Clinical trial NCT02783729
Conditions: Insomnia
Keywords: E2006 Lemborexant zolpidem tartrate Ambien CR Insomnia
Sponsor: Eisai Inc.
Start date: 2016-05-31; Completion date: 2018-01-30
Enrollment: 1006 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to demonstrate, using polysomnography, that lemborexant 10 milligrams (mg) and 5 mg is superior to placebo on objective sleep onset as assessed by latency to persistent to sleep (LPS) after the last 2 nights of 1 month of treatment in participants 55 years and older with insomnia disorder.

Detailed description:
The study is a multicenter, randomized, double-blind, placebo-controlled, active comparator, parallel-group study of 2 dose levels of lemborexant for 30 nights in approximately 950 participants, 55 years or older with insomnia disorder. Participants will be males 65 years or older or females 55 years or older. Approximately 60% of the participants will be age 65 years or older. The study will have 2 phases: The Prerandomization Phase and the Randomization Phase. Including both phases, the study will last for a minimum of 65 and a maximum of 81 days per participant.

Arms: arm 1: Participants will receive one lemborexant 5 mg tablet and one zolpidem-matched placebo tablet each night arm 2: Participants will receive one lemborexant 10 mg tablet and one zolpidem-matched placebo tablet each night arm 3: Participants will receive one zolpidem 6.25 mg tablet and one lemborexant-matched placebo tablet each night arm 4: Participants will receive one zolpidem-matched placebo tablet and one lemborexant-matched placebo tablet each night
Interventions: intervention 1: Lemborexant intervention 2: Lemborexant intervention 3: Lemborexant-matched placebo intervention 4: Zolpidem tartrate intervention 5: Zolpidem-matched placebo
Intervention descriptions: intervention 1: Lemborexant 5 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep. intervention 2: Lemborexant 10 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep. intervention 3: Lemborexant-matched placebo be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep. intervention 4: Zolpidem tartrate extended release 6.25 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep. intervention 5: Zolpidem-matched placebo will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
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E2006-G000-304
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Confidential
Page i of xi
Revision History:
Previous Version (Amendment 03):  V6.0
Current Version (Amendment 04):  V7.0
Date of Revisions:  05 Feb 2018
Change
Rationale
Affected Protocol Sections
Revised order of key 
secondary objectives and 
related endpoints
To incorporate feedback 
from regulatory authorities
Synopsis – Objectives
Synopsis – Statistical 
Methods 
Synopsis – Sample Size 
Rationale
Section 8.2.1
Section 9.7.1.1.2
Section 9.7.1.6
Figure 2
Section 9.7.1.6.2
Section 9.7.2
Added sensitivity analysis
To incorporate feedback 
from regulatory authorities
Section 9.7.1.6.1
Revised process for Control 
of Type I Error
To align with revised order 
of objectives and endpoints
Section 9.7.1.6
Revised age ranges for 
categorical variables
Correction
Synopsis – Statistical 
Methods
Section 9.7.1.4
Section 9.7.1.6.1


Clinical Study Protocol
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Page ii of xi
Revision History:
Previous Version (Amendment 02):  V5.0
Current Version (Amendment 03):  V6.0
Date of Revisions:  16 Jun 2017
Change
Rationale
Affected Protocol Sections
Revised order of Primary, Key 
Secondary, Additional 
Secondary, and Exploratory 
objectives and related endpoints
To incorporate feedback 
from regulatory 
authorities
Synopsis – Objectives
Synopsis – Statistical 
Methods
Synopsis – Sample Size 
Rationale
Section 7.2
Section 8.1
Section 8.2
Section 8.3
Section 9.2.2
Section 9.2.3
Section 9.2.7
Section 9.7.1.1.1
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.1
Section 9.7.1.6.2
Section 9.7.1.6.3
Section 9.7.1.8.6
Section 9.7