and LEM15 
compared to PBO on the change from baseline of actigraphy-derived Wake Efficiency 
(aWE) during each week of treatment.  (revised per Amendment 06)

To determine the efficacy of lemborexant LEM2.5, LEM5, LEM10, and LEM15 
compared to PBO on the change from baseline of the Wake Fragmentation Index (WFI)
during each week of treatment. (revised per Amendments 01 and 06)

To determine the change from baseline of the mean duration of sleep bouts 
(aMeanDurSB) over each week of treatment.  (revised per Amendment 06)
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8.3
Circadian Rhythm-Related Objectives  (revised per Amendments 
05 and 06)

To evaluate onset and treatment course effect as measured by change from baseline of
intradaily variability (IV), interdaily stability (IS), amplitude of the rest-activity rhythm 
(AMP), relative amplitude of the rest-activity rhythm (RA), and other actigraphy 
variables during each week of treatment.  (revised per Amendment 06)
8.4
Additional Objectives  (revised per Amendment 05 and 06)

To evaluate the safety and tolerability of lemborexant.

To explore the effects of LEM2.5, LEM5, LEM10, LEM15, and PBO at the end of 
4 weeks of treatment (unless otherwise specified)` on the following:

Change from baseline of sum of activity counts and change from baseline of the 
number of bouts >10 minutes of sleep in the first 3 hours after morning waketime on 
each of the first 3 days and last 3 days of treatment as an indicator of next-morning 
residual effects.

Potential rebound ISWRD in the 2 weeks following 4 weeks of treatment.

Onset and course of treatment effect as measured by change from baseline of 
Clinician's Global Impression of Change-ISWRD (CGIC-ISWRD) Scale on 
symptoms of ISWRD total score and domains. (revised per Amendments 01 and 06)

Change from baseline of Alzheimer’s Disease Assessment Scale – Cognitive 
Subscale (ADAS-cog).

Change from baseline in Mini Mental State Examination (MMSE).

Change from baseline in sleep quality in caregivers  as measured by the Pittsburgh 
Sleep Quality Index (PSQI).

Change from baseline of caregiver burden on the Zarit Burden Interview – short form 
(ZBI).

Change from baseline of Health outcomes of the subject and/or caregiver on the 
EuroQOL version 5D-5L (EQ-5D-5L) (subject Self Version, caregiver Self Version, 
caregiver Proxy 1 Version).

Change from baseline of Mood and behavior on the Neuropsychiatric Inventory (NPI-
10; by caregiver as proxy for the subject).

To characterize the pharmacokinetics (PK) of lemborexant using the population 
approach.

To explore the PK/pharmacodynamic (PD) relationship between exposure to 
lemborexant and selected efficacy variables and most frequently occurring treatment-
emergent adverse events (TEAEs).

To assess the plasma concentrations of cognitive enhancers (cholinesterase inhibitors 
and/or memantine) and lemborexant in subjects taking such drugs.
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
To evaluate the long-term safety and tolerability of flexible doses of LEM5, LEM10, 
and LEM15 per day over a period of 30 months in subjects with ISWRD who have 
completed the Core Study (revised per Amendments 05 and 06).
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E2006-G000-202 is a multicenter, randomized, double-blind, PBO-controlled, parallel-group 
study of 4 doses of lemborexant or PBO taken daily for 4 weeks in approximately 60 male or 
female subjects, ages 60 to 90 years, with mild or moderate AD-D who complain of 
disrupted sleep or multiple awakenings at night along with frequent periods of falling asleep 
during the day that impacts the quality of life of the subject.  For each subject, an individual 
who knows the subject well and will provide the information about themselves will also be 
enrolled in the study (see Caregivers and Informants, below).  Additional informants may 
also be associated with the study but will not be required to complete a consent form.
(revised per Amendments 01 and 06)
The study will have 3 phases: the Prerandomization Phase, the Randomization Phase, and the 
Extension Phase (Figure 3). The Prerandomization Phase will comprise 2 periods that will 
last up to a maximum of 42 days: a Screening Period and a Baseline Period. 
The 
Randomization Phase will comprise a Treatment Period during which subjects will be treated 
for 4 weeks, and a minimum 14-day Follow-Up Period before an End of Study visit.  The 
Extension Phase comprises a 30-month Maintenance Period and a 14-day Follow-Up Period.  
Subjects who complete the Core Study End of Study (EOS) Visit within 30 days prior to 
enrollment in the Extension Phase will be eligible for participation.  For subjects continuing 
directly from the Core Study into the Extension Phase, the EOS Visit of the Core Study will 
be the start of the Extension Phase.  Subjects who complete the Core Study, but who do not 
elect to immediately continue into the Extension Phase have up to 30 days after the EOS 
Visit to participate.  These subjects will be required to return to the site within 30 days of 
completion of the EOS Visit to repeat selected assessments before being dispensed drug for 
the Extension Phase.  (revised per Amendments 03 and 05)
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will 
undergo routine safety assessments at specified visits, including questioning regarding AEs; 
suicidality; 12-lead electrocardiograms (ECGs); vital signs, weight; clinical hematology and 
chemistry analysis; and urinalysis.  (revised per Amendment 01)
Subjects will not be excluded if they attend adult day care as long as the day care staff can 
ensure that the actigraph remains on the subject’s wrist and, if removed, is returned as 
promptly as possible, with notation of the replacement noted for the informant to include on 
the sleep log.  (revised per Amendment 01)
9.1.1
Caregivers and Informants (revised per Amendment 01)
For the subject to enroll, there must be 1 or more persons who can provide the required 
information for assessments, complete the sleep log for actigraphy, and ensure that the 
subject is dosed at the appropriate time.  These roles can be fulfilled by the same or different 
individuals. For each subject, one individual will be designated as the “caregiver informant”
(or “caregiver”), who will be sufficiently familiar with the subject to provide information to 
the site staff with respect to the subject’s sleep and wake patterns, behavior, mood, AEs, and 
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quality of life.  Typically, the caregiver informant will need to spend at least 10 hours per 
week with the subject.  (revised per Amendment 01)
If the caregiver informant does not reside with the patient, then the other informant(s) will be 
responsible for ensuring that the sleep log is completed daily and that dosing occurs at the 
appropriate time.  There can be more than one such informant, as in the case of home health 
aides who stay with the subject during the week and change on the weekend.  (revised per 
Amendment 01)
If the individual who is originally designated as the caregiver informant cannot fulfill the 
function, he/she may be replaced by a suitable alternate until the Baseline Visit, and 
thereafter only following consultation with the Sponsor.  (revised per Amendment 01)
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Figure 3
Study Design (revised per Amendments 03 and 05)
Note:  Visit 1 is an optional Prescreening Period for subjects and caregivers who are unsure whether the subject has Irregular Sleep-Wake Rhythm Disorder 
(ISWRD). Subjects will wear an activity tracker for approximately 4 days, then return to the site to have the data from the activity tracker downloaded and 
analyzed to determine whether they are candidates for the study.  (revised per Amendment 05)
V6A
V7 to V24
   V5
  V4
VE25
Extension Phase
Maintenance
(up to 30 months)
Follow-Up
(2 weeks)
V 1
   V2
   V1
   V3
Phase
Prerandomization
Randomization
Optional
Pre-
Screen-
ing
Screening
(up to 6 weeks)
(≥2 weeks
actigraphy)
Treatment (4 weeks)
(4 weeks actigraphy)
Follow-Up
(2 weeks 
actigraphy)
Period
Baseline /
Randomi-
zation
V6A
EOS Visit for Core 
Study / First visit 
for Extension 
Phase
V7 and V8
Days 73 and 
103
Clinic visits
V9, V12, V15, V18, V19, V20, V21, V22, V23, V24
Days 133, 223, 313, 403, 493, 583, 673, 763, 853, 
and 943
Clinic visits
V10, V11, V13, V14, V16, V17
Days 163, 193, 253, 283, 343, and 373
Telephone visits
V25
Day 957
End of Study
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Note:  Visit 2 is a caregiver visit for downloading actigraphy data to determine eligibility; Visit 3 is the baseline visit for both subject and caregiver; Visit 4 
is a visit for both subject and caregiver to download actigraphy data and perform safety assessments; Visit 5 is the end-of-treatment assessments visit; and Visit 
6A is for end-of-study assessments for the Core Study. For subjects continuing directly from the Core Study into the Extension Phase, Visit 6A will be the start 
of the Extension Phase.  Subjects who complete the Core Study, but who do not elect to immediately continue into the Extension Phase have up to 30 days after
Visit 6A to participate.  These subjects will be required to repeat selected assessments (Visit 6B) before being dispensed drug for the Extension Phase.  Some 
subjects will have fewer visits based on the availability of lemborexant commercially.  (revised per Amendment 05)
, ISWRD = Irregular Sleep-Wake Rhythm Disorder, V = Visit.
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9.1.2
Prerandomization Phase
9.1.2.1
Optional Prescreening
There may be circumstances where the subject and/or caregiver is not sure whether the 
subject has an ISWRD pattern of sleep and wake, and would benefit from reviewing a report 
on the subject’s sleep/wake pattern before agreeing to participate in the study.  In these cases, 
the sites can offer the subject an opportunity to wear a designated activity tracker before 
consenting to the rest of the study procedures.  A separate prescreening consent form would 
be signed by the subject and his/her legal representative for this purpose.  After wearing the 
device for approximately 4 days, the subject and caregiver would be scheduled to return to 
the clinic so that the output from the device can be reviewed.  At that time, the subject and 
caregiver would decide whether to participate in the study, which will require the study 
consent forms to be completed as described above. (revised per Amendment 05)
9.1.2.2
Screening Period 
The maximum duration of the Screening Period will be 42 days. At the first visit, informed 
consent will be obtained after the study has been fully explained to each subject and 
caregiver and before the conduct of any screening procedures or assessments (see Optional 
Prescreening [above]).  Subjects or their legal representative will sign the informed consent; 
caregivers must sign a separate consent form.  The clinician will confirm that the subject 
meets diagnostic criteria for AD-D, based on the National Institute on Aging/Alzheimer’s 
Association Diagnostic Guidelines. If documentation of the AD diagnosis is not available, 
investigators may order a computed tomography (CT) scan and relevant blood tests to rule 
out other possible causes of dementia. A medical, psychiatric, and sleep history interview 
will be conducted, and will include confirmation that the subject meets diagnostic criteria for 
Circadian Rhythm Sleep Disorder, Irregular Sleep Wake Type.  Subjects will be administered 
the MMSE and the electronic version of the Columbia Suicide Severity Rating Scale 
(eC-SSRS), and will undergo the subject component of the Cornell Scale for Depression in 
Dementia (CSDD) interview.  Additional eligibility criteria will be evaluated and clinical 
laboratory tests, ECG, vital signs, height, and weight will be assessed.  Caregivers will be 
administered the caregiver input component of the CSDD.  (revised per Amendments 03 and 
05)
Eligible subjects will be provided with an actigraph (for actigraphy) to wear continuously 
throughout the study.  They will be asked to provide a typical (habitual) time when the 
subject goes to sleep at night. (revised per Amendments 02 and 05)
The appropriate informants will be provided with a daily log (sleep period log) to note the 
start and end times of the subject’s actual time in bed each day during the night and to log the 
approximate times that the actigraph was replaced on the subject’s wrist, if inadvertently
removed.  The informants will be trained in the use of the actigraph and the log.  Site staff 
will instruct informants (1) in the evening, to fill in the times when the actigraph was not 
worn; and (2) in the morning, to fill out the bedtimes and morning rise times, and will 
emphasize the importance of doing so.  Sites will also arrange for the subject to undergo a 
diagnostic sleep study either at a sleep center or at home to determine the presence or 
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absence of sleep apnea, unless one has been obtained within the previous 6 months.  Before 
randomization, the investigator will be required to review a report detailing the subject’s 
apnea-hypopnea index. (revised per Amendments 01, 02, 03, and 05)
After subjects have worn the actigraph for at least 14 days, caregivers will return to the 
clinic.  The actigraph data will be downloaded and transmitted to the central reader along 
with the sleep log of bedtimes, morning wake times, and times when the actigraph was 
replaced on the subject’s wrist.  Adverse events and concomitant medication use will be 
recorded.  The sites will keep the actigraph at the clinic until the Baseline visit, when the 
device will again be provided to the subjects.  The central scoring will determine whether the 
data from the screening period meet the quality standards required by the inclusion criteria.
(revised per Amendment 05)
During the Screening Period, subjects who meet the eligibility criteria for ISWRD on the 
basis of actigraphy and are not excluded on the basis of the diagnostic sleep study for sleep 
apnea will then be scheduled for the Baseline visit.  Subjects who did not meet eligibility 
criteria based on actigraphy may be rescreened, following consultation with the Sponsor, as 
long as they were not excluded based on apnea-hypopnea index (AHI).  (revised per 
Amendments 01 and 05)
9.1.2.3
Baseline Period
On Day 1, the Screening Period will end and the Baseline Period will take place.  The 
Baseline visit must occur no earlier than 2 days and no later than 27 days after Visit 2 
(caregiver visit), and may be scheduled across 2 consecutive days if necessary. Clinical 
laboratory tests, an ECG, vital signs, AEs, concomitant medications, and weight will be 
assessed.  The site on the arm where the actigraph is applied will be examined.  A plasma 
sample will be obtained from any subject taking any cognitive enhancer(s) and will be used 
to measure plasma concentrations of the enhancer(s).  As proxy for the subject, caregivers 
will complete the SDI, NPI-10 and the EQ-5D-5L (Proxy Version 1).  The caregiver will also 
complete the EQ-5D-5L, ZBI-short, and the PSQI for himself/herself.  The subject will be 
administered the ADAS-cog and the EQ-5D-5L (Self version). The rater will complete the 
baseline assessment for the CGIC-ISWRD Scale.  (revised per Amendment 01 and 03)
9.1.3
Randomization Phase
9.1.3.1
Treatment Period
The Treatment Period will begin on the evening of Day 1 and will continue for 4 weeks.  
Subjects will be randomized, in a double-blind manner, to receive LEM2.5, LEM5, LEM10, 
LEM15, or PBO.  Study drug will be dispensed to the caregiver.  During the Treatment 
Period, subjects will take study drug each night immediately (ie, within 5 minutes) before 
bedtime (defined as the median bedtime [median calculated bedtime (MCB)], calculated 
based on the sleep log during Screening). Time of dosing will be collected on the sleep log 
and entered by the sites into the appropriate electronic case report form (eCRF).  (revised per 
Amendments 01 and 05)
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After approximately 2 weeks of the Treatment Period, caregivers and subjects will return to 
the clinic.  The actigraph data will be downloaded and transmitted to the central reader along 
with the sleep log.  Vital signs will be assessed at this visit.  Adverse events, treatment 
compliance, and concomitant medication use will be recorded.  The site on the arm where the 
actigraph is applied will be examined.
If the subject experiences an AE that results in a temporary discontinuation of study 
medication, a rechallenge is possible following consultation with the Medical Monitor.  
(revised per Amendment 05)
At the end of 4 weeks, subjects will return to the clinic with their caregivers for end of 
Treatment Period assessments.  The site on the arm where the actigraph is applied will be 
examined.  Clinical laboratory tests, an ECG, vital signs, and weight will be assessed, and 
AEs and concomitant medications will be recorded.  Treatment compliance will be assessed.  
As proxy for the subject, caregivers will complete the SDI, NPI-10 and the EQ-5D-5L (Proxy 
Version 1).  The caregiver will also complete the EQ-5D-5L, ZBI-short, and PSQI for 
himself/ herself. Subjects will be administered the ADAS-cog, MMSE, EQ-5D-5L, and the 
eC-SSRS.  A PK sample will be obtained.  The CGIC-ISWRD Scale rater will complete the 
CGIC-ISWRD Scale.  Actigraphy data will be downloaded, and the actigraph will be returned 
to the subject for the Follow-Up Period. (revised per Amendment 01)
During the End of Treatment visit, the study staff will discuss the Extension Phase with
potentially eligible subjects and caregivers. (revised per Amendment 05)
9.1.3.2
Follow-Up Period
The Follow-Up Period will begin when subjects leave the clinic at the end of the Treatment 
Period. Subjects will cease taking study drug but will continue to wear the actigraph until the 
End of Study visit.
At least 14 days but no more than 18 days after the end of the Treatment Period, subjects and 
caregivers will return to the clinic for the End of Study Visit.  Clinical laboratory tests, an 
ECG, vital signs, and weight will be assessed, AEs and concomitant medication use will be 
recorded, and the site on the arm where the actigraph is applied will be examined.  
Actigraphy data will be downloaded and transmitted to the central reader along with the sleep 
log.   
A subject who prematurely discontinues taking study drug should return to the clinic as soon 
as possible after discontinuing study drug, to complete an Early Termination Visit and a 
Follow-Up Visit after 14 days.  If the subject discontinues from the study due to an AE, the 
subject must complete an Early Termination Visit, and the AE must be followed to resolution 
or for 2 weeks, whichever comes sooner.  (revised per Amendment 05)
9.1.4
Extension Phase
The Extension Phase will provide supportive data on the safety and tolerability of 
lemborexant in the long-term treatment of ISWRD in subjects with AD.  The Extension 
Phase will consist of a 30-month Maintenance Period and a 14-day Follow-Up Period.  
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Subjects who complete the Core Study EOS Visit within 30 days prior to enrollment in the 
Extension Phase will be eligible for enrollment. (revised per Amendment 05)
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Rationale for Efficacy Assessments
Irregular Sleep-Wake Rhythm Disorder (ISWRD) is clinically differentiated from insomnia 
(Section 7.1.1).  Therefore, although Study E2006-G000-202 (Study 202) includes typical 
insomnia endpoints, these endpoints only relate to nighttime sleep and are not sufficient to 
assess ISWRD.  In Study 202, both sleep efficiency and wake efficiency will be calculated.  
In addition to aSE and aWE, actigraphy also provides sleep fragmentation and activity 
indices, which can help determine the effect of treatment.  While the primary efficacy 
analyses will be conducted on data from the end of treatment, actigraphy data will also be 
analyzed during each week to detect the onset of efficacy.  
9.2.2
Rationale for Subject Population
Patients with AD-D constitute the subject population (Section 7).  Irregular Sleep-Wake 
Rhythm Disorder occurs in other types of dementia besides AD-D.  However, the Lewy 
Body Dementias, which include both Dementia with Lewy Bodies and Parkinson’s Disease 
Dementia, are associated with REM behavior disorder, a sleep disorder in which the normal 
inhibition of the motor muscles during REM sleep is reduced, allowing bodily movement.  
As a result, patients can act out their dreams, putting them and their bed partners at risk of 
bodily injury.  These subjects are, therefore, excluded from participation, as are subjects with 
Parkinson’s disease (a Lewy body disorder) even without Parkinson’s Disease Dementia, and 
any subject with a history of REM behavior disorder within the previous year, or with 
evidence of REM behavior disorder from the diagnostic recording.
9.2.3
Rationale for Dose Selection
The rationale for dose selection is explained in Section 9.4.4.
9.2.4
Rationale for Duration of Treatment
In the Core Study, subjects will be treated for 4 weeks.  Based on data from Study 201, it 
would be expected that nocturnal sleep variables may improve early in treatment, since 
lemborexant was efficacious after the first 2 doses.  However, it may take longer for the 
daytime variables to improve.  (revised per Amendment 05)
In the Extension Phase, treatment will last for a maximum duration of 30 months, until 
lemborexant is commercially available, or until the lemborexant clinical development 
program for ISWRD is discontinued. (revised per Amendment 05)
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9.2.5
Rationale for Study Endpoints
As noted, ISWRD is not insomnia.  While this study includes typical insomnia endpoints, 
these are not sufficient to assess ISWRD, since these endpoints only relate to nighttime sleep.  
In Study 202, both sleep efficiency and wake efficiency will be derived from actigraphy, 
since assessment requires recording throughout the 24-hour day.  In addition to aSE and 
aWE, actigraphy also provides sleep fragmentation and activity indices, which can help 
determine the effect of treatment.  During the nocturnal sleep period, sleep and wake bouts 
will be assessed to determine whether subjects are able to return to sleep more quickly at 
night.
9.2.6
Randomization
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
9.2.7
Study Controls
A placebo control has been incorporated into the study design in a 1:1:1:1:1 ratio.  Subjects 
receiving placebo will undergo the same procedures as subjects receiving lemborexant.  No 
active control is available as there are no currently approved treatments for ISWRD.
9.2.8
Adjudication Committee (revised per Amendment 02)
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure. A set of 
preferred terms constituting a customized Medical Dictionary for Regulatory Activities 
(MedDRA) query for cataplexy or seizure will be used to identify events for adjudication 
(including cataplexy, muscle fatigue, muscular weakness, muscle tone disorder, hypotonia, 
drop attacks, slurred speech, diplopia, falls, convulsions [standardized MedDRA query 
(SMQ) narrow and broad], atypical migraine, loss of consciousness, decreased 
consciousness, myoclonus, syncope, transient global amnesia, lipothymia, [faintness] and 
transient ischemic attack). To assist in the preparation of narratives about such events and to 
support the committee’s adjudication process, investigators and site staff will be instructed to 
query subjects who report any of the above events for supplemental information using a 
questionnaire for events potentially related to cataplexy and the serious adverse event (SAE) 
form for any of the above events considered serious.  (revised per Amendments 02 and 06)
9.3
Selection of Study Population
It is expected that approximately 230 subjects will be screened to provide approximately 60
randomized subjects at approximately 60 sites in the US, EU, and Japan.  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. (revised per Amendments 01, 04, 05, and 06)
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9.3.1
Inclusion Criteria for Subjects (revised per Amendment 05)
Subjects must meet all of the following criteria to be included in this study:
1. Male or female, age 60 to 90 years at the time of informed consent (revised per 
Amendment 01)
2. Able to provide informed consent. If a subject lacks capacity to consent in the 
investigator's opinion, the subject's assent should be obtained, if required in accordance 
with local laws, regulations and customs, and the written informed consent of a legal 
representative should be obtained (capacity to consent and definition of legal 
representative should be determined in accordance with applicable local laws and 
regulations).
3. Documentation of diagnosis with Alzheimer’s disease dementia on the basis of the 
National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines 
4. MMSE 10 to 26 at Screening (revised per Amendments 01 and 03)
5. Meets criteria for Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type (DSM-
5) and the 10th revision of the ICD-10, as follows: Complaint by the subject or caregiver 
of difficulty sleeping during the night and/or excessive daytime sleepiness associated 
with multiple irregular sleep bouts during a 24-hour period (revised per Amendment 03)
6. Frequency of complaint of sleep and wake fragmentation ≥3 days per week
7. Duration of complaint of sleep and wake fragmentation ≥3 months
8. During the Screening Period, mean aSE <87.5% within the defined nocturnal sleep period 
and mean aWE <87.5% during the defined wake period (revised per Amendments 02 and 
05)
9.
Confirmation by actigraphy of a combination of sleep bouts of >10 minutes during the 
wake period plus wake bouts of >10 minutes during the sleep period, totaling at least 4 
bouts per 24 hours period, ≥3 days per week
10. Ambulatory and living in the community or in a residence not classified as a skilled 
nursing facility (an assisted living facility with separate living quarters for subjects and 
caregiver or informants is acceptable) (revised per Amendment 01)
11. Willing not to start a behavioral or other treatment program for sleep or wake difficulties 
and not to start a new treatment for other symptoms of AD-D during participation in the 
study
12. Has a reliable and competent caregiver (or caregiver or informants) who can accompany 
the subject to study visits, administer study medication on a nightly basis and provide 
information on the status of the subject (revised per Amendment 01)
13. For subjects taking a cholinesterase inhibitor and/or memantine, dosing regimen must 
have been stable for at least 3 months
Inclusion Criteria for Caregivers (per Amendment 05)
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Caregivers must meet all of the following inclusion criteria for subjects to be included in the 
study:
14. Able to provide informed consent
15. Spends at least 10 hours per week with the subject (revised per Amendment 01)
16. Able to meet caregiver requirements (Subject Inclusion Criterion #13)
17. Willing to provide information on himself/herself regarding sleep quality and caregiver 
burden
9.3.2
Exclusion Criteria for Subjects (revised per Amendment 05)
1. A diagnosis of vascular dementia, dementia following multiple strokes, or any 
synucleinopathy/Lewy body disorder.  This includes Dementia with Lewy Bodies and 
Parkinson’s disease with or without dementia.
2. A current diagnosis of moderate to severe obstructive sleep apnea (OSA) or central sleep 
apnea, or current use of continuous positive airways pressure even if mild severity of 
OSA, restless legs syndrome, or narcolepsy
3. An Apnea-Hypopnea Index or equivalent ≥15 events/hour on diagnostic sleep study 
conducted prior to Baseline or within 6 months of Screening 
4. A clinically significant movement disorder that would affect the differentiation of sleep 
and wake by the actigraphy analytic algorithm
5. Current symptoms or history during the past year of Rapid Eye Movement (REM) 
Behavior Disorder or sleep-related violent behavior 
6. Probable Major Depression, as evidenced by score >10 on the CSDD at Screening
7. Unable to tolerate wearing the actigraph.  At a minimum, subjects must be able to wear 
the actigraph for 5 complete days out of 7 days’ data.  A day will be considered complete 
as long as data from 90% of the 24-hour period are able to be scored.
8. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
ISWRD
9. History of drug or alcohol dependency or abuse within approximately the previous 
2 years
10. Reports habitually consuming more than 14 drinks containing alcohol per week or 
habitually consumes alcohol within 3 hours before bedtime and unwilling to limit alcohol 
intake to 2 or fewer drinks per day or to forego having alcohol within 3 hours before 
bedtime for the duration of his/her participation in the study
11. Known to be human immunodeficiency virus positive
12. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
13. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at 
Screening (repeated only if initial ECG indicates a QTcF interval >450 ms) (subjects with 
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evidence of bundle branch block are not excluded if the block is not clinically significant, 
as documented by the investigator in the source document) (revised per Amendment 01)
14. Current evidence of clinically significant disease that in the opinion of the investigator(s) 
could affect the subject’s safety or interfere with the study assessments
15. Any history of a medical or psychiatric condition other than AD-D that in the opinion of 
the investigator(s) could affect the subject’s safety or interfere with the study assessments
16. History of  malignancy within the previous 5 years except for adequately treated basal 
cell or squamous cell skin cancer or cervical carcinoma in situ
17. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 and 5 on the Suicidal 
Ideation section of the eC-SSRS.
18. Any suicidal behavior in the past 10 years based on the eC-SSRS (revised per 
Amendment 01)
19. History of violence toward the caregiver or others
20. Scheduled for surgery using general anesthesia during the study (revised per 
Amendment 03)
21. Used any prohibited prescription or over-the-counter concomitant medications within 1 
week or 5 half-lives, whichever is longer, before starting actigraphy during Screening (A 
list of prohibited concomitant medications is presented in Appendix 3 of the protocol)
22. Used any modality of treatment for ISWRD between Screening and Randomization, 
based on approaches related to circadian rhythms, including phototherapy (light therapy), 
melatonin and melatonin agonists (revised per Amendment 03)
23. Failed treatment with Belsomra® (efficacy and/or safety) following treatment with an 
appropriate dose and of adequate duration in the opinion of the investigator
24. Transmeridian travel across more than 3 time zones between Screening and 
Randomization, or plans to travel across more than 3 time zones during the study
25. Hypersensitivity to lemborexant or to its excipients
26. Currently enrolled in another clinical trial, except for observational studies with no 
treatment component (revised per Amendment 01)
27. Used any investigational drug or device before informed consent (ie, within 30 days or 
5× the investigational drug half-life whichever is longer or 6 months for potential 
disease-modifying drugs)
28. Previously participated in any clinical trial of lemborexant
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
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A subject who discontinues study treatment should complete the set of end-of-treatment 
procedures, and protocol-specified information will be collected.  The primary reason for 
discontinuation and all other reason(s) contributing to the subject’s discontinuation from 
study drug(s) should be collected on the Subject Disposition eCRF page.  In addition, the 
date of last dose of study drug(s) will be recorded.  
9.4
Treatments
9.4.1
Treatments Administered (revised per Amendment 05)
Core Study
Lemborexant 2.5 mg, 5 mg, 10 mg, 15 mg or lemborexant-matched placebo treatments will 
be taken orally in tablet form each night for 28 consecutive nights immediately (ie, 
5 minutes) before the time the subject intends to try to sleep.  All subjects will receive 
2 tablets as described below, according to the treatment arm to which the subject has been 
randomized:
•
LEM2.5: one lemborexant 2.5-mg tablet and one lemborexant-matched placebo tablet 
•
LEM5: one lemborexant 5-mg tablet and one lemborexant-matched placebo tablet
•
LEM10: one lemborexant 10-mg tablet and one lemborexant-matched placebo tablet 
•
LEM15: one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
•
PBO: two lemborexant-matched placebo tablets 
9.4.2
Identity of Investigational Products
The sponsor will provide lemborexant tablets in strengths of 2.5 mg, 5 mg, 10 mg and 
lemborexant-matched placebo, identical in appearance.  Tablets will be packaged in blister 
packs in a double-blind manner.  For US and EU sites only, the blister packs will be child 
resistant. (revised per Amendment 04)
Each subject will be dispensed a single pack at on Day 1. The subject will take 2 tablets a 
day; in a combination of 2.5
mg, 5 mg and 10 mg lemborexant tablets or 
lemborexant-matched placebo tablets.  Each pack will contain a 33-day supply of tablets in 
double-blind fashion.
Extension Phase
Details on treatments administered during the Extension Phase are provided in Appendix 4.  
(revised per Amendment 05)
9.4.2.1
Chemical Name, Structural Formula of E2006
•
Test drug code:   E2006
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•
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
Placebo to match lemborexant
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
The following information must be provided:
•
For clinical study use only
•
Name and address of the sponsor
•
Chemical name/drug identifier
•
Lot number/batch number
•
Storage conditions, expiration date if necessary
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 if regionally required, the head 
of the medical institution) 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
Approximately 60 subjects will be randomized to one of the following treatment arms: PBO, 
LEM2.5, LEM5, LEM10, or LEM15, in an approximate 1:1:1:1:1 ratio, stratified by country.  
Randomization will be based on a computer-generated randomization scheme that will be 
reviewed and approved by an independent statistician.  The randomization scheme and 
identification for each subject will be included in the final clinical study report for this study.
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9.4.4
Selection of Doses in the Study
The primary objective is to characterize the dose response of LEM2.5, LEM5, LEM10 and 
LEM15 compared to PBO.  The doses were chosen based on those included in the insomnia 
Phase 3 program (LEM2.5, LEM5 and LEM10).  A higher dose (LEM15) was also included 
because this is a new population for studies of lemborexant.  If LEM15 is associated with 
unexpected tolerability issues, sufficient preliminary data from lower doses of lemborexant 
will be available upon which to assess efficacy and inform dose selection for the Phase 3 
program.
9.4.5
Selection and Timing of Dose for Each Subject
Lemborexant 2.5 mg, 5 mg, 10 mg, 15 mg or lemborexant-matched PBO treatments will be 
taken orally in tablet form each night for 28 consecutive nights immediately before the time 
the subject intends to try to sleep.  All subjects will receive 2 tablets.
9.4.6
Blinding
During the Randomization Phase, subjects and all personnel involved with the conduct and 
interpretation of the study, including investigators, site personnel, and sponsor staff will be 
blinded to the treatment codes.  Randomization data will be kept strictly confidential, filed 
securely by an appropriate group with the sponsor or CRO and accessible only to authorized 
persons (eg, Eisai Global Safety) until the time of unblinding, per standard operating 
procedure.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor to ascertain the necessity of 
breaking the code.
9.4.7
Prior and Concomitant Therapy
Potential subjects who are taking a cholinesterase inhibitor and/or memantine will be allowed 
in the study provided that the treatment regimen has been stable for at least 3 months. 
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a 
maximum of 2 alcohol-containing drinks on a given day while in the study, and will be 
instructed not to consume any alcohol within 3 hours before bedtime.  Because the definition 
of a standard drink varies among countries and regions, no definition of the volume or 
alcohol content of a standard drink is provided, with the exception of Japan.  For sites and 
subjects in Japan, a drink will be defined as 360 mL of beer, 150 mL of wine, or 50 mL of 
liquor.
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9.4.7.1
Drug-Drug Interactions
Not applicable
9.4.7.2
Prohibited Concomitant Therapies and Drugs
Prohibited medications include anticholinergic drugs, moderate and strong CYP3A inhibitors 
and all CYP3A inducers.  Prohibited therapies include any treatment for ISWRD based on 
modifying circadian rhythms, including bright light therapy, melatonin and melatonin 
agonists. In this context, phototherapy refers specifically to the use of timed bright light as a 
therapeutic intervention. (revised per Amendments 03 and 06)
Medications that are used to treat behaviors associated with ISWRD, such as antipsychotic 
medications or trazodone, are permitted provided that the subject has been taking a stable 
dose for at least 1 month. The prohibition applies even if the entire class to which that 
medication belongs is not prohibited (eg, anticonvulsants).  (revised per Amendment 03)
If a medication is not on the list of prohibited medications but, in the opinion of the 
investigator, causes or exacerbates the subject’s ISWRD, it must not be used throughout the 
study.  If a medication is not specified as prohibited but is in the same class as a medication 
that is listed in Appendix 3, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy that would compromise the safety of 
the subject, he/she must discontinue from the study, with the exception that certain prohibited 
medications may be used for a short duration (not to exceed 2 weeks) to treat an acute 
condition if this is agreed with the Medical Monitor.  Note that moderate and strong CYP3A 
inhibitors and CYP3A4 inducers will not be permitted at any time for any duration during the 
study.  (revised per Amendment 06)
Rescue medications will be permitted to treat significant agitation or anxiety. They should be 
used for the shortest period of time, and no more than 3 days per week, and at the lowest 
possible dose. If not used daily, benzodiazepines and non-benzodiazepine hypnotics and 
antipsychotics may be used as rescue medications. Before prescribing, whenever practicable, 
the investigator should discuss the proposed rescue medication with the Medical Monitor. 
The timing of the study visit following the use of rescue medication should be adjusted if a 
rescue medication has been taken within 24 hours of the scheduled visit.
(revised per 
Amendment 03)
9.4.8
Treatment Compliance
Compliance will be assessed by examination of blister packs returned to the investigator at 
the end of the Treatment Periods.  
All caregivers will be reminded of the importance of taking study medication as directed, ie, 
the correct number of tablets every night within 5 minutes before bedtime, and they will be 
reminded that their bedtime should be the same throughout the study.  Subjects will be told 
that following these instructions about taking study medication is important for the treatment 
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to be effective.  Compliance will be monitored closely and determined at specific visits by 
tablet count.  
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) 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/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
•
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable
•
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable
•
A signed and dated curriculum vita of the Principal Investigator (PI), including a copy of 
the PI’s current medical license or medical registration number on the curriculum vita
•
A signed and dated clinical studies agreement
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) 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.
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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.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs, dispensing, and return 
reconciliation log, (c) study drug accountability log, (d) all shipping service receipts, (e) 
documentation of returns to the sponsor, and (f) certificates of destruction for any destruction 
of study drugs that occurs at the site.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA; Medicine and Healthcare products Regulatory Agency).  As applicable, all unused 
study drugs and empty and partially empty containers from used study drugs are to be 
returned to the investigator (or if regionally required, the head of the medical institution or 
the designated pharmacist) by the subject and, together with unused study drugs that were 
shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study.  Upon 
completion of drug accountability and reconciliation procedures by the site’s personnel and 
documentation procedures by the sponsor’s personnel, study drugs that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back to 
the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  
Drug accountability will be reviewed during site visits and at the completion of the study.
Study sites are also responsible for tracking receipt, distribution, and return of all study 
equipment (eg, Actigraphy devices) to the sponsor or designated entity.   
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic 
information will include date of birth, sex, and race/ethnicity. 
9.5.1.2
Screening Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
A medical, psychiatric, and sleep history interview will be conducted at the Screening Visit, 
and will include confirmation that the subject meets diagnostic criteria for Circadian Rhythm 
Sleep Disorder, Irregular Sleep Wake Type.  All sleep, medical, and psychiatric history must 
be noted in the Medical History and Current Medical Conditions eCRF.  
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Physical examinations (full or brief) will be performed as described in Section 9.5.1.5.  
9.5.1.2.2
CORNELL SCALE FOR DEPRESSION IN DEMENTIA
The subject component of the CSDD interview will also be administered at Screening.  
Caregivers will be administered the caregiver input component of the CSDD.  The CSDD 
(Alexopoulos et al., 1988) derives information from the patient and the informant (caregiver) 
to assess signs and symptoms of major depression in patients with dementia.  Information is 
elicited through two semi-structured interviews; an interview with an informant and an 
interview with the patient, both of which focus on depressive symptoms and signs that 
occurred during the week preceding the interview.  The final ratings of the CSDD items 
represent the rater’s clinical impression rather that the responses of the informant or the 
patient.  The CSDD, which takes approximately 20 minutes to administer, assesses a total of 
19 items in the following 5 categories: mood-related signs, behavioral disturbance, physical 
signs, cyclic functions, and ideational disturbance.  Each item within each category is rated 
for severity on a scale of 0-2 (0=absent, 1=mild or intermittent, 2=severe).  The item scores 
are added. Scores above 10 indicate a probable major depression.  Scores above 18 indicate a 
definite major depression. Scores below 6 are associated with absence of significant 
depressive symptoms.
9.5.1.2.3
VIRAL TEST
Viral testing for hepatitis B and C will be conducted from a 6-mL blood sample obtained at 
Screening.  The specific test for hepatitis B is the surface antigen panel (HBsAg) with 
confirmation as needed.  The specific tests for hepatitis C are the hepatitis C virus (HCV) 
antibody immunoglobulin G, with confirmation as needed using the HCV score.  (revised per 
Amendment 05)
9.5.1.3
Efficacy Assessments
9.5.1.3.1
ACTIGRAPHY (REVISED PER AMENDMENT 05)
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity 
monitor which looks like a wrist watch. 
This device incorporates a multidirectional 
accelerometer to monitor degree and intensity of motion.  Data from an actigraph can be
fitted to an algorithm from which rest / activity patterns can be derived. 
Eligible subjects will be provided with an actigraph (for actigraphy) to wear continuously 
throughout the study.  Informants will be provided with a daily log (sleep period log) for 
noting the start and end times of nocturnal sleep periods and to log the approximate times 
that the actigraph was replaced on the subject’s wrist, if inadvertently removed.  Informants 
will be trained in the use of the actigraph and the log.  Site staff will instruct informants (1) in 
the evening, to fill in the times when the actigraph was not worn; and (2) in the morning, to 
fill out the bedtimes and morning rise times, and will emphasize the importance of doing so.  
(revised per Amendments 01, 02, 03, and 05)
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A central actigraphy reader will score daily actigraphy records using a customized algorithm.  
The in-bed intervals will be provided to the central reader based on the sleep logs completed 
by the caregivers.  The actigraphy data obtained during the Screening Period will be used to 
a) determine eligibility and b) derive baseline actigraphy parameters for those subjects who 
are randomized.  The nocturnal sleep period will be defined for each subject as the 8 hours  
starting at the subject’s MCB, calculated from the sleep log completed during screening.
(revised per Amendment 05)
Also note that the calculated MCB will determine time of dosing for a given subject such that 
the dose each night should be taken within 5 minutes before bedtime.
(revised per 
Amendments 01 and 05)
Actigraphy parameters are as follows:
•
Sleep efficiency (aSE): 100% × the total duration of sleep epochs during the predefined 
8-hour nocturnal sleep period divided by 8 hours   (revised per Amendment 05)
•
Sleep fragmentation index (SFI) from actigraphy: The SFI will be calculated as the sum 
of a Movement Index (MI) and a Fragmentation Index (FI), with MI = (epochs of wake 
per TIB)*100 and FI = (number of ≤1-minute periods of immobility/total number of 
periods of immobility of all durations during the defined nocturnal sleep period)*100.
(revised per Amendments 01 and 05)
•
Wake fragmentation index (WFI) from actigraphy: The WFI will be calculated as the 
sum of an Immobility Index (II) and a FI, with II = (epochs of immobility per the 16 
hours outside of the defined sleep period)*100 and FI = (number of ≤1-minute periods of 
mobility/total number of periods of mobility the 16 hours outside of the defined sleep 
period)*100.  (revised per Amendments 01 and 05)
•
Wake efficiency (aWE): 100% × the total duration of wake epochs during the defined 
wake period (ie, the 16 hours outside of the predefined sleep period) divided by 16 hours  
(revised per Amendment 05)
•
Mean Duration of Wake Bouts (aMeanDurWB): average duration of all wake bouts (with 
wake bout defined as continuous wake of 10 minutes or longer) that occur during the 
defined nocturnal predefined sleep period  (revised per Amendment 05)
•
Mean Duration of Sleep Bouts (aMeanDurSB): average duration of all sleep bouts (with 
sleep bout defined as continuous sleep of 10 minutes or longer) that occur during the 16 
hours outside of the predefined nocturnal sleep period (revised per Amendments 01 and 
05 and Administrative Change)
•
Intradaily Variability (IV): gives an indication of ISWRD by quantifying the number and 
strength of transitions between rest and activity bouts, with a higher number indicating 
more fragmentation; derived by the ratio of the mean squares of the difference between 
all successive hours (first derivative) and the mean squares around the grand mean 
(overall variance)
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•
Interdaily Stability (IS): gives an indication of the stability of the sleep-wake rhythm 
across days, and varies from zero (low stability) to 1 (high stability); derived by the ratio 
between the variance of the average 24-hour pattern around the mean and the overall 
variance
•
L5: the average activity across the least active 5-hour period per 24 hour period, with 
high values indicating restlessness  
•
M10: the average activity during the most active 10-hour period per 24 hour period with 
low levels indicating inactivity
•
AMP: amplitude of the rest-activity rhythm calculated as the difference between M10 and 
L5
•
RA: relative amplitude of the rest-activity rhythm calculated as the difference between 
M10 and L5 divided by M10 plus L5
9.5.1.3.2
CLINICIAN’S GLOBAL IMPRESSION OF CHANGE IRREGULAR SLEEP-WAKE 
RHYTHM DISORDER (CGIC-ISWRD) SCALE (REVISED PER AMENDMENT 01)
The CGIC-ISWRD Scale uses the standardized methodology for obtaining global clinical 
ratings, and is an assessment conducted by an independent rater at the end of the treatment 
period who has no access to the source data or other psychometric test scores conducted as 
part of the given protocol.  The instrument consists of 3 parts: a guided baseline interview 
administered to the subject and an informant, a follow-up interview administered to the 
subject and an informant, and a clinician’s rating review.  The informant must be a person 
who knows the subject well.  The baseline interview serves as a reference for future ratings.  
During the baseline interview, the rater will evaluate subjects regarding domains of (1) sleep 
and wake symptoms; (2) mood and behavioral symptoms; (3) attention/arousal; and (4) social 
functioning.  In the follow-up interview, a 7-point scale is used, from 1 = marked 
improvement, 4 = no change, to 7 = marked worsening, to score each of the four domains 
and to provide an overall score.  The overall score is used to address the secondary objective; 
the domain scores are exploratory. In this study, the assessment will focus on the symptoms 
of ISWRD, not the general condition of dementia.
9.5.1.3.3
NEUROPSYCHIATRIC INVENTORY (NPI-10) (REVISED TO BE AN EFFICACY 
ASSESSMENT PER AMENDMENT 05)
The NPI-10 (Trzepacz et al., 2013) assesses a wide range of behaviors seen in dementia for 
both frequency and severity. These include delusions, agitation, depression, irritability and 
apathy. The scale takes 10 minutes for a clinician to administer. This scale will be 
administered with the caregiver as proxy for the subject.  The NPI-10 has good psychometric 
properties and is widely used in drug trials. (revised per Amendment 01)
9.5.1.3.4
MINI MENTAL STATE EXAMINATION (REVISED TO BE AN EFFICACY ASSESSMENT 
PER AMENDMENT 05)
The MMSE (Folstein et al., 1975) is a cognitive instrument commonly used for screening 
purposes. It is a 30-point scale with higher scores indicating less impairment and lower 
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scores indicating more impairment.  Seven items are assessed that measure orientation to 
time and place, registration, recall, attention, language and drawing. The MMSE will be 
administered to the subject by site staff. 
9.5.1.3.5
ALZHEIMER’S DISEASE ASSESSMENT SCALE-COGNITIVE (ADAS-COG)  (REVISED 
TO BE AN EFFICACY ASSESSMENT PER AMENDMENT 05)
The ADAS-cog (Rosen et al., 1984) is the most widely used cognitive scale in Alzheimer's 
disease trials.  It is a structured scale that evaluates memory (word recall, delayed word 
recall, and word recognition), reasoning (following commands), language (naming, 
comprehension), orientation, ideational praxis (placing letter in envelope) and constructional 
praxis (copying geometric designs).  Ratings of spoken language, language comprehension, 
word finding difficulty, ability to remember test instructions, maze, and number cancellation 
are also obtained.  The modified version (ADAS-cog-13) used in this study is scored from 0 
to 90 points with a score of 0 indicating no impairment, and a score of 90 indicating 
maximum impairment. 
9.5.1.3.6
SLEEP DISORDERS INVENTORY (SDI)  (REVISED TO BE AN EFFICACY 
ASSESSMENT PER AMENDMENT 05)
The SDI (Tractenberg et al, 2003) is an expanded version of one item of the NPI. It describes 
the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period 
prior to its administration. The SDI consists of the seven subquestions from the NPI sleep 
disturbance item. Each of the subquestions is a separate question with frequency, severity, 
and caregiver distress rated by the caregiver with respect to the patient-participant for the 
2 weeks prior to the visit. 
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
A blood sample (4 mL) for plasma concentrations of lemborexant and its metabolites M4, 
M9, and M10 will be taken at the end of treatment visit (Visit 5).  The time and date of the 
2 most recent doses before this sample and the time and date of the sample will be 
documented.  
One blood sample (approximately 4 mL) will be obtained at  Baseline (Visit 3) for only those 
subjects taking specific cognitive enhancers (ie, donepezil or galantamine or memantine
alone or both donepezil and memantine or both galantamine and memantine). 
Another 
blood sample (approximately 4 mL) will be obtained at Visit 5 or ET for all subjects to 
measure lemborexant and its metabolites, as well as cognitive enhancers, as appropriate. 
(revised per Amendments 03 and 05)
For those subjects taking donepezil, the date and time of the 2 most recent doses of donepezil
will be documented. For all subjects taking lemborexant, the date and time of the 2 most 
recent doses of lemborexant will also be documented.
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In case of early termination due to safety or any other reasons, a plasma sample for 
lemborexant (and its metabolites), and for any cognitive enhancer (as applicable) will be 
taken from the subject.
PK sample collection, processing and handling will be detailed in a laboratory manual to be 
provided to the study sites or be incorporated in the central labs manual.
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
For modeling purposes, the change from baseline at the last week of treatment for the 
following efficacy variables aSE, aWE, SFI, WFI, IV, IS, AMP and RA will be treated as PD 
variables. 
9.5.1.4.3
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS
For PK/PD assessments, the following efficacy variables aSE, aWE, SFI, WFI, IV, IS, AMP 
and RA will be treated as PD variables.
9.5.1.4.4
PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS
Blood samples for genotyping and for additional exploratory analyses will be obtained at 
Baseline from consenting subjects. Further details are provided in Appendix 2.
9.5.1.5
Safety Assessments
All subjects will undergo routine safety assessments at specified visits, including monitoring,
questioning and recording of AEs, 12-lead ECGs, vital signs, weight, clinical hematology 
and chemistry analyses and urinalysis, and suicidality, assessed using the eC-SSRS.  
9.5.1.5.1
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  
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
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•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit.   SAEs will be collected for 28 days after 
the last dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 msec and there is an increase of more than 60 msec from baseline.  Any ECG 
abnormality that the investigator considers as an AE should be reported as such. (revised per 
Amendment 02)
It is the responsibility of the investigator to review the results of the eC-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5  for a description of the eC-SSRS). 
AEs in clinical investigation subjects include any change in the subject’s condition.  This 
includes symptoms, physical findings, or clinical syndromes.  All AEs encountered during 
the clinical study will be reported on the eCRF.  
All AEs must be followed for 14 days after the subject’s last dose, or until resolution, 
whichever comes first.   
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
ASSESSING SEVERITY OF ADVERSE EVENTS
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the eCRF.  The definitions are as follows:
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
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The criteria for assessing severity are different than those used for seriousness (see below, 
this Section, 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
9.5.1.5.2
CLASSIFICATION OF CAUSALITY
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related): A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related): A causal relationship between the study drug and the AE is not a reasonable 
possibility.
9.5.1.5.3
SERIOUS ADVERSE EVENTS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE  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)
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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 (EASSs) include pregnancy 
or exposure to study drug through breastfeeding and AEs associated with study drug 
overdose, misuse, abuse, or medication error.  These EASSs are to be captured using the 
SAE procedures but are to be considered as SAEs only if they meet one of the above criteria.  
All AEs associated with special situations are to be reported on the eCRF whether or not they 
meet the criteria for SAEs.
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care 
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests are to be performed according to the schedule in Table 3.  
Blood and urine samples will be collected for the clinical laboratory tests as listed in Table 1.
Subjects should be in a seated or supine position during blood collection.  Blood volumes are 
listed in Table 2.  
Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
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Table 1
Clinical Laboratory Tests
Category
Parameters
Liver function tests
alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function parameters
blood urea/blood urea nitrogen, creatinine
Other
albumin, calcium, cholesterol, globulin, glucose, iron, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Table 2
Blood Sampling Volumes for Laboratory and Pharmacokinetic 
Assessments (revised per Amendments 03 and 05)
Approximate
Volume per 
Sample 
(mL)
Collection
Timepoints
Total Volume Collected 
(mL)
Clinical laboratory tests
12
Screening
Baseline
Visit 5
End of Study or ET
48
Viral tests
6
Screening
6
Pharmacogenomic testing
6
Baseline 
6
Pharmacokinetic sampling
4
Baseline
Visit 5 or ET visit
8
Total
68
Extension Phase
Clinical laboratory tests
12
Visit 6A or 6B, 
Visits 9, 12, 15, 18, 
19, 20, 21, 22, 23, 
24, and 25 (End of 
Study for the 
Extension Phase)
144
ET = early termination
Clinical laboratory tests during the study will be performed by a central laboratory.
All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  In cases of a safety concern, blood samples will be 
split (or two samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  Laboratory certification as available will be included in the final clinical study 
report for this study. 
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A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5) and the case report form (CRF) Completion Guidelines.  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event eCRF.
For laboratory abnormalities meeting the criteria of SAEs, the site must fax or email the SAE 
report including the laboratory report (as regionally required) to the sponsor using the SAE 
form (see Reporting of Serious Adverse Events, Section 9.5.4.1).
9.5.1.5.5
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], and body temperature [in centigrade]) and weight 
(kg) will be obtained at the visits designated in the Schedule of Procedures/Assessments 
(Table 3) by a validated method.  Blood pressure and pulse will be measured after the subject 
has been in a sitting position for 5 minutes.  All BP measurements should be performed on 
the same arm, preferably by the same person.  Validated methods will be used for all vital 
sign measurements, and values will be recorded.  Height (cm) will be measured only at 
Screening.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.6
PHYSICAL EXAMINATIONS
At Screening and at the end-of-study visit, a full physical examination will be conducted, 
including evaluation of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, skin.  The full physical examination will include a brief neurological 
examination to assess possible impairment in major functions (ie, motor, cerebellar, sensory, 
major pathological reflexes).  A urogenital examination will only be required in the presence 
of clinical symptoms related to this region and at the discretion of the investigator.  At other 
study visits as designated in Table 3 a brief physical examination will be conducted to assess 
health status by brief evaluation of the head, eyes, ears, nose, throat, heart, lungs, abdomen, 
and extremities, and other physical conditions of note.  Documentation of the physical 
examinations, including the brief neurological examinations, will be included in the source 
documentation at the site.  Only changes from screening physical examination findings that 
meet the definition of an AE will be recorded on the Adverse Event eCRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Procedures/
Assessments (Table 3) and before blood samples are collected.
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An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Event eCRF.
For ECG abnormalities meeting criteria of an SAE, the site must fax or email the SAE report 
including the ECG report to the sponsor using the SAE form (see Reporting of Serious 
Adverse Events [Section 9.5.4.1]).
9.5.1.5.8
OTHER SAFETY ASSESSMENTS (REVISED PER AMENDMENT 05)
ELECTRONIC COLUMBIA-SUICIDE SEVERITY RATING SCALE (EC-SSRS)
Suicidality will be assessed using an electronic version of the eC-SSRS (Posner et al., 2011).  
The eC-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  Qualified personnel must evaluate positive responses on the eC-SSRS 
and take appropriate action as detailed in the training and certification process for 
administering the eC-SSRS.
MORNING RESIDUAL EFFECTS
To assess morning residual effects, activity levels from the 1st 3 hours after waketime from 
the first 3 days of the first week of treatment and the last 3 days of treatment will be 
compared with the mean activity levels from the 1st 3 hours after waketime during the 
actigraphy baseline period.
9.5.1.6
Other Assessments
9.5.1.6.1
EQ-5D-5L
The EQ-5D-5L is a generic instrument that can be used in the clinical and economic 
evaluation of health care, and to collect data on quality of life and preferences/utility (The 
EuroQol Group, 1990; Brooks, 1996). The instrument comprises questions on mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression, and a visual analogue 
scale from 0 (“Worst imaginable health state”) to 100 (“Best imaginable health state”). 
Three forms will be collected per subject per visit:

Subject Self Version
o
The form will not be labeled Self Version but the wording will be for self-completion.
o
Caregivers or study coordinators can provide assisted self-completion services to the 
subject where the subject has physical impairments (eg, arthritis, severe visual 
impairment) that prevent self-completion.  Assistance can be in the form of reading 
the instructions, questions, and responses verbatim (without interpretation) and in the 
order provided on the questionnaire.  Assistance can be in the form of recording 
responses of the subject.  
o
To be considered self-completed, all responses must have come from the subject.
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
Caregiver Self Version
o
The caregiver completes the standard version regarding his/her own health status.
o
Study coordinators may provide assisted self-completion services as described above 
for physically impaired caregivers.

Caregiver Proxy 1 Version
o
During the Core Study only, the caregiver completes the both the Self Version 
(regarding the caregiver) and the Proxy version (regarding the caregiver’s perception 
of the subject’s health status).
o
Study coordinators may provide assisted self-completion services as described above 
for physically impaired caregivers.
9.5.1.6.2
ZARIT BURDEN INTERVIEW – SHORT FORM
The ZBI – short version was developed from the full ZBI, to be suitable for caregivers of 
cognitively impaired older adults across diagnostic groups (Bédard et al., 2001). The ZBI can 
be used for cross-sectional, longitudinal, and intervention studies. It has been designed to 
reflect the stresses experienced by caregivers of dementia patients. It can be completed by 
caregivers directly or as part of an interview of the caregiver by the study coordinator. 
Caregivers are asked to respond to a series of 12 questions in 2 domains: personal strain and 
role strain. Each question is scored on a 5-point Likert scale from 0 to 4 (never to almost 
always).  The range of summed scores is from 0 to 48. Higher scores reflect a higher feeling 
of burden.
9.5.1.6.3
PITTSBURGH SLEEP QUALITY INDEX
The PSQI (Buysse et al., 1989) is an instrument used to measure the quality and patterns of 
sleep in adults by measuring seven components: subjective sleep quality, sleep latency, sleep 
duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and 
daytime dysfunction, over the previous month. In scoring the PSQI, seven component scores 
are derived, each scored from 0 (no difficulty) to 3 (severe difficulty). The component scores 
are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep 
quality
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the Schedule of Procedures/Assessments for the study.
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Table 3
Schedule of Procedures/Assessments in Study E2006-G000-202 (revised per Amendments 01, 02, 05, and 06)
(Core Study)
Phase
Prerandomization
Randomization
Period
Optional 
Prescreen-
ing
Screening
Baselinea
Treatment
Follow-Up
ETf
UNg
Visit
1
1
2b
3
4
5c
6Ad,e
Study Day
-42 to -16
-27 to -2
1
10 to 18
29
30 to 42
43
Procedures/Assessments
Informed consent
X
X
Activity tracker
X
Inclusion/exclusion criteria
Mini Mental State Examh
X
X
Cornell Scale for Depression in 
Dementiai
X
Demographics
X
Physical examj
X
X
X
X
X
Sleep, medical, and psychiatric 
history
X
Prior / concomitant medications
Height
X
Weight
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
Clinical laboratory tests and 
urinalysis
X
X
X
X
X
Viral screening
X
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Table 3
Schedule of Procedures/Assessments in Study E2006-G000-202 (revised per Amendments 01, 02, 05, and 06)
(Core Study)
Phase
Prerandomization
Randomization
Period
Optional 
Prescreen-
ing
Screening
Baselinea
Treatment
Follow-Up
ETf
UNg
Visit
1
1
2b
3
4
5c
6Ad,e
Study Day
-42 to -16
-27 to -2
1
10 to 18
29
30 to 42
43
Procedures/Assessments
eC-SSRS
X
X
X
X
Sleep Log
Actigraphy
Download actigraphy data
X
X
X
X
X
ADAS-cog
X
X
NPI-10k
X
X
X
SDIl
X
X
X
Diagnostic sleep studym
X
EQ-5D-5Ln
X
X
PSQIo
X
X
ZBI-shorto
X
X
CGIC-ISWRD Scale
X
X
PK blood samplingp
X
X
X
Randomization
X
PG blood sample
X
Dispense study drug
X
X
Study drug at bedtimeq
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Table 3
Schedule of Procedures/Assessments in Study E2006-G000-202 (revised per Amendments 01, 02, 05, and 06)
(Core Study)
Phase
Prerandomization
Randomization
Period
Optional 
Prescreen-
ing
Screening
Baselinea
Treatment
Follow-Up
ETf
UNg
Visit
1
1
2b
3
4
5c
6Ad,e
Study Day
-42 to -16
-27 to -2
1
10 to 18
29
30 to 42
43
Procedures/Assessments
Study drug compliance
X
X
Retrieve unused study drug
X
Discharge from study
X
X
Adverse eventsr
ADAS-cog = Alzheimer’s Disease Assessment Scale – Cognitive Subscale, CGIC-ISWRD = Clinician’s Global Impression of Change-Irregular Sleep-Wake 
Disorder, CSDD = Cornell Scale for Depression in Dementia; ECG = electrocardiogram; eC-SSRS = electronic Columbia-Suicide Severity Rating Scale,, 
EOS = End of Study, EQ-5D-5L = EuroQOL 5 Dimensions 5 Levels; ET = early termination, NPI-10 = Neuropsychiatric Inventory; PG = 
pharmacogenomics, PGI- C = Patient Global Impression of Change, PGI-S = Patient Global Impression of Severity, PSQI = Pittsburgh Sleep Quality Index,
PK = pharmacokinetic, SDI = Sleep Disorders Inventory,  UN = unscheduled visit, ZBI = Zarit Burden Inventory
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Footnotes for Table 3:
a:
Baseline procedures can be scheduled across 2 days, with Day 1 being the first day of dosing. (revised per Amendment 01)
b:
To be done at the end of 2 weeks of actigraphy and less than 2 days before the Baseline Visit 
c:
To be done within +4 days of the schedule
d:
Assessments at Visit 6A are the baseline assessments for subjects entering the Extension Phase.  Subjects may enter the Extension Phase up to 30 days 
after Visit 6A; however, those who do so must repeat these assessments at the time of enrollment (at Visit 6B [see Schedule of Assessments and 
Procedures for the Extension Phase]).  (revised per Amendment 05)  
e:
Extension Phase study drug will be dispensed to subjects at Visit 6A who enter the Extension Phase directly after completing the Core Study.  (revised 
per Amendment 05)
f:
Subjects who discontinue the study early for any reason after Randomization should complete this visit.
g:
Additional assessments may be conducted at this visit if the investigator considers them to be necessary. 
h:
The MMSE test instrument will be administered to subjects after informed consent has been obtained from caregivers and subjects and after caregiver 
eligibility has been established, but before clinical laboratory tests are drawn, so as to avoid performing venipuncture on subjects whose MMSE scores 
disqualify them from entry into the study.  Informants are not required to provide informed consent. (revised per Amendment 01)
i:
CSDD will be completed by interview with subject and with caregiver.
j:
Full physical examination (including a brief neurological exam) will be conducted at Screening. An abbreviated physical examination will be conducted 
at other visits. 
k:
NPI-10 will be completed by the caregiver as proxy for the subject.
l:
SDI will be completed by the caregiver as proxy for the subject. The SDI at Visit 6A will only be completed for subjects entering the Extension Phase.
(revised per Amendment 05)
m:
Diagnostic sleep study to be completed during Screening and reviewed by the investigator for the apnea-hypopnea index or equivalent, unless a 
diagnostic sleep study has been obtained within 6 months of the Screening visit  (revised per Amendment 05)
n:
EQ-5D-5L administered to the caregiver twice at each specified visit (once as proxy for the subject and separately for self) and once to the subject
o:
PSQI and ZBI-short will be administered to the caregiver for self-completion.
p:
One blood sample (approximately 4 mL) will be obtained at  Baseline (Visit 3) for only those subjects taking specific cognitive enhancers (donepezil or 
galantamine or memantine alone or both donepezil and memantine or both galantamine and memantine). Another blood sample (approximately 4 mL) 
will be obtained at Visit 5 or ET for all subjects to measure lemborexant and its metabolites, as well as cognitive enhancers, as appropriate. (revised per 
Amendment 03).
q:
Caregivers or Informants will administer study drug to subjects.  All study drug administration must be within 5 minutes of bedtime (defined as the
median calculated bedtime [MCB]).  (revised per Amendments 01 and 06)
r:
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a 
narrative for the event, per Section 9.2.8 Adjudication Committee. (revised per Amendment 02)
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9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 3.
9.5.3
Appropriateness of Measurements
The safety assessments to be performed in this study, including clinical laboratory tests, physical 
examinations, vital signs, ECG, and assessment of AEs are standard evaluations to ensure subject 
safety.  The eC-SSRS is a standard assessment of suicidality in studies of CNS-active drugs.  The 
CSDD is specifically designed to determine depressive symptomatology in patients with 
dementia.  The NPI-10 and MMSE are also very common scales in dementia research to 
determine behavioral and cognitive symptoms.
Actigraphy is a standard measure used to record rest/activity patterns across multiple 24-hour 
periods, and has been used in basic research and clinical trials to evaluate the effectiveness of 
treatments.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated with 
Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the event.  (revised per 
Amendment 05)
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase and for 28 days after the subject’s last dose.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its receipt.  
If the follow-up information changes the investigator’s assessment of causality, this should also 
be noted on the follow-up SAE form.  (revised per Amendment 05)
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Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the sponsor to be filed 
in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
The female subject population will be exclusively postmenopausal.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose,
misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel
or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on the 
Adverse Event eCRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is always 
to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or medication 
error does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the Adverse Event 
eCRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
There are no study-specific events.
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9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) 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.   
All studies that are conducted within any European country will comply with European Good
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC. All suspected 
unexpected serious adverse reactions will be reported, as required, to the competent authorities 
of all involved European member states.  (revised per Amendment 04)
9.5.5
Completion/Discontinuation of Subjects
For analysis purposes, a subject will be considered to have completed the study once the 
assessments after the last dose of study drug have been completed.  
The investigator or 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 3).  In the event of discontinuation, 
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, or administrative/other.  Discontinuations due 
to non-compliance with study drug or alcohol restrictions will be assigned to 
“administrative/other.”  In addition to the primary reason, the subject may indicate 1 or more 
secondary reason(s) for discontinuation.  Study disposition information will be collected on the 
Subject Disposition eCRF.
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A subject removed from the study for any reason will not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of one or both 
study drugs.  Adverse events associated with abuse or diversion will be appropriately reported as 
AEs and monitored per Section 9.5.1.5.  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 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, standard 
operating procedures, working practice documents, and applicable regulations and guidelines.  
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the eCRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the eCRF must follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on Form FDA 1572 
must sign the completed eCRF to attest to its accuracy, authenticity, and completeness.
Completed, original eCRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
9.7.1
Statistical and Analytical Plans
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 Statistical Analysis Software (SAS) software or other validated statistical software as 
required.
The statistical analyses are described in this section.  Further details of the statistical analyses 
will be included in a separate Statistical Analysis Plan (SAP).  There will be 2 separate SAPs:  1 
for the Core Study, and 1 for the Extension Phase. (revised per Amendment 05)
All statistical tests will be based on the 5% level of significance (2-sided), unless otherwise 
stated.  If statistical comparisons are not defined, all pairwise comparisons will be tested.
9.7.1.1
Study Endpoints
9.7.1.1.1
SLEEP-RELATED ENDPOINTS (REVISED PER AMENDMENTS 05 AND 06)
The sleep-related endpoints are: 
•
The change from baseline of mean aSE with LEM compared to PBO during the last week of 
treatment. (revised per Amendments 01 and 06)
•
The change from baseline of aSE during each week of treatment with LEM compared to 
PBO.  (revised per Amendment 06) 
•
Change from baseline in mean SFI during each week of treatment. (revised per Amendments 
01 and 06)
•
Change from baseline of the aMeanDurWB during each week of treatment. (revised per 
Amendment 06)
9.7.1.1.2
WAKE-RELATED ENDPOINTS (REVISED PER AMENDMENTS 05 AND 06)
•
The change from baseline of mean aWE with LEM compared to PBO during each week of 
treatment. (revised per Amendments 01 and 06)
•
Change from baseline of the aMeanDurSB during each week of treatment.  (revised per 
Amendment 06)
•
Change from baseline of mean WFI during each week of treatment (revised per Amendments 
01 and 06)
9.7.1.1.3
CIRCADIAN RHYTHM-RELATED ENDPOINTS (REVISED PER AMENDMENTS 05 AND 06)
•
Change from baseline of IV, IS, L5, M10, AMP and RA over each week of treatment 
(revised per Amendments 01 and 06)
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9.7.1.1.4
ADDITIONAL ENDPOINTS (REVISED PER AMENDMENT 06)
The following additional endpoints will be explored for LEM2.5, LEM5, LEM10 and LEM15 
compared to PBO:  
•
Safety and tolerability of LEM, including AEs and SAEs
•
Change from baseline in Clinician's Global Impression of Change-ISWRD (CGIC-ISWRD) 
Scale on symptoms of ISWRD total score and domains.  (revised per Amendments 01 and 
06)  
•
Change from baseline of the sum of activity counts and change from baseline in the number 
of bouts >10 minutes of sleep in the first 3 hours after morning waketime on the first 3 days 
and last 3 days of treatment 
•
Number and percentage of subjects in each category of the CGIC-ISWRD Scale at Day 29
(revised per Amendment 01)
•
Rebound sleep and wake fragmentation endpoints as assessed from actigraphy during the 
Follow-Up Period
o
Change from baseline in mean aSE of the first 7 nights, and aSE of the second 7 nights of 
the Follow-Up Period
o
Change from baseline in mean aWE of the first 7 days and mean aWE of the second 7 
days of the Follow-Up Period
o
Proportion of subjects whose mean aSE is higher than at baseline for the first 7 nights or 
the second 7 nights of the Follow-Up Period
o
Proportion of subjects whose mean aWE is longer than at baseline for the first 7 days or 
the second 7 days of the Follow-Up Period (revised per Amendment 03)
•
Change from baseline on ADAS-Cog at Day 29
•
Change from baseline on MMSE at Day 29
•
Change from baseline sleep quality in caregivers as measured by the PSQI at Day 29 
•
Change from baseline of caregiver burden on all scores of the ZBI-short form at Day 29. 
(revised per Amendment 06)
•
Change from baseline on the EQ-5D-5L utility and Visual Analogue Scale (VAS) scores at 
Day 29 for both subject and caregiver
•
Change from baseline of the total score of NPI-10 at Day 29 
•
Change from baseline on SDI at Day 29
•
Characterize the PK of lemborexant using the population approach and descriptive statistics 
for the plasma concentrations of its metabolites M4, M9, and M10.  (revised per Amendment 
06)
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•
Relationships between exposure to lemborexant, efficacy, and/or safety variables using 
PK/PD modeling
•
Assess the plasma concentrations of cognitive enhancers and lemborexant in subjects taking 
both drugs.
•
Evaluate the long-term safety and tolerability of flexible doses of LEM5, LEM10, and 
LEM15 per day over a period of 30 months in subjects with ISWRD who have completed the 
Core Study.  (revised per Amendments 05 and 06)
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of randomized subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose efficacy measurement.
The PK Analysis Set is the group of subjects who have at least 1 quantifiable plasma 
concentration of lemborexant, with adequately documented dosing history.
The PK/PD Analysis Set is the group of subjects receiving either lemborexant or placebo who 
have efficacy or safety data with documented dosing history.  In addition, subjects receiving 
lemborexant should have at least 1 quantifiable lemborexant concentration data point as per the 
PK Analysis Set.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for
failure) will be summarized. Screen failure data will be listed. The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
The number of subjects completing the study will be presented. Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for study 
termination. Other reasons for study drug and study terminations will also be summarized. These 
tabulations will be produced for all randomized subjects by treatment group.
9.7.1.4
Demographic and other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
for each treatment group using descriptive statistics.  Continuous demographic and baseline 
variables include age, height, and weight; body mass index (BMI); categorical variables include 
sex, age group (<65, 65 to 74 years, 75 to 84 years, and 85 and older), BMI group, race, and 
ethnicity.  Other baseline characteristics for actigraphy data and MMSE will also be summarized.  
(revised per Amendment 01)
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If the Safety Analysis Set and FAS differ substantially, the demographic summaries will be 
repeated on the FAS.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (Mar 2016 or latest version). The number 
(percentage) of subjects who take prior and concomitant medications will be summarized on the 
Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and World 
Health Organization Drug Dictionary-preferred term (PT). If the Safety Analysis Set and FAS 
differ substantially, then the prior and concomitant medication summaries will be repeated on the 
FAS.
Prior medications are defined as medications that stopped before the first dose of study drug, 
where study drug includes PBO.
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
9.7.1.6.1
ANALYSIS FOR THE SLEEP-RELATED, WAKE-RELATED, AND CIRCADIAN RHYTHM-
RELATED ENDPOINTS (REVISED PER AMENDMENT 06)
The changes from baseline of the mean aSE for the last week of treatment and for each week of 
treatment, and the change from baseline for the mean aWE for the last week on treatment will be 
analyzed using MCP-MOD (Multiple Comparisons and Modelling) approach.  Dose response 
models that will be evaluated are linear, linear log, quadratic, exponential, emax, sigmoid emax, 
beta and logistic.   (revised per Amendments 05 and 06)
Analysis stage – MCP-step: Establish a dose-response signal (the dose-response curve is not flat) 
using multiple comparison procedure. Based on the observed data, the model that shows a 
statistically significant trend test will be selected (at one-sided 5% significance). If more than 
one is statistically significant, then the most optimal model using Akaike Information Criteria 
will be selected. This method prospectively controls the type I error at 5%.
Analysis Stage – Mod-step: Dose response and target dose estimation will be based on dose 
response modelling. MCP-MOD approach allows for interpolation between doses. 
As a sensitivity analysis to the aSE and aWE endpoints mean aSE and mean aWE for Week 4 
will be analyzed using the longitudinal data analysis (LDA).  (revised per Amendment 06)
The change from baseline of the following endpoints will be analyzed using LDA on the FAS for 
LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, as appropriate: mean SFI, mean WFI, 
mean aSE, mean aWE, mean aMeanDurSB, mean aMeanDurWB, IV, IS, L5, M10, AMP, and
RA. (revised per Amendment 06)
The model will include all data and will be adjusted for the corresponding baseline value, 
country, treatment, time (Week 1, Week 2, Week 3 and Week 4) and the interaction of treatment 
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by time.  Treatment by time interaction will be used to construct the treatment comparisons at a 
specific time.  The LDA model accounts for any missing data, and assumes that the missing data 
are missing at random.  An unstructured covariance matrix will be used, and if the model fails to 
converge, then an autoregressive matrix will be used.  Where data are normally distributed, least 
square (LS) means, difference in LS means of each lemborexant dose compared to PBO, 95% 
CIs and P values at the appropriate time point will be presented.  (revised per Amendment 01)
Additional analyses, as deemed necessary, may include the investigation of subgroup analyses 
and/or addition of covariates to the model of age, sex, race, BMI, severity of aSE, severity of 
aWE, wake fragmentation, severity of AD-D based on MMSE  and/or other subgroups.  (revised 
per Amendment 06)
9.7.1.6.2
ANALYSES FOR ADDITIONAL ENDPOINTS (REVISED PER AMENDMENT 06)
The overall score of CGIC-ISWRD Scale at Day 29 will be analyzed using the Cochran–Mantel–
Haenszel test, adjusted for country.  (revised per Amendment 01)
To assess residual morning sleepiness levels, change from baseline in the sum of activity counts 
in the 3 hour interval after morning waketime will be compared for each treatment group relative 
to placebo for each of the 6 mornings comprising the first 3 days and last 3 days of treatment.  
The change from baseline will be analyzed using analysis of covariance (ANCOVA), with 
treatment and baseline as fixed effects. LS means, difference in LS means of LEM2.5, LEM5, 
LEM10 and LEM15 compared to PBO, 95% CIs, and p-values will be presented.  (revised per 
Amendment 06)  In addition, the change from baseline will be analyzed using ANCOVA for the
number of bouts >10 min scored as sleep will be determined counts in the 3 hour interval after 
morning waketime, for each of the 6 mornings comprising the first 3 days and last 3 days of 
treatment.  (revised per Amendment 06)
Rebound sleep and wake fragmentation are defined as worsened aSE or aWE compared to 
baseline after study drug treatment is completed.  Actigraphy data from the Follow-Up Period 
will be compared to actigraphy data from the baseline to assess whether subjects experience 
rebound sleep or wake fragmentation.  Specifically, a lower value for aSE or aWE during the 
Follow-Up Period compared to the mean aSE or aWE value during baseline will be considered 
worsened sleep or wake fragmentation.
To assess rebound sleep and wake fragmentation, both categorical analysis at the subject level 
and continuous analysis at the group mean level will be performed.  For each of the 2 weeks of 
the Follow-Up Period the proportion of subjects whose corresponding value for aSE or aWE 
exceeds the corresponding baseline value by 1% for aSE and 0.5% for aWE (which is 
approximately 5 minutes based on the a typical 8-hour sleep period and 16-hour wake period) 
will be summarized by treatment group and compared to placebo. The percentage of 
‘rebounders’ between each treatment and placebo group will be analyzed using a Cochran-
Mantel-Haenszel test, adjusted for country, if deemed appropriate.  (revised per Amendment 06)
To assess statistical significance using the continuous data at the group mean level, the data will 
be analyzed using ANCOVA, adjusted for country and treatment.  The LS mean of each week of 
the Follow-Up Period will be compared to the baseline between each treatment group and 
placebo.  If the upper bound of the 95% CI of aSE or aWE for the mean of each week of the 
Follow-Up Period is less than the lower bound of a 95% CI for the values during the baseline in 
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the given treatment group, it will be considered strong evidence for rebound sleep or wake 
fragmentation. If the LS means for aSE and aWE for the Follow-Up Period are all higher than for 
the baseline, then no rebound sleep or wake fragmentation is suggested.  Otherwise, the degree to 
which the parameters worsen, and the time point(s) at which they worsen will be considered to 
evaluate whether clinically meaningful rebound sleep and/or wake fragmentation is present.
Each domain of CGIC-ISWRD Scale at Day 29 will be analyzed using the Cochran–Mantel–
Haenszel test, adjusted for country.  (revised per Amendment 01)
The change from baseline of total score from the NPI-10, SDI, ADAS-Cog and MMSE at Day 
29 will be analyzed with ANCOVA, with treatment and baseline as fixed effects on the Efficacy 
Analysis Set.  The difference in LS means of LEM2.5, LEM5, LEM10 and LEM15 compared to 
PBO, 95% confidence intervals (CIs) and p-values will be presented.  (revised per Amendment 
05)
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 plasma concentration listings of lemborexant 
and its metabolites M4, M9, and M10.  The PK Analysis Set will be used for summaries of 
plasma concentrations of lemborexant and its metabolites M4, M9, and M10, by dose and day.
A population PK approach will be used to characterize the PK of lemborexant.  For this 
approach, PK data from this study will be pooled with relevant data from Phase 1 and 2 studies, 
and other Phase 3 studies if available.  The effect of intrinsic and extrinsic factors (ie, 
demographics, concomitant medications) on the PK of lemborexant will be evaluated.  The PK 
model will be parameterized for oral clearance (CL/F) and volume of distribution (V/F).  
Derived exposure parameters such as AUC, Cmax and any other relevant parameters will be 
calculated from the model using the individual posterior estimate of CL/F and dosing history.
Baseline cognitive enhancer(s) plasma concentrations from appropriate subjects will be 
compared to those at end of treatment.
Further details of the PK analyses will be provided in a separate analysis plan.
9.7.1.7.2
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
All of the PD variables are considered efficacy variables for the purposes of analysis.  (revised 
per Amendment 01)
9.7.1.7.3
PHARMACOKINETIC/EFFICACY ANALYSES
The relationship between exposure to lemborexant and efficacy variables including but not 
limited to SFI and WFI, and the most frequently occurring TEAEs, will be explored graphically.  
For modeling purposes, the change from baseline at the last week of treatment for the following 
efficacy variables aSE, aWE, SFI, WFI, IV, IS, AMP, and RA will be treated as PD variables.
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Any emergent relationships will be evaluated by population PK/efficacy modeling.  The 
population PK/efficacy analysis plan will be described and results will be reported in a separate 
document. 
Population PK and PK/efficacy analyses will be performed using NONMEM version 7.2 or later.
9.7.1.7.4
PHARMACOGENOMIC ANALYSES
DNA samples will be collected and stored, and may be used to examine the role of genetic 
variability in absorption, distribution, metabolism, and excretion, or development of AEs. 
Variations in lemborexant exposure or AEs may be explored by correlation of single-nucleotide 
polymorphisms with PK, safety, or efficacy data.  Efficacy will be explored in relation to the 
APOɛ4 genotype.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study drug 
will be summarized descriptively for lemborexant.
Compliance for lemborexant will be calculated on the basis of the number of tablets dispensed, 
lost, and returned, separately for each type (dose) of tablet.  Summaries will provide descriptive 
summary statistics and number (percentage) of subjects below 80%, between 80% and 120%, 
and greater than 120%.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into
standardized medical terminology using the MedDRA.
Adverse events will be coded to the
MedDRA (Version 17.0 or higher) lower level term closest to the verbatim term. The linked
MedDRA PT and primary system organ class (SOC) are also captured in the database.  
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables. All AEs,
treatment-emergent or otherwise, will be presented in subject data listings. AEs will be classified 
as TEAEs up to 14 days after the last study treatment.
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The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT. A subject will be counted only once within an SOC and PT, even if the subject
experienced more than 1 TEAE within a specific SOC and PT. The number (percentage) of 
subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to
study drug (Yes [related] and No [not related]). Treatment-related TEAEs include those events 
considered by the investigator to be related to study treatment.
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.
The number (percentage) of subjects with TEAEs of cataplexy that are characterized according 
to the customized MedDRA query PT as potential cataplexy-related events (Section 9.5.1.5), as 
seizure-related events, as well as somnolence and related events, and drug abuse liability will be 
summarized separately. (revised per Amendment 02)
9.7.1.8.3
CLINICAL LABORATORY VALUES
Clinical laboratory values will be evaluated for each laboratory parameter by subject. Abnormal 
laboratory values will be identified as those outside (above or below) the normal range.  
Reference (normal) ranges for laboratory parameters will be included in the clinical study report 
for this study.  Descriptive summary statistics (eg, mean, SD, median, minimum, maximum for 
continuous variables, and number and percentage for categorical variables) for the laboratory 
parameters and changes from baseline will be evaluated by treatment group and visit.
Laboratory test results will be assigned a low- normal-high (LNH) classification according to
whether the value was below (L), within (N), or above (H) the reference range for the laboratory 
parameter.  Within-treatment comparisons will be based on 3 by 3 tables (shift tables) that, for a 
particular laboratory test, compare the Baseline LNH classification to the LNH classification at 
end of study/early termination, by treatment group.
Clinical laboratory results post-baseline will be evaluated for markedly abnormal values. A 
laboratory test will be considered markedly abnormal if the result worsens to meet Eisai grading 
criteria for laboratory values limit of Grade 2 or higher. If the Grade 2 limit is missing, the 
Grade 1 limit will be considered. Appendix 1 presents the Eisai grading criteria for laboratory 
values that were used to identify subjects with markedly abnormal laboratory values. For the 
incidence of markedly abnormal laboratory values, each subject may be counted once in the 
laboratory parameter value high and in the laboratory parameter low categories as applicable.
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9.7.1.8.4
VITAL SIGNS AND WEIGHT
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, respiration 
rate, temperature) and weight, and changes from Baseline will be presented by visit and 
treatment group. 
Vital sign values will be listed. Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 4).  Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital sign 
ranges will also be presented by treatment group and visit.
Table 4
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.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from Baseline will be presented by 
treatment group. Shift tables will present changes from Baseline in ECG interpretation 
(categorized as normal or abnormal) by time point.  (revised per Amendment 02)
For each subject, the maximum observed QTcF and the maximum prolongation from baseline in 
QTcF will be compiled. Categorical analyses of subjects (number and percent) with maximum 
observed QTcF values >450 msec, >480 msec, and >500 msec and maximum prolongations 
(from Baseline) in QTcF >30 msec and >60 msec will be presented by treatment group and by 
time point. Categorical analyses of subjects (number and percent) with maximum observed PR 
values >220 msec, and QRS values > 120 msec will be presented by treatment group and by time 
point. (revised per Amendment 01)
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9.7.1.8.6
OTHER SAFETY ANALYSES (REVISED PER AMENDMENT 05)
The results of eC-SSRS assessments will be listed for each subject. The incidence of treatment-
emergent suicidal ideation or suicidal behavior will be summarized by treatment group using 
descriptive statistics as appropriate.
9.7.1.9
Other Analyses
Endpoints may also be presented graphically or analyzed by modeling methods if warranted.  
(revised per Amendment 06)
The change from baseline of the EQ-5D-5L utility and VAS scores, the global score of PSQI, all 
scores of the ZBI-short and the SDI at Day 29 will be analyzed using ANCOVA, with treatment 
and baseline as fixed effects. Provided that the data are normally distributed, LS means, 
difference in LS means of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, 95% 
confidence intervals (CIs) and p-values will be presented. The analyses for the EQ-5D-5L 
(caregiver self-version), PSQI, and ZBI will be conducted for a) caregivers who reside in the 
same residence as the subjects, b) caregiver informants who do not, reside in the same residence 
as the subjects, and c) all types of caregivers/informants combined.  (revised per Amendment 01)
9.7.2
Determination of Sample Size (revised per Amendment 06)
Approximately 60 subjects will enroll in this proof-of- concept study.  (revised per 
Amendment 06)
Some supporting exploratory power estimation is based on testing the dose response using the 
MCP-Mod package in R; several dose response curves were explored at one-sided 0.05 level of 
significance with different values of n (12, 13, and 14 subjects) per treatment group (Table 5, 
Table 6, and Table 7).  (revised per Amendment 06)
Conservative scenarios based on a 10-percentage point difference between the active dose and 
placebo will be presented.  (revised per Amendment 06)
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Table 5
Power Calculations for Actigraph Sleep Efficiency Under 
Different Dose Response Curves (n=12 and sigma=12) (revised 
per Amendment 06)
Model (R variables) 
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.6674254
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.6588761
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.6807728
E-max 1 (0.66)
–0.883, 0.095, 0.209, 0.277, 0.301
0.6953901
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.6879214
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.6782399
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.6843346
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 
0.881
0.6890958
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.6830898
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.670295
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.714469
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8027349
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.7642835
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.6840342
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.662415
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7117789
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Table 6
Power Calculations for Actigraph Sleep Efficiency Under 
Different Dose-Response Curves (n=13 and sigma=12) (revised 
per Amendment 06)
Model (R variables) 
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.6990587
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.6908521
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.7140683
E-max 1 (0.66)
–0.883, 0.095, 0.209, 0.277, 0.301
0.7286372
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.7206645
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.7098843
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.7170187
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 
0.881
0.7225359
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.7148674
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.7011122
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.7477969
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8321559
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.7948821
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.7160553
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.6949806
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7447213
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Table 7
Power Calculations for Actigraph Sleep Efficiency Under 
Different Dose Response Curves (n=14 and sigma=12) (revised 
per Amendment 06)
Model (R variables) 
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.7293262
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.7217665
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.7453197
E-max 1 (0.66)a
–0.883, 0.095, 0.209, 0.277, 0.301
0.7587574
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.7508701
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.7396949
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.7473776
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 0.881
0.7537709
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.7447648
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.7311277
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.7783044
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8576103
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.8224386
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.7454875
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.725321
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7753528
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9.7.3
Interim Analysis
A database lock will occur after all of the subjects have completed the Core Study, including 
the End of Study visit.  The Core Study data will be analyzed according to the Core Study 
SAP.  A second database lock will occur after the End of Study visits have been completed 
for the Extension Phase.  Analyses for the Extension Phase will be based on the Extension 
Phase SAP.  (revised per Amendment 05)
An interim analysis will be conducted with only the subjects from the US and Japan; details 
will be provided in the SAP.  (revised per Amendments 05 and 06)
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
(revised per Amendment 01)
Abbott SM, Zee PC.  Irregular Sleep-Wake Rhythm Disorder. Sleep Med Clin. 2015;10:517-
22.
Alexopoulos GS, Abrams RC, Young RC, Shamoian CA.  Cornell scale for depression in 
dementia.  Biol Psychiatry. 1988;23:271-84.
Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice 
guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced 
sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-
hour sleepwake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder 
(ISWRD). An update for 2015. J Clin Sleep Med. 2015;11(10):1199-236.
Bédard M, Molloy DW, Squire L, Dubois S, Lever JA, O'Donnell M. The Zarit Burden 
Interview: a new short version and screening version. Gerontologist. 2001 Oct;41(5):652-7.
Bornkamp B, Pinheiro J, Bretz F.  MCPMod: An R Package for the Design and Analysis of 
Dose-Finding Studies.  J Statistical Software. 2009 (7):29.
Bretz F, Pinheiro JC, Branson M.
Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics. 2005; 61:738-48.
Brooks R. EuroQol: the current state of play. Health Policy. 1996 Jul;37(1):53-72.
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality 
Index: a new instrument for psychiatric practice and research. Psychiatry Res. 
1989;28(2):193-213.
Camargos EF, Louzada FM, Nóbrega OT.  Wrist actigraphy for measuring sleep in 
intervention studies with Alzheimer’s disease patients: Application, usefulness, and 
challenges. Sleep Med Rev. 2013;17:475-88.
Campbell SS, Murphy PJ, van den Heuvel CJ, Roberts ML, Stauble TN. Etiology and 
treatment of intrinsic circadian sleep disorders.  Sleep Med Rev. 1999;3:179-200.
Carvalho-Bos, SS, Riemersma-van der Lek RF, Waterhouse J, Reilly T, Van Someren JW.  
Strong association of the rest-activity rhythm with well-being in demente elderly women.  
Am J Geriatr Psychiatry. 2007;15:92-100.
EuroQOL Group. EuroQol—a new facility for the measurement of health-related quality of 
life.  Health Policy. 1990;16:199–208.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98.
Goncalves BSB, Cavalcanti PRA, Tavares GR, Campos TF, Araujo JF. Nonparametric 
methods in actigraphy: An update.  Sleep Sci. 2014;7:158-64.
Guarnieri B, Sorbi S. Sleep and cognitive decline: A strong bidirectional relationship. It is 
time for specific recommendations on routine assessment and the management of sleep 
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disorders in patients with mild cognitive impairment and dementia. Eur Neurol. 
2015;74:43-8.
Hoekert M, der Lek RF, Swaab DF, Kaufer D, Van Someren EJ. Comparison between 
informant-observed and actigraphic assessments of sleep-wake rhythm disturbances in 
demented residents of homes for the elderly. Am J Geriatr Psychiatry. 2006 Feb;14(2):104-
11.
Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A. et al.  
Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer 
Disease.  JAMA Neurol. 2014;71:1498-505.
Liguori C, Nuccetelli M, Izzi F, Sancesario G, Romigi A, Martorana A, et al. REM sleep 
disruption and sleep fragmentation are associated with increased orexin-A Cerebrospinal 
Fluid levels in Mild Cognitive Impairment due to Alzheimer’s Disease, Neurobiology of 
Aging. 2016; doi: 10.1016/j.neurobiolaging.2016.01.007.
Miller MA. The role of sleep and sleep disorders in the development, diagnosis, and 
management of neurocognitive disorders. Front Neurol. 2015;6:224.
Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light 
therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatrica 
Scandinavica. 1994; 89: 1–7.
Musiek ES, Xiong DD, Holtzman DM.  Sleep, circadian rhyhms, and the pathogenesis of 
Alzheimer Disease.  Exp Mol Med. 2015;47: (electronic)doi:10.1038/emm.2014.121
Peron EP, Gray SL, Hanlon JT. Medication use and functional status decline in older adults: 
a narrative review. Am J Geriatr Pharmacother. 2011;9:378-91.
Peter-Derex L, Yammine P, Bastuji H, Croisile B.  Sleep and Alzheimer’s disease.  Sleep 
Med Rev. 2015;19:29-38.
Pillai V, Cheng P, Kalmbach DA, Roehrs T, Roth T, Drake CL. Prevalence and predictors of 
prescription sleep aid use among individuals with DSM-5 insomnia: the role of hyperarousal. 
Sleep. 2016;39(4):825-32.
Pollak CP, Perlick D.  Sleep problems and institutionalization of the elderly.  J Geriatr 
Psychiatry Neurol. 1991;4:204-10.
Posner, K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia–Suicide Severity Rating Scale: Initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry.
2011;168(12):1266–77.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J 
Psychiatry. 1984;141:1356–64.
Salami O1, Lyketsos C, Rao V. Treatment of sleep disturbance in Alzheimer's dementia. Int J 
Geriatr Psychiatry. 2011;26(8):771-82.
Satlin A, Volicer L, Ross V, Herz L, Campbell C. Bright light treatment of behavioral and 
sleep 
disturbances 
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patients 
with 
Alzheimer's 
disease. 
Am 
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Psychiatry. 
1992;1β49(8):1028-32.
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Satlin A, Volicer L, Stopa AG, Harper D.  Circadian locomotor activity and core-body 
temperature rhythms in Alzheimer's disease. Neurobiol Aging. 1995;16(5) 765-771.
Tractenberg RE, Singer CM, Cummings JL, Thal LJ.
The Sleep Disorders Inventory: an 
instrument for studies of sleep disturbance in persons with Alzheimer’s disease.  J Sleep Res. 
2003;12:331-37.
Trzepacz, PT, Saykin A, Yu, P, Bhamditipati P, Sun, J, Dennehy, EB, et al.  Subscale 
Validation of the Neuropsychiatric Inventory Questionnaire (NPI-A):  Comparison of ADNI 
and NACC Cohorts.  Am J Geriatr Psychiatry. 2013;21:607-22.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:
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•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes that have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, (eg, ECGs, rhythm strips, 
electroencephalograms, polysomnographs, actigraphy) regardless of how these images 
are stored, including microfiche and photographic negatives
•
Quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  Source 
data for actigraphy will be located at the central scoring vendor.  The investigator agrees to 
allow direct access to source documents and study facilities to sponsor representatives, 
monitors and auditors and agree to inspection by regulatory authorities or IRB/IEC 
representative.  (revised per Amendments 01 and 04)
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
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representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures 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 drugs 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.
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 
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pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
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12 APPENDICES
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Appendix 1
Sponsor's Grading for Laboratory Values (revised per 
Amendment 03)
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)a
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 28 May 2009 (v4.03: 14 Jun, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, , LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.
a
Please note that it is not required to measure fasting glucose in this protocol.  (revised per Amendment 03)
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Appendix 2 Pharmacogenomic Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacogenomic (PG) 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.
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or non-coding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug pharmacokinetics or therapeutic response.
Collection of the PG samples will be bound by the sample principles and processes outlined 
in the main study protocol.  Sample collection for PG analysis is not required, and will be 
obtained only from consenting subjects.  
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
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it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy. 
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  Genomic DNA samples used to explore the 
effects on PK, treatment response, and safety will be single coded.  Genomic DNA samples 
that will be stored for long-term use (defined as 15 years after the completion of the study) 
will be double coded.  Double coding involves removing the initial code (subject ID) and 
replacing with another code such that the subject can be re-identified by use of 2 code keys.  
The code keys are usually held by different parties.  The key linking the sample ID to the 
subject number will be maintained separately from the sample.  At this point, the samples 
will be double-coded, the first code being the subject number.  Laboratory personnel 
performing genetic analysis will not have access to the “key.”  Clinical data collected as part 
of the clinical trial will be cleaned of subject identifying information and linked by use of the 
sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:
•
Clinical research organizations retained by the sponsor
•
IECs or IRBs that have responsibility for this research study
•
National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PG analysis, it will not be possible to return individual data 
to subjects. The results that may be generated are not currently anticipated to have clinical 
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relevance to the patients or their family members. Therefore, these results will not be 
disclosed to the patients or their physicians.
If at any time, PG results are obtained that may have clinical relevance, IRB review and 
approval will be sought to determine the most appropriate manner of disclosure and to 
determine whether or not validation in a Clinical Laboratory Improvement Amendments 
(CLIA)-certified setting will be required.  Sharing of research data with individual patients 
should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories.
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Appendix 3 Prohibited Concomitant Medications 
(revised per Amendments 03 and 06)
If a medication is not presented in the list below, but does fit into a class of medications 
noted in the list, the medical monitor must be consulted to determine whether it is permitted.
Category
Medication
Anticholinergics (centrally-acting)
-
Antidepressants with anticholinergic properties
-
Strong CYP3A inhibitors
•
Amiodarone 
•
Bocepravir
•
Clarithomycin 
•
Cobicistat
•
Conivaptan
•
Diltiazem
•
Danoprevir
•
Eltegravir
•
Fluvoxamine
•
Grapefruit juice
•
Idelalisib
•
Indinavir
•
Itraconazole 
•
Ketoconazole 
•
Lopinavir
•
Mibefradil 
•
Nefazodone 
•
Nelfinavir
•
Posaconazole
•
Ritonavir
•
Saquinavir
•
Telapravir
•
Telethromycin
•
Tipranavir
•
Troleandomycin 
•
Voriconazole
•
(revised per Amendment 02)
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Category
Medication
Moderate CYP3A inhibitors

Amprenavir

Aprepitant

Atazanavir

Casopitant

Cimetidine

Ciprofloxacin

Clotrimazole

Crizotinib

Cyclosporin

Darunavir

Dronadarone

Erythromycin

Faldaprevir

Fluconazole

Fluvoxamine

Imatinib

Netupitant

Tofisopam

Verapamil (revised per Amendment 06)
CYP3A inducers
•
Avasimibe
•
Bosentan
•
Carbamazepine 
•
Efavirenz
•
Enzaluteamide
•
Etravirine
•
Lersivirine
•
Modafinil
•
Nafcillin
•
Phenobarbital 
•
Phenytoin
•
Rifabutin 
•
Rifampin
•
St. John’s Wort
•
Talviraline
•
Troglitazone 
•
Thioridazine
(revised per Amendment 02)
Drugs that affect the circadian timing system
•
Melatonin 
•
Ramelteon
•
Tasimelteon
MAOIs
-
Opioid Analgesics
-
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Category
Medication
Muscle relaxants (centrally-acting) with known sedating 
effects
•
GABA analogues 
•
Hydantoins 
•
Phenyltriazines
Orexin receptor antagonists (revised per Amendment 05)
•
Suvorexant
Other
•
Warfarin, heparin, ticlopidine
•
Non-stimulant diet pills
•
Systemic isoretinoin
•
Systemic glucocorticoids
•
Tryptophan
GABA = gamma-aminobutyric acid, H1 = histamine type 1 receptor, MAOI = monoamine oxidase inhibitors
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Appendix 4 Extension Phase
(revised per Amendments 05 and 06)
DESIGN AND PLAN
The Extension Phase comprises a 30-month Maintenance Period and a 14-day Follow-Up 
Period. 
Subjects who complete the Core Study End of Study (EOS) Visit within 30 days prior to 
enrollment in the Extension Phase will be eligible for participation. 
For subjects continuing directly from the Core Study to the Extension Phase, the End of 
Study (EOS) Visit of the Core Study will be the start of the Extension Phase.  
Subjects who complete the Core Study, but who do not elect to immediately roll over to the 
Extension Phase will be required to return to the site within 30 days of completion of the 
Core Study and repeat selected assessments before being dispensed drug for the Extension 
Phase.  If subjects return before 30 days of the last study visit, the tests that are required at 
that time are vital signs, weight, SDI, and eC-SSRS.  All other data will be carried over from 
Visit 6A. If subjects return on Day 30, all tests listed for Visit 6B will be performed.
Maintenance Period
During the Maintenance Period, all subjects initially will receive lemborexant 10 mg per day 
(LEM10). At the discretion of the investigator, subjects will have the option of increasing the 
dose to lemborexant 15 mg per day (LEM15) or decreasing to lemborexant 5 mg per day 
(LEM5).  All dose adjustments will be performed at an unscheduled visit or at the next 
scheduled visit.  The dose can be adjusted more than once during the Extension Phase.  
All doses will be taken orally in tablet form each night for the duration of the Extension 
Phase immediately (ie, within 5 minutes) before the time the subject intends to sleep.  
Subjects will receive 1 or 2 tablets as described below: 

LEM5:  one lemborexant 5-mg tablet

LEM10:  one lemborexant 10-mg tablet

LEM15:  one lemborexant 5-mg tablet and one lemborexant 10-mg tablet
Study visits, either in person or by telephone, will be conducted according to the Schedule of 
Procedures and Assessments for the Extension Phase (Table 8).  If the phone visit indicates 
an ongoing AE, the subject should be brought to the clinic for an Unscheduled Visit.  
Subjects may discontinue from study drug for any reason.  A subject who prematurely 
discontinues taking study drug should return to the clinic within 2 weeks of discontinuation 
to complete an Early Termination Visit.  The assessments of the Early Termination (ET)
Visit are the same as those for the EOS Visit for the Core Study.  If the subject discontinues 
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from the study due to an adverse event (AE), the subject must complete an ET Visit, and the 
AE must be followed to resolution for a period of 4 weeks, whichever comes sooner.
Follow-Up Period
The Follow-Up Period will be 14 to 18 days in duration and begins when subjects leave the 
clinic at the end of the Maintenance Period.  Subjects and caregivers will return to the clinic 
at least 14 days but no more than 18 days after the end of the Maintenance Period for the End 
of Study Visit, including the recording of AEs and concomitant medications, and assessment 
of clinical laboratory tests, vital signs, and weight, and measurement of an electrocardiogram 
(ECG).  
Treatment in the Extension Phase will last for a maximum duration of 30 months, until 
lemborexant is commercially available, or until the lemborexant clinical development 
program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is discontinued.
END OF EXTENSION PHASE
Estimates for End of the Extension Phase are as follows: 
The End of the Extension Phase will be the date of the last study visit for the last subject in 
the Extension Phase.
Duration of Treatment: Up to 30 months, or until lemborexant is commercially available, or 
until the lemborexant clinical development program for ISWRD is discontinued.
INCLUSION CRITERIA
1. Completed the Core Study (EOS Visit).  Subjects who participated in the Core Study 
and completed the EOS Visit within 30 days may return to participate in the 
Extension Phase as long as there are no contraindications due to ongoing AEs or 
prohibited medications.  
EXTENSION PHASE ASSESSMENTS
Efficacy Assessments
The Sleep Disorders Inventory (SDI), completed by the caregiver as proxy for the subject, 
will be performed according to the Schedule of Procedures and Assessments (Table 8). The 
SDI is described in detail in Section 9.5.1.3.
Safety Assessments
Subjects will have routine safety assessments during the Extension Phase, including 
monitoring, questioning and recording of AEs, measurements for ECGs, vital signs, and 
weight, and blood and urine collection for clinical hematology and chemistry analysis, 
urinalysis, and electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) (Table 8)  
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Complete descriptions of all safety parameters are located in Section 9.5.1.5.
SCHEDULE OF PROCEDURES and ASSESSMENTS
Table 8 presents the Schedule of Procedures/Assessments for the Extension Phase.
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Table 8
Schedule of Procedures and Assessments for Study E2006-G000-202 Extension Phase (revised 
per Amendment 06)
Phase
Extension 
Period
Maintenance
FU
Visit 
Numbera
6Bb
7c
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
EOS/
ET
25d,e
UNf
Study Day
73
103
133
163
193
223
253
283
313
343
373
403
493
583
673
763
853
943
957
Procedures/ 
Assessments
Physical 
exam g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
laboratory 
tests 
X
X
X
X
X
X
X
X
X
X
X
X
SDIh
X
X
X
X
X
X
X
X
X
X
X
X
eC-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Phone call 
follow-up
X
X
X
X
X
X
Dispense 
study drugi
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Retrieve 
unused study 
drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
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Table 8
Schedule of Procedures and Assessments for Study E2006-G000-202 Extension Phase (revised 
per Amendment 06)
Phase
Extension 
Period
Maintenance
FU
Visit 
Numbera
6Bb
7c
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
EOS/
ET
25d,e
UNf
Study Day
73
103
133
163
193
223
253
283
313
343
373
403
493
583
673
763
853
943
957
Procedures/ 
Assessments
Concomitant 
medications
Adverse 
eventsj
ECG = electrocardiogram, eC-SSRS = electronic Columbia-Suicide Severity Rating Scale, EOS = End of Study, ET = Early Termination, FU = Follow-
Up, MCB = median calculated bedtime, SDI = Sleep Disorders Inventory, UN = Unscheduled Visit.
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Table 8
Schedule of Procedures and Assessments for Study E2006-G000-202 Extension Phase (revised 
per Amendment 06)
Phase
Extension 
Period
Maintenance
FU
Visit 
Numbera
6Bb
7c
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
EOS/
ET
25d,e
UNf
Study Day
73
103
133
163
193
223
253
283
313
343
373
403
493
583
673
763
853
943
957
Procedures/ 
Assessments
a:
Visits 7, 8, and 9 to be conducted within a window of ±3 days of the scheduled visit day. Visit 10 through Visit 24 to be conducted within a window of 
±7 days of the scheduled visit day.  (revised per Amendment 06)
b:
For subjects who enter directly into the Extension Phase, the End of the Study (EOS) Visit for the Core Study is the first visit in the Extension Phase. 
Subjects may enter the Extension Phase up to 30 days after the EOS Visit of the Core Study (see Schedule of Assessments and Procedures for the Core 
Study); these subjects are required to have the following evaluations at study enrollment: vital signs, weight, SDI, and eC-SSRS.  Subjects who enroll in 
the Extension Phase the 30th day following the EOS Visit, must repeat the EOS Visit assessments at the time of enrollment (at Visit 6B). (revised per 
Amendment 06)
c:
Visit 7 should be up to and including 30 days after Visit 6B if the subject does not enter directly. The days between Visit 6A and 6B are not included in 
the calculation of study days. (revised per Amendment 06)
d:
Visit 25 occurs at least 14 days but no more than 18 days after the Visit 24.
e:
Subjects who discontinue the study early for any reason should complete the Early Termination (ET) Visit.
f:
In case of dose adjustment, the subject will need to come for an Unscheduled Visit (UN), or have the adjustment made at a scheduled clinic visit.
Additional assessments may be conducted at the Unscheduled Visit if the investigator considers them to be necessary.
g:
A full physical examination will be conducted at Visit 6B for subjects with a >30-day gap before enrollment into the Extension Phase) and at the End of 
Study Visit for the Extension Phase; an abbreviated physical examination will be conducted at all other visits. (revised per Amendment 06)
h:
The Sleep Disorders Inventory (SDI) will be completed by the caregiver as proxy for the subject.
i:
Drug will be dispensed to caregivers who will administer study drug to subjects. All study drug administration must be within 5 minutes of bedtime 
(defined as the time the subject attempts to sleep). (revised per Amendment 06)
j:
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a 
narrative for the event.  
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EXTENSION PHASE STATISTICAL METHODS
Endpoints
Efficacy Endpoint
The efficacy endpoint is the change from baseline in SDI total score.
Safety Endpoint
The safety endpoints are:

Safety and tolerability of lemborexant, including AEs and serious adverse events 
(SAEs).

eC-SSRS
Definitions of Analysis Sets
•
Safety Analysis Set:  the group of Extension Phase subjects who received at least 1 
dose of Treatment Phase study drug and had at least 1 postdose safety assessment 
•
The Full Analysis Set (FAS):  the group of subjects who received at least 1 dose of 
study drug and had at least 1 postdose measurement in the Extension Phase
Statistical Analyses
All statistical analyses will be performed using Statistical Analysis Software (SAS) or other 
validated statistical software. Details of the statistical analyses will be included in a separate 
statistical analysis plan (SAP).
Efficacy Analysis
The change from Baseline of the scale domains, as well as total score from the efficacy 
endpoint SDI will be summarized by time point and by modal dose.
Other comparisons may be performed as appropriate in the future (subjects who remain on 
LEM10 and never switch vs subjects who switch from LEM10), and these will be included in 
the Extension Phase SAP.
Safety Analysis
The analysis of safety data will be performed by time point and modal dose.
Other 
comparisons may be performed if appropriate and these will be included in the Extension 
Phase SAP.
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The safety endpoints of adverse events (treatment-emergent adverse events [TEAEs], SAEs, 
and AEs leading to discontinuation) will be summarized by System Organ Class (SOC) and 
Preferred Term (PT), and the incidence of AEs will be summarized by maximum severity 
and relationship to study drug.  Change from baseline analyses will be presented for clinical 
laboratory values, vital signs and weight, ECGs, and physical examination results. The 
results of eC-SSRS assessments will be listed for each subject, and the incidence of 
treatment-emergent suicidal ideation or suicidal behavior will be summarized by treatment 
group as above using descriptive statistics.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-G000-202
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study with Open-Label Extension Phase of the 
Efficacy and Safety of Lemborexant in Subjects with Irregular Sleep-
Wake Rhythm Disorder and Mild to Moderate Alzheimer’s Disease 
Dementia  (revised per Amendment 05)
Investigational Product
Name:
lemborexant
IND Number:
130798
EudraCT Number:
2017-003306-40 (revised per Amendment 05)
SIGNATURES
Authors: (revised per Amendments 02 and 04)
Neuroscience Business Group
Eisai Inc.
Date
Neuroscience Business Group 
Eisai Inc. (revised per Amendment 06)
Date
Neuroscience Business Group
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc. (revised per Amendment 06)
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-G000-202
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study with Open-Label Extension Phase of the 
Efficacy and Safety of Lemborexant in Subjects with Irregular 
Sleep-Wake Rhythm Disorder and Mild to Moderate 
Alzheimer’s Disease Dementia (revised per Amendment 05)
Investigational Product
Name:
lemborexant
IND Number:
130798
EudraCT Number:
2017-003306-40 (revised per Amendment 05)
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.
Medical Institution
Investigator
Signature
Date
Medicine Development 
Center
Eisai Co., Ltd.
Signature
Date
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SAP_003.pdf: 
Statistical Analysis Plan
E2006-G000-202
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2006-G000-202
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study with Open-Label Extension Phase of the Efficacy and 
Safety of Lemborexantin Subjects with Irregular Sleep-Wake Rhythm 
Disorder and Mild to Moderate Alzheimer’s Disease Dementia
Date:
20 JUN 2018
Version:
Final  Version 1.0
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Statistical Analysis Plan
E2006-G000-202
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TABLE OF CONTENTS
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
2
INTRODUCTION .............................................................................................................6
2.1
STUDY OBJECTIVES............................................................................................6
2.1.1
Sleep-Related Objectives (Revised per Amendments 05 and 06)..................6
2.1.2
Wake-Related Objectives (revised per Amendments 05 and 06)...................6
2.1.3
Circadian Rhythm-Related Objectives...........................................................7
2.1.4
Additional Objectives (revised per Amendment 05 and 06) ..........................7
2.2
Overall Study Design and Plan................................................................................8
3
DETERMINATION OF SAMPLE SIZE........................................................................10
4
STATISTICAL METHODS............................................................................................12
4.1
Study Endpoints.....................................................................................................13
4.1.1
Sleep-Related Endpoints..............................................................................13
4.1.2
Wake-Related Endpoints .............................................................................13
4.1.3
Circadian Rhythm-Related Endpoints .........................................................13
4.1.4
Additional Endpoints ...................................................................................13
4.2
Study Subjects........................................................................................................14
4.2.1
Definitions of Analysis Sets.........................................................................14
4.2.2
Definitions of Analysis Sets (Open Label Extension).................................15
4.2.3
Subject Disposition......................................................................................15
4.2.4
Protocol Deviations......................................................................................16
4.2.5
Demographic and Other Baseline Characteristics .......................................16
4.2.5.1
Medical History .................................................................................16
4.2.6
Prior and Concomitant Therapy...................................................................16
4.2.7
Treatment Compliance.................................................................................16
4.3
Data Analysis General Considerations ..................................................................17
4.3.1
Pooling of Centers........................................................................................17
4.3.2
Adjustments for Covariates..........................................................................17
4.3.3
Multiple Comparisons/Multiplicity .............................................................17
4.3.4
Examination of Subgroups...........................................................................17
4.3.5
Handling of Missing Data, Dropouts, and Outliers .....................................18
4.3.6
Other Considerations ...................................................................................18
4.3.7
Visit Window...............................................................................................19
4.4
Efficacy Analyses ..................................................................................................20
4.4.1
Efficacy Analysis for the Sleep-Related, Wake-Related, and Circadian 
Rhythm-Related Endpoints..........................................................................20
4.4.2
Subgroup Analyses ......................................................................................21
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4.4.3
Additional Analyses.....................................................................................21
4.5
Other Efficacy: Exploratory and Pharmacodynamic Analyses .............................21
4.6
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.................................................................................................................22
4.6.1
Pharmacokinetic Analyses...........................................................................22
4.6.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....22
4.7
Safety Analyses......................................................................................................23
4.7.1
Extent of Exposure.......................................................................................23
4.7.2
Adverse Events ............................................................................................23
4.7.3
Laboratory Values........................................................................................24
4.7.4
Vital Signs....................................................................................................25
4.7.5
Electrocardiograms ......................................................................................25
4.7.6
Other Safety Analyses..................................................................................26
5
INTERIM ANALYSES...................................................................................................26
6
CHANGES IN THE PLANNED ANALYSES...............................................................26
7
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................26
8
PROGRAMMING SPECIFICATIONS ..........................................................................26
9
STATISTICAL SOFTWARE..........................................................................................27
10
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................27
11
REFERENCES ................................................................................................................28
12
APPENDICES .................................................................................................................29
Appendix 12.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results....................................................................................................................29
Appendix 12.2  SAS Code Example for Dose Response Analysis....................................31
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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
AE
adverse event
AMP
Amplitude of the rest-activity rhythm
ANCOVA
analysis of covariance
aSE
Actigraphy sleep efficiency
ATC
anatomical therapeutic class
aWE
Actigaphy wake efficiency
BMI
body mass index
CGIC- ISWRD
Clinician’s Global Impression of Change - Irregular Sleep-Wake 
Rhythm Disorder version
CI
confidence interval
CRF
case report form
CSR
clinical study report
E2006
lemborexant
EQ-5D-5L
EuroQOL version 5D-5L
FAS
full analysis set
IS
Interdaily Stability 
ISWRD
Irregular Sleep-Wake Rhythm Disorder
IV
Intradaily Variability
LEM
lemborexant
LEM2.5 
lemborexant 2.5 mg
LEM5 
lemborexant 5 mg
LEM10 
lemborexant 10 mg
LEM15
lemborexant 15 mg 
LS
least squares
MCP-MOD
Multiple Comparisons and Modelling
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
NPI-10
Neuropsychiatric Inventory
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Abbreviation
Term
PBO
Placebo
PD
pharmacodynamic
PK
pharmacokinetic
PSG
Polysomnography
PSQI
Pittsburgh Sleep Quality Index
RA
Relative amplitude of the rest-activity rhythm
SAE
serious adverse event
SAP
statistical analysis plan
SD
Standard deviation
SDI
Sleep Disorders Inventory
SE
Sleep efficiency (PSG)
SFI
Sleep Fragmentation Index
SI
Système International
TEAE
treatment-emergent adverse event
TIB
Time in bed
TLG
tables, listings, and graphs
WFI
Wake Fragmentation Index
WHO
World Health Organization
ZBI
Zarit Burden Interview – short form
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2
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Eisai Protocol E2006-G000-202 (core 
study). The Open-Label Extension of this study will be covered by a separate SAP. Additional 
exploratory or post-hoc analyses not identified in this SAP may be performed to facilitate 
interpretation of study results and documented in the clinical study report. 
This document is prepared on the basis of the final study protocol version 10.0 amendment 6
(dated 20 Jun 2018). The reader is referred to the study protocol, the case report form (CRF), 
general CRF completion guidelines, and various data collection instruments employed in the 
study for details of study design, conduct, and data collection.  
This SAP was reviewed and approved prior to study database lock.  If any updates are made 
upon blinded review of study data or for any other reasons in the course of the study, such 
modifications and rationale are likewise to be documented and approved prior to unblinding of 
study database. 
2.1
STUDY OBJECTIVES
2.1.1
Sleep-Related Objectives (Revised per Amendments 05 and 06)

To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 10 mg 
(LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change from baseline 
in actigraphy-derived Sleep Efficiency (aSE) during the last week of treatment  in 
subjects with Alzheimer’s disease dementia (AD-D) who have ISWRD. 

To determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO on 
the change from baseline aSE  during  each  week  of  treatment.  

To determine the efficacy of lemborexant LEM2.5, LEM5, LEM10 and LEM15 
compared to PBO on the change from baseline on the Sleep Fragmentation Index (SFI) 
during each week of treatment. 

To determine the change from baseline of the mean duration of wake bouts 
(aMeanDurWB) over each week of treatment.  
2.1.2
Wake-Related Objectives (revised per Amendments 05 and 06)

To determine the dose response of lemborexant 2.5 mg (LEM2.5), 5 mg (LEM5), 10 mg 
(LEM10) and 15 mg (LEM15) compared to placebo (PBO) on the change from baseline 
in actigraphy-derived Wake Efficiency (aWE) during the last week of treatment  in 
subjects with Alzheimer’s disease dementia (AD-D) who have ISWRD. 

To determine the efficacy of lemborexant LEM2.5, (LEM5, LEM10, and LEM15 
compared to PBO on the change from baseline of actigraphy-derived Wake Efficiency 
(aWE) during each week of treatment.  
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
To determine the efficacy of lemborexant LEM2.5, LEM5, LEM10, and LEM15 
compared to PBO on the change from baseline of the Wake Fragmentation Index (WFI) 
during each week of treatment. 

To determine the change from baseline of the mean duration of sleep bouts 
(aMeanDurSB) over each week of treatment.  
2.1.3
Circadian Rhythm-Related Objectives 

To evaluate onset and treatment course effect as measured by change from baseline of 
intradaily variability (IV), interdaily stability (IS), amplitude of the rest-activity rhythm 
(AMP), relative amplitude of the rest-activity rhythm (RA), and other actigraphy 
variables during each week of treatment. 
2.1.4
Additional Objectives (revised per Amendment 05 and 06)

To evaluate the safety and tolerability of lemborexant.

To explore the effects of LEM2.5, LEM5, LEM10, LEM15, and PBO at the end of 4 
weeks of treatment (unless otherwise specified)` on the following:

Change from baseline of sum of activity counts and change from baseline of the number 
of bouts >10 minutes of sleep in the first 3 hours after morning waketime on each of the 
first 3 days and last 3 days of treatment as an indicator of next-morning residual effects.

Potential rebound ISWRD in the 2 weeks following 4 weeks of treatment.

Onset and course of treatment effect as measured by change from baseline of Clinician's 
Global Impression of Change-ISWRD (CGIC-ISWRD) Scale on symptoms of ISWRD 
total score and domains. 

Change  from  baseline  of  Alzheimer’s  Disease  Assessment  Scale  –  Cognitive 
Subscale (ADAS-cog).

Change from baseline in Mini Mental State Examination (MMSE).

Change from baseline in sleep quality in caregivers  as measured by the Pittsburgh Sleep 
Quality Index (PSQI).

Change from baseline of caregiver burden on the Zarit Burden Interview – short form 
(ZBI).

Change from baseline of Health outcomes of the subject and/or caregiver on the 
EuroQOL version 5D-5L (EQ-5D-5L) (subject Self Version, caregiver Self Version, 
caregiver Proxy 1 Version).

Change from baseline of mood and behavior on the Neuropsychiatric Inventory (NPI- 10; 
by caregiver as proxy for the subject).

To characterize the pharmacokinetics (PK) of lemborexant using the population 
approach.

To explore the PK/pharmacodynamic (PD) relationship between exposure to lemborexant 
and selected efficacy variables and most frequently occurring treatment- emergent 
adverse events (TEAEs).

To assess the plasma concentrations of cognitive enhancers (cholinesterase inhibitors 
and/or memantine) and lemborexant in subjects taking such drugs.
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
To evaluate the long-term safety and tolerability of flexible doses of LEM5, LEM10, and 
LEM15 per day over a period of 30 months in subjects with ISWRD who have completed 
the Core Study.
2.2
Overall Study Design and Plan
E2006-G000-202 is a multicenter, randomized, double-blind, PBO-controlled, parallel-group 
study of 4 doses of lemborexant or PBO taken daily for 4 weeks in approximately 60 male or 
female subjects, ages 60 to 90 years, with mild or moderate AD-D who complain of disrupted 
sleep or multiple awakenings at night along with frequent periods of falling asleep during the day 
that impacts the quality of life of the subject.  For each subject, an individual who knows the 
subject well and will provide the information about themselves will also be enrolled in the study 
(see Caregivers and Informants, below).  Additional informants may also be associated with the 
study but will not be required to complete a consent form. 
The study will have 3 phases: the Prerandomization Phase, the Randomization Phase, and the 
Extension Phase (Figure 1).  The Prerandomization Phase will comprise 2 periods that will last 
up to a maximum of 42 days: a Screening Period and a Baseline Period.  The Randomization 
Phase will comprise a Treatment Period during which subjects will be treated for 4 weeks, and a 
minimum 14-day Follow-Up Period before an End of Study visit.  The Extension Phase 
comprises a 30-month Maintenance Period and a 14-day Follow-Up Period.  Subjects who 
complete the Core Study End of Study (EOS) Visit within 30 days prior to enrollment in the 
Extension Phase will be eligible for participation.  For subjects continuing directly from the Core 
Study into the Extension Phase, the EOS Visit of the Core Study will be the start of the 
Extension Phase.  Subjects who complete the Core Study, but who do not elect to immediately 
continue into the Extension Phase have up to 30 days after the EOS Visit to participate.  These 
subjects will be required to return to the site within 30 days of completion of the EOS Visit to 
repeat selected assessments before being dispensed drug for the Extension Phase.
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Figure 1
Study Design
Note:  Visit 1 is an optional Prescreening Period for subjects and caregivers who are unsure whether the subject has Irregular Sleep-Wake Rhythm Disorder (ISWRD). Subjects will wear an activity 
tracker for approximately 4 days, then return to the site to have the data from the activity tracker downloaded and analyzed to determine whether they are candidates for the study.  (revised per 
Amendment 05)
Note:  Visit 2 is a caregiver visit for downloading actigraphy data to determine eligibility; Visit 3 is the baseline visit for both subject and caregiver; Visit 4 is a visit for both subject and caregiver to 
download actigraphy data and perform safety assessments; Visit 5 is the end-of-treatment assessments visit; and Visit 6A is for end-of-study assessments for the Core Study.  For subjects continuing 
directly from the Core Study into the Extension Phase, Visit 6A will be the start of the Extension Phase.  Subjects who complete the Core Study, but who do not electto immediately continue into the 
Extension Phase have up to 30 days after Visit 6A to participate.  These subjects will be required to repeat selected assessments (Visit 6B) before being dispensed drug for the Extension Phase.  Some 
subjects will have fewer visits based on the availability of lemborexant commercially.  
ISWRD = Irregular Sleep-Wake Rhythm Disorder, V = Visit.
V6A
V7 to V24
   V5
  V4
VE25
Extension Phase
Maintenance
(up to 30 months)
Follow-Up
(2 weeks)
V 1
   V2
   V1
   V3
Phase
Prerandomization
Randomization
Optional
Pre-
Screen-
ing
Screening
(up to 6 weeks)
(≥2 weeks
actigraphy)
Treatment (4 weeks)
(4 weeks actigraphy)
Follow-Up
(2 weeks 
actigraphy)
Period
Baseline /
Randomi-
zation
V6A
EOS Visit for Core 
Study / First visit 
for Extension 
Phase
V7 and V8
Days 73 and 
103
Clinic visits
V9, V12, V15, V18, V19, V20, V21, V22, V23, V24
Days 133, 223, 313, 403, 493, 583, 673, 763, 853, 
and 943
Clinic visits
V10, V11, V13, V14, V16, V17
Days 163, 193, 253, 283, 343, and 373
Telephone visits
V25
Day 957
End of Study
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3
DETERMINATION OF SAMPLE SIZE
Approximately 60 subjects will enroll in this proof-of- concept study. (revised per Amendment 
06)
Some supporting exploratory power estimation is based on testing the dose response using the 
MCP-Mod package in R; several dose response curves were explored at one-sided 0.05 level of 
significance with different values of n (12, 13, and 14 subjects) per treatment group (Table 1, 
Table 2, and Table 3) and are presented as conservative scenarios based on a 10-percentage 
point difference between the active dose and placebo.
Table 1
Power Calculations for Actigraph Sleep Efficiency Under 
Different Dose Response Curves (n=12 and sigma=12) 
Model (R variables)
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.6674254
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.6588761
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.6807728
E-max 1 (0.66)
–0.883, 0.095, 0.209, 0.277, 0.301
0.6953901
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.6879214
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.6782399
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.6843346
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 0.881
0.6890958
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.6830898
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.670295
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.714469
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8027349
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.7642835
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.6840342
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.662415
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7117789
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Table 2
Power Calculations for Actigraph Sleep Efficiency Under
Different Dose-Response Curves (n=13 and sigma=12)
Model (R variables)
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.6990587
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.6908521
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.7140683
E-max 1 (0.66)
–0.883, 0.095, 0.209, 0.277, 0.301
0.7286372
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.7206645
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.7098843
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.7170187
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 0.881
0.7225359
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.7148674
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.7011122
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.7477969
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8321559
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.7948821
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.7160553
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.6949806
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7447213
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Table 3
Power Calculations for Actigraph Sleep Efficiency Under
Different Dose Response Curves (n=14 and sigma=12) 
Model (R variables)
Optimal Contrasts
(PBO, 2.5, 5, 10, 15)
Power (%)
BetaMod 1 (0.339,0.05)
–0.82, –0.074, 0.116, 0.336, 0.442
0.7293262
BetaMod 2 (0.5,0.3)
–0.834, –0.073, 0.187, 0.414, 0.305
0.7217665
BetaMod 3 (0.19,0.15)
–0.887, 0.124, 0.236, 0.304, 0.223
0.7453197
E-max 1 (0.66)a
–0.883, 0.095, 0.209, 0.277, 0.301
0.7587574
E-max 2 (1.1)
–0.869, 0.033, 0.195, 0.301, 0.340
0.7508701
E-max 3 (3)
–0.804, –0.123, 0.133, 0.349, 0.445
0.7396949
Exponential 1 (6.2)
–0.378, –0.319, –0.231, 0.097, 0.832
0.7473776
Exponential 2 (3)
–0.285, –0.274, –0.251, -0.071, 0.881
0.7537709
Lineara
–0.540, –0.332, –0.125, 0.291, 0.706
0.7447648
Linear-log (3.3)
–0.732, –0.210, 0.048, 0.351, 0.543
0.7311277
Logistic 1 (0.13,0.732)
–0.892, 0.165, 0.241, 0.243, 0.243
0.7783044
Logistic 2 (5,1)
–0.531, –0.459, –0.016, 0.500, 0.507
0.8576103
Logistic 3 (6,2)
–0.517, –0.399, –0.130, 0.460, 0.587
0.8224386
Quadratic (-0.029)
–0.643, –0.307, –0.023, 0.386, 0.586
0.7454875
SigEMax 1 (20.46,0.5)
–0.809, –0.093, 0.106, 0.329, 0.467
0.725321
SigEMax 2 (0.89,2.4)
–0.892, 0.162, 0.233, 0.247, 0.249
0.7753528
4
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 statistical tests will be based on the 5% level of significance (2-sided), unless otherwise 
stated.  If statistical comparisons are not defined, all pairwise comparisons will be tested.
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4.1
Study Endpoints
4.1.1
Sleep-Related Endpoints
The sleep-related endpoints are:
•
The change from baseline of aSE during each week of treatment with LEM compared to 
PBO
•
Change  from  baseline  in  mean  SFI  during  each  week  of  treatment
•
Change from baseline of the aMeanDurWB during each week of treatment
4.1.2
Wake-Related Endpoints
•
The change from baseline of mean aWE with LEM compared to PBO during each week 
of treatment
•
Change from baseline of the aMeanDurSB during each week of treatment
•
Change  from  baseline  of  mean  WFI  during  each  week  of  treatment  
4.1.3
Circadian Rhythm-Related Endpoints
•
Change from baseline of IV, IS, L5, M10, AMP and RA over each week of treatment
4.1.4
Additional Endpoints
•
The  following  additional  endpoints  will  be  explored  for  LEM2.5,  LEM5,  LEM10  
and LEM15 compared to PBO:
•
Safety and tolerability of LEM, including AEs and SAEs
•
Change from baseline in Clinician's Global Impression of Change-ISWRD (CGIC-
ISWRD) Scale on symptoms of ISWRD total score and domains.  (revised per 
Amendments 01 and 06)
•
Change from baseline of the sum of activity counts and change from baseline in the 
number of bouts >10 minutes of sleep in the first 3 hours after morning waketime on the 
first 3 days and last 3 days of treatment.
•
Number and percentage of subjects in each category of the CGIC-ISWRD Scale at Day 
29 (revised per Amendment 01)
•
Rebound sleep and wake fragmentation endpoints as assessed from actigraphy during the 
Follow-Up Period
•
Change from baseline in mean aSE of the first 7 nights, and aSE of the second 7 nights of 
the Follow-Up Period
•
Change from baseline in mean aWE of the first 7 days and mean aWE of the second 7 
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days of the Follow-Up Period
•
Proportion of subjects whose mean aSE is higher than at baseline for the first 7 nights or 
the second 7 nights of the Follow-Up Period
•
Proportion of subjects whose mean aWE is longer than at baseline for the first 7 days or 
the second 7 days of the Follow-Up Period (revised per Amendment 03)
•
Change from baseline on ADAS-Cog at Day 29
•
Change from baseline on MMSE at Day 29
•
Change from baseline sleep quality in caregivers as measured by the PSQI at Day 29
•
Change from baseline of caregiver burden on all scores of the ZBI-short form at Day 29. 
(revised per Amendment 06)
•
Change from baseline on the EQ-5D-5L utility and Visual Analogue Scale (VAS) scores 
at Day 29 for both subject and caregiver
•
Change from baseline of the total score of NPI-10 at Day 29
•
Change from baseline on SDI at Day 29
•
Characterize the PK of lemborexant using the population approach and descriptive 
statistics for the plasma concentrations of its metabolites M4, M9, and M10. (revised per 
Amendment 06)
•
Relationships between exposure to lemborexant, efficacy, and/or safety variables using 
PK/PD modeling
•
Assess the plasma concentrations of cognitive enhancers and lemborexant in subjects 
taking both drugs.
•
Evaluate the long-term safety and tolerability of flexible doses of LEM5, LEM10, and 
LEM15 per day over a period of 30 months in subjects with ISWRD who have completed 
the Core Study.  (revised per Amendments 05 and 06)
4.2
Study Subjects
4.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of randomized subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 dose of 
randomized study drug.
The PK Analysis Set is the group of subjects who have at least 1 quantifiable plasma 
concentration of lemborexant, with adequately documented dosing history.
The PK/PD Analysis Set is the group of subjects receiving either lemborexant or placebo who 
have efficacy or safety data with documented dosing history.  In addition, subjects receiving 
lemborexant should have at least 1 quantifiable lemborexant concentration data point as per the 
PK Analysis Set.
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4.2.2
Definitions of Analysis Sets (Open Label Extension)
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
during the open label extension.
4.2.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized. Screen failure data will be listed. The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
The number of subjects completing the core study will be presented. Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for study 
termination. Other reasons for study drug and study terminations will also be summarized. These 
tabulations will be produced for all randomized subjects by treatment group.
The number of subjects enrolling in the open label extension will be presented.
The number and percentage of subjects will be summarized with the number in the FAS as the 
denominator, together with the number of subjects randomized but never dosed:
•
Randomized but never dosed (only showing number of subjects)
•
Completed treatment
•
Prematurely discontinued treatment and the reasons for discontinuations
•
Completed study
•
Prematurely discontinued the study and the reasons for discontinuations
Kaplan-Meier analysis for time to treatment discontinuation will be performed to produce 
graphical presentations of the treatment completion curves and to estimate treatment 
discontinuation rates by treatment group. Time to treatment discontinuation (in days) is 
calculated as: last dose date – first dose date +1. Subjects who complete the treatment period will 
be considered to have no event. Subjects who prematurely discontinued treatment will be 
considered to have an event at the time of treatment discontinuation.
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing will be provided with subjects ordered 
by randomization date.
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4.2.4
Protocol Deviations
Protocol deviations, as specified by the monitor, will be categorized into major and minor 
deviations prior to unblinding and will be listed. Major protocol deviations will be summarized 
by treatment group.
4.2.5
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
for each treatment group using descriptive statistics.  Continuous demographic and baseline 
variables include age, height, and weight; body mass index (BMI); categorical variables include 
sex, age group (<60, 60 to 74 years, 75 to 84 years, and 85 and older), BMI group (<18.5, 18.5 to 
<25, 25 to ≤30, and >30 kg/m2, or other suitable categorization), race, ethnicity, and country.  
Other baseline characteristics for actigraphy data and MMSE will also be summarized.  
Caregiver demography including relationship of the caregiver to the subject, caregiver’s sleeping 
location, etc.) will also be summarized.
If the Safety Analysis Set and FAS differ substantially, the demographic summaries will be 
repeated on the FAS.
4.2.5.1
Medical History
The number (percentage) of subjects in the Safety Analysis Set reporting a history of any 
medical condition, as recorded on the CRF, will be summarized for each treatment group and 
overall.  A subject data listing of medical and surgical history will be provided.
4.2.6
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (Mar 2016 or latest version). 
The number (percentage) of subjects who take prior and concomitant medications will be 
summarized on the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical 
class (ATC), and WHO DD -preferred term (PT). If the Safety Analysis Set and FAS differ, then 
the prior and concomitant medication summaries will be repeated on the FAS. 
Prior medications are defined as medications that stopped before the first dose of study drug.
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.
4.2.7
Treatment Compliance
Compliance for each study drug will be calculated on the basis of the number of tablets 
dispensed, lost and returned, separately for each row of tablets and overall, for all randomized 
subjects.
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Compliance = (Total number of tablets dispensed - total number of tablets returned or lost) x 100  
Number of tablets expected to be taken by the subject for the treatment period
Summaries will provide descriptive summary statistics and number (percentage) of subjects 
using the categories <80%, >= 80% to <= 100%, >100% to <= 120%, and > 120% for each 
treatment group.  
If deemed necessary, treatment compliance will be calculated for the Safety Analysis Set and 
FAS as well.
4.3
Data Analysis General Considerations
The FAS will be used as the primary population for all efficacy analyses.  
4.3.1
Pooling of Centers 
This study was a multicenter study across the United States, UK and Japan, with approximately 
40-50 sites across the two countries. As country is used as randomization stratification factor, 
country will be used as a covariate in many planned analyses. Therefore, data from centers of the 
same country will be pooled together as strata.  It was planned that each country would enroll a 
minimum of 20 subjects in the study. UK subjects will be pooled with US subjects if deemed 
necessary.  In the case of low enrollment as the study approaches completion, decisions 
regarding eliminating country as a factor in the analysis models will be made and documented 
before treatment unblinding.
4.3.2
Adjustments for Covariates
In the statistical models, the covariate of country will be included in the model since country was 
used for the randomization stratification. Details of adjustment for covariates for other efficacy 
analyses are defined in the description of each individual efficacy analysis.  
4.3.3
Multiple Comparisons/Multiplicity
No multiplicity adjustments will be made.  The study is aimed to find the best dose response 
curve for each endpoint and will not be used for labelling claims.
However, this proof of concept (PoC) study uses the multiple comparison procedures-modeling 
(MCP-Mod) approach with set of candidate dose response models and test for a dose response 
relationship via model associated statistics. The multiplicity adjusted p-value and critical values 
are numerically computed based on the assumption that the multiple T test statistics, are jointly 
multivariate t-distributed under the null hypothesis of no dose response.
4.3.4
Examination of Subgroups
Due to the sample size reduction, there will bo no formal subgroup analysis. Basic summary 
statistics may be explored for various subgroups in order to assess whether the treatment effects 
are consistent across different subgroups.  These subgroups include: age group (<60, 60 to 74 
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years, 75 to 84 years, and 85 and older), sex (male and female), race (White, Black or African 
American, Japanese, Chinese, Other Asian, American Indian or Alaska Native, Native Hawaiian 
or Other Pacific Islander, Other), country (USA, Japan), BMI group (< 18.5, >=18.5 to <25,
>=25 to <30, and >=30), severity of baseline aSE (less than 65%, 65% to 75%), severity of 
baseline aWE (less than 75%, 75% to 87%), frequency of complaint of sleep and wake 
fragmentation at baseline (4, 5, 6 or 7 days per week, maybe subsumed depending on data), 
APOɛ4 genotype, and severity of AD-D based on MMSE (10 to 20, greater than 20 to 25).  Age 
group is classified by the subject’s age at the time of Informed Consent; sex and race are defined 
as entered on the study CRF, country is the same as that used for the randomization stratification; 
BMI group is defined by weight taken from the baseline vital sign visit; and severity of aSE, 
aWE, MMSE and frequency of complaint of sleep and wake fragmentation are from data 
collected during screening. 
For some subgroup variables, in the event that the sample size in a subgroup is so small that 
interpretation of the results is challenging, some subgroups with small sample sizes may be 
regrouped.  For example, BMI group can be re-grouped as <25 and >=25; race can be re-grouped 
as White, Black or African American, Japanese, and All Others.  If re-grouping of subgroups is 
warranted, it will be documented before treatment unblinding. 
Additional subgroup analyses may also be conducted, such as subgrouping by combinations of 
aforementioned variables or other criteria of clinical relevance, if deemed necessary to provide 
additional understanding of study data, interpretation of results, or to address questions of 
clinical interest, and will be documented in the updates of this SAP or clinical study report. 
4.3.5
Handling of Missing Data, Dropouts, and Outliers
Specific methods for handling missing values in calculating the efficacy endpoints (aSE and 
aWE) are detailed in Section 8 Definitions and Conventions for Data Handling.  In general, 
missing values due to subject discontinuation, missed or unusable assessments will not be 
imputed.
Since this is actigraphy study, and as long as subject wears his/her  actigraph during the last 
week of treatment, primary endpoint will most likely not be missing.
Incomplete/Missing data: Will not be imputed, unless otherwise specified; i.e., all missing 
values will remain as missing in all statistical analyses and listings, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers.
4.3.6
Other Considerations
Individual subject data in the database will be presented in data listings.
The following estimands (Table 4) are evaluated for the primary efficacy endpoint (aSE and 
aWE change from baseline during last week of treatent) in this study (Mallinckrodt, et al., 2012, 
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and ICH, E9(R1) Final  Concept Paper, 2014).  The details of the analysis method are discussed 
in Section 4.4.
Table 4
Estimate
Description
Popu-
lation
Intervention Effect of Interest
Analysis 
Type
Dose Response: 
Testing the 
hypothesis that  
(the dose-response 
curve is not flat)
Establish a dose-response signal 
using 
multiple 
comparison 
procedure. Based on the observed 
data, the model that shows a 
statistically significant trend test 
will be selected (at one-sided 5% If 
more than one is statistically 
significant, then the most optimal 
model using Akaike Information 
Criteria will be selected. This 
method prospectively controls the 
type I error at 5%.
FAS
Subjects who completed all 
efficacy endpoint assessments 
(aSE or aWE) during the 4th
week of treatment without 
missing the week 4 value.
(This is first 
important 
analysis since 
there is no 
primary or 
secoandary 
analysis in 
this proof of 
concept 
study).
Difference in 
outcome 
improvement for 
all randomized 
subjects
- all randomized subjects 
regardless of what treatment 
subjects actually received 
- include data after dropout
FAS
Missing values will not be 
imputed; MMRM model is 
used on all available data 
assuming MAR
(Assumes subjects with missing 
values behave the same as the 
observed data within that 
treatment group, i.e., the 
missingness is independent of 
unobserved data after 
accounting for the observed 
data in the model.  Thus the 
dropouts or subjects with 
missing values may continue to 
benefit from the treatment as if 
they were still on treatment 
(just like completers).
(This is 
second 
important 
analysis since 
there is no 
primary or 
secoandary 
analysis in 
this proof of 
concept 
study).
(MMRM 
analysis 
assuming 
MAR)
FAS = full analysis set; MAR = missing at random, MMRM = mixed effect for repeated measures model
4.3.7
Visit Window
All efficacy and safety data will be presented using nominal visits as reported in the data. No 
additional derivation will be performed for analysis visit window. Actigraphy data will be 
presented by visit as derived by the actigraphy vendor.
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4.4
Efficacy Analyses
Efficacy analyses will be performed on the FAS unless otherwise specified.
4.4.1
Efficacy Analysis for the Sleep-Related, Wake-Related, and Circadian Rhythm-
Related Endpoints
The change from baseline of the mean aSE and mean aWE (separately) for the last 7 nights/days
on treatment will be analyzed using MCP-MOD (Multiple Comparisons and Modelling) 
approach.  Dose response models that will be evaluated are linear, linear log, quadratic, 
exponential, emax, sigmoid emax, beta and logistic. 
For all actigraphy parameters, baseline will be defined as the average value of the last 7 days of 
screening. For IS, IV, RA, AMP, L5, M10 parameters, the weekly averages are calculated by 
actigraphy vendor.  For these variables, the last record of screening period will be considered as
the baseline (the average of the last 7 days) of screening period.
Analysis stage – MCP-step: Establish a dose-response signal (the dose-response curve is not flat) 
using multiple comparison procedure. Based on the observed data, the model that shows a 
statistically significant trend test will be selected (at one-sided 5% significance). If more than 
one is statistically significant, then the most optimal model using Akaike Information Criteria 
will be selected. This method prospectively controls the type I error at 5%.
Analysis Stage – Mod-step: Dose response and target dose estimation will be based on dose 
response modelling. MCP-MOD approach allows for interpolation between doses. 
The p-value and Akaike Information Criteria for the trend test will be reported for all models 
explored for the MCP-step. The dose response and target dose estimation for the chosen model 
will be reported for the Mod-step.
The change from baseline of secondary endpoints mean SFI, mean WFI, mean aMeanDurSB, 
mean aMeanDurWB, IV, IS, L5, M10, AMP and RA of the last 7 days of treatment (ie, Week 4) 
will be analyzed using mixed methods for repeated measures (MMRM) model on the FAS for 
LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, as appropriate. The model will include 
all data and will be adjusted for the corresponding baseline value, country, treatment, time 
(Week 1, Week 2, Week 3 and Week 4) and the interaction of treatment by time. Treatment by 
time interaction will be used to construct the treatment comparisons at a specific time. The 
MMRM model accounts for any missing data, and assumes that the missing data are missing at 
random. An unstructured covariance matrix will be used, and if the model fails to converge, then 
an autoregressive matrix will be used. Where data are normally distributed, least square (LS) 
means, difference in LS means of each lemborexant dose compared to PBO, 95% CIs and P 
values at the appropriate time point will be presented.
The overall score of CGIC-ISWRD Scale at Day 29 will be analyzed using the Cochran–Mantel–
Haenszel (CMH) test, adjusted for country.
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4.4.2
Subgroup Analyses
Subgroup analysis, as deemed necessary, will be presented using basic summary statistics. No 
hypothesis testing will be made on subgroup analysis. 
4.4.3
Additional Analyses
The mean aSE and aWE change from baseline will be analyzed using the MMRM. The linear 
least squares will be performed on aSE and aWE change from baseline at Week 1, Week 2, 
Week 3 and Week 4 of treatment on the FAS for LEM2.5, LEM5, LEM10 and LEM15
compared to PBO, where the model will be explored with baseline value, country and treatment 
as covariates/factors, and with and without age and MMSE score as further exploratory 
covariates. Least square (LS) means, difference in LS means of each lemborexant dose compared 
to PBO, 95% CIs and P values at the appropriate time point will be presented.
4.5
Other Efficacy: Exploratory and Pharmacodynamic Analyses
To assess residual morning sleepiness levels, change from baseline in the sum of activity counts 
in the 3 hour interval after morning waketime will be compared for each treatment group relative 
to placebo for each of the 6 mornings comprising the first 3 days and last 3 days of treatment. 
The change from baseline will be analyzed using analysis of covariance (ANCOVA), with 
treatment and baseline as fixed effects. LS means, difference in LS means of LEM2.5, LEM5, 
LEM10 and LEM15 compared to PBO, 95% CIs, and p-values will be presented. In addition, the 
change from baseline of the number of bouts >10 min scored as sleep will be determined. The 
change from baseline will be analyzed using ANCOVA, as above.
Rebound sleep and wake fragmentation is defined as worsened aSE or aWE compared to 
baseline after study drug treatment is discontinued. Actigraphy data from the Follow-Up Period 
will be compared to actigraphy data from the baseline to assess whether subjects experience 
rebound sleep or wake fragmentation. Specifically, a lower value for aSE or aWE during the 
Follow-Up Period compared to the mean aSE or aWE value during baseline will be considered 
worsened sleep or wake fragmentation.
To assess rebound sleep and wake fragmentation, both categorical analysis at the subject level 
and continuous analysis at the group mean level will be performed. For each of the 2 weeks of 
the Follow-Up Period the proportion of subjects whose corresponding value for aSE or aWE is 
less than the corresponding baseline value by 5% for aSE and 1% for aWE (which is 
approximately minutes based on the a typical 8-hour sleep period and 16-hour wake period) will 
be summarized by treatment group and compared to placebo. The percentage of ‘rebounders’ 
between each treatment and placebo group will be analyzed using a CMH test, adjusted for 
country.
To assess statistical significance using the continuous data at the group mean level, the data will 
be analyzed using ANCOVA, adjusted for country. The LS mean of each week of the Follow-Up 
Period will be compared to the baseline between each treatment group and placebo. If the upper 
bound of the 95% CI of aSE or aWE for the mean of each week of the Follow-Up Period is less 
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than the lower bound of a 95% CI for the values during the baseline in the given treatment group, 
it will be considered strong evidence for rebound sleep or wake fragmentation. If the LS means 
for aSE and aWE for the Follow-Up Period are all higher than for the baseline, then no rebound 
sleep or wake fragmentation is suggested. Otherwise, the degree to which the parameters worsen, 
and the time point(s) at which they worsen will be considered to evaluate whether clinically 
meaningful rebound sleep and/or wake fragmentation is present.
Each domain of CGIC-ISWRD Scale and the total score at Day 29 will be analyzed using the 
CMH test, adjusted for country. 
The change from baseline of the EQ-5D-5L utility and VAS scores, the global score of PSQI, all 
scores of the ZBI-short form and the SDI at Day 29 will be analyzed using ANCOVA, with 
treatment and baseline as fixed effects. Provided that the data are normally distributed, LS 
means, difference in LS means of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, 95% 
confidence intervals (CIs) and p-values will be presented.  
For the PSQI, caregivers who do not attend to the subject in the night will not be included in the 
summaries and analysis. Caregiver data will not be included in analyses if they do not live in the 
same dwelling as the subject, and will be presented as a subgroup data for exploratory purposes.
4.6
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses
4.6.1
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual plasma concentration listings of lemborexant 
and its metabolites M4, M9, and M10. The PK Analysis Set will be used for summaries of 
plasma concentrations of lemborexant and its metabolites M4, M9, and M10, by dose and day.
Further details of the PK and population PK analyses will be provided in a separate analysis plan.
4.6.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
DNA samples will be collected and stored, and may be used to examine the role of genetic 
variability in absorption, distribution, metabolism, and excretion, or development of AEs.
Variations in lemborexant exposure or AEs may be explored by correlation of single nucleotide 
polymorphisms with PK, safety, or efficacy data. Efficacy may be explored in relation to the 
APOɛ4 genotype as follows:
The change from baselines of the mean aSE and mean aWE (separately) for the last 7 nights/days 
on treatment may be explored by APOɛ4 genotype comparing total lemborexant to placebo. 
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4.7
Safety Analyses
Safety analyses will be performed on the Safety Analysis Set unless otherwise specified. Safety 
data, presented by treatment group, will be summarized on an “as treated” basis using descriptive 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables).  Safety variables include treatment-emergent adverse 
events (TEAEs), clinical laboratory parameters, vital signs, 12-lead ECG results, electronic 
Columbia-Suicide Severity Rating Scale (eC-SSRS).  Study Day 1 for all safety analyses is 
defined as the date of the first dose of study drug.
4.7.1
Extent of Exposure
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study drug 
will be summarized descriptively for lemborexant.
Compliance for lemborexant will be calculated on the basis of the number of tablets dispensed, 
lost, and returned, separately for each type (dose) of tablet.  Summaries will provide descriptive 
summary statistics and number (percentage) of subjects below 80%, between 80% and 120%, 
and greater than 120%.
4.7.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 or higher) lower level 
term closest to the verbatim term. The linked MedDRA PT and primary system organ class 
(SOC) are also captured in the database.  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment, 
having been absent at pretreatment (Baseline) or 
•
Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsened in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. AEs will be classified 
as TEAEs up to 14 days after the last study treatment.
An overview of the TEAEs will be summarized by treatment group, including the number and 
percentage of subjects who experience TEAEs, treatment-related TEAEs, severe TEAEs, TEAEs 
leading to death and discontinuation from study/study drug.  
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT. A subject will be counted only once within an SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT. The number (percentage) of 
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subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of non-serious TEAEs with an incidence of greater than 5% will be 
summarized.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). Treatment-related TEAEs include those events 
considered by the investigator to be related to study treatment. 
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. 
Adverse events will be summarized by the following subgroups: age (≤64 years, 65 to 74 years, 
75 to 84 years, ≥85 years), sex (male, female),  race (white, black, Asian, other), and country
The number (percentage) of subjects with TEAEs of cataplexy that are characterized according 
to the customized MedDRA query PT as potential cataplexy-related events (Section 9.5.1.5 of 
the Protocol), or as seizure-related events will be summarized as deemed necessary. Adjudicated 
events will also be presented separately.
4.7.3
Laboratory Values
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  Abnormal 
laboratory values will be identified as those outside (above or below) the normal range.  
Reference (normal) ranges for laboratory parameters will be included in the clinical study report 
for this study.  Descriptive summary statistics (eg, mean, SD, median, minimum, maximum for 
continuous variables, and number and percentage for categorical variables) for the laboratory 
parameters and changes from baseline will be evaluated by treatment group and visit.  
Laboratory test results will be assigned a low-normal-high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons will be based on 3 by 3 tables (shift tables) that, for a 
particular laboratory test, compare the Study Baseline LNH classification to the LNH 
classification at end of study/early termination, by treatment group.
Clinical laboratory results post-baseline will be evaluated for markedly abnormal values.  A 
laboratory test will be considered markedly abnormal if the result worsens to meet Eisai grading 
criteria for laboratory values limit of Grade 2 or higher.  If the Grade 2 limit is missing, the 
Grade 1 limit will be considered.  Appendix 12.1 presents the Eisai grading criteria for 
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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.
4.7.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, respiration 
rate, temperature) and weight, and changes from Baseline will be presented by visit and 
treatment group. 
Vital sign values will be listed. Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table ). Categorical analyses 
of subjects (number and percent) who fall outside the below clinically notable vital sign ranges 
will also be presented by treatment group and visit.
Table 5
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.
Clinically notable means that a value must meet the criterion value and must attain the specified magnitude of 
change relative to baseline.
4.7.5
Electrocardiograms
Descriptive statistics for ECG parameters and changes from Baseline will be presented by 
treatment group. Shift tables will present changes from Baseline in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically significant) 
by time point.
For each subject, the maximum observed corrected QT interval calculated using Fridericia’s 
formula (QTcF), and the maximum prolongation from baseline in QTcF will be compiled.  
Categorical analyses of subjects (number and percent) with maximum observed QTcF values 
>450 msec, >480 msec, and >500 msec and maximum prolongations (from Baseline) in QTcF 
>30 msec and >60 msec will be presented by treatment group and by time point. Categorical 
analyses of subjects (number and percent) with maximum observed PR values >220 msec, and 
QRS values > 120 msec will be presented by treatment group and by time point.
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4.7.6
Other Safety Analyses
The results of eC-SSRS assessments will be listed for each subject. The incidence of treatment-
emergent suicidal ideation or suicidal behavior will be summarized by treatment group using 
descriptive statistics as appropriate.
The change from baseline of total score from the NPI-10, ADAS-Cog and MMSE at Day 29 will 
be analyzed with ANCOVA, with treatment and baseline as fixed effects on the Safety Analysis 
Set.  Provided that the data are normally distributed LS means, difference in LS means of 
LEM2.5, LEM5, LEM10 and LEM15 compared to PBO, 95% confidence intervals (CIs) and p-
values will be presented.  
5
INTERIM ANALYSES
No formal interim analyses will be performed for this study. However, due to the fact that the 
last subject has enrolled at a very late stage in this study, analysis for top-line results will be 
performed based on the first 61 randomized subjects without unblinding the study site and CRO 
regarding the last subject. All TLGs then will be produced based on all data when all subjects 
complete the study.
6
CHANGES IN THE PLANNED ANALYSES
It has been decided to stop the study early after enrolling about 60 subjects while original sample 
size was 125 subjects. Due to the reduction of sample size, no formal subgroup analysis will be 
performed.
7
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
Actigraph data will be excluded from the analysis where there are fewer than 5 complete days 
out of 7 days’ data.  A day will be considered complete as long as data from 90% of the 24-hour 
period are scorable. Actigraphy vendor will not derive actigraphy parameters for weeks where 
subject has fewer than 5 complete days out of 7 days’ data, and therefore such data will not be 
available for analysis nor it will be imputed.
Actigraph data will be calculated based on habitual TIB and waketime values for the protocol 
described analyses, and also based on actual TIB and waketime values as an exploratory 
analysis.
  
8
PROGRAMMING SPECIFICATIONS
For all actigraphy parameters, baseline will be defined as the average value of the last available 
seven days’ values of screening period . For all other safety and efficacy enpoints, the last 
measurement before dosing will be defined as the baseline. Unless it is specified otherwise.
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All efficacy and safety data will be presented using nominal visit as reported in the data. No 
additional derivation will be performed for analysis visit window. 
The rules for programming derivations and dataset specifications are provided in separate 
documents.
9
STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS v 9.3 or later.
10 MOCK TABLES, LISTINGS, AND GRAPHS
The study table, listing, and graph (TLG) shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail.
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11 REFERENCES
Bornkamp B, Pinheiro J, Bretz F.  MCPMod: An R Package for the Design and Analysis of
Dose-Finding Studies.  J Statistical Software. 2009 (7):29.
Gehrman PR, Marler M, Martin JL, et al. The timing of activity rhythms in patients with 
dementia is related to survival. J Gerontol Biol Sci Med Sci. 2004;59A:1050–1055.
Marler MR, Gehrman P, Ancoli-Israel S, et al. The sigmoidally transformed cosine curve: a 
mathematical model for circadian rhythms with non-sinusoidal shapes. Stat Med. 2006;25:3893–
3904. 
Martin et al, Sleep and Sleep Disorders in Older Persons: A Multicomponent 
Nonpharmacological Intervention Improves Activity Rhythms Among Nursing Home Residents 
With Disrupted Sleep/Wake Patterns Journal of Gerontology: MEDICAL SCIENCES, 2007, Vol. 
62A, No. 1, 67–72
Martin J, Marler MR, Shochat T, et al. Circadian rhythms of agitation in institutionalized patients 
with Alzheimer’s disease. Chronobiol Int. 2000;17:405–418.
Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light
therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatrica
Scandinavica. 1994; 89: 1–7.
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12 APPENDICES
Appendix 12.1 Sponsor’s Grading for Determining Markedly Abnormal 
Laboratory Results 
The following table of Sponsor’s Grading for Laboratory Values is taken from the protocol.
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 28 May 2009 (v4.03: 14 Jun, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, , LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.
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Appendix 12.2  SAS Code Example for Dose Response Analysis
PROC MCPMOD DATA = XXXX OUT = XXXXX COMPMETHOD = pval
ALPHA = 0.025;
RESPONSE Resp;
DOSE Dose;
MODELDOSES 0 2.5 5 10 15/ PLACEFF = 50 MAXEFF = 90;
EmaxS: MODEL SigEmaxS(20.46,0.5);
Linear: MODEL LinearS;
Log:    MODEL Log(3.3);
EXP:    MODEL EXP(6.2)
Logistic: MODEL LogitS(0.13,0.732);
Quadratic: MODEL QuadS(-0.029);
Beta: MODEL Beta_mods(0.339,0.05);
Emax: MODEL EmaxS (0.66);
DOSESEL TD (DELTA = 10);
SELMODEL AIC;
DOSSUMRY OUT = DOSSUMRY_d;
OPTCONT OUT = OPTCONT_d ;
CORMAT OUT = CORMAT_d ;
run;
Note to Programmers: Please use initial points as in the table of sample size determination 
section.
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SIGNATURE PAGE
Author:  
Date
Approval:
 
Date
Date
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PPD
PPD
PPD
PPD
PPD
PPD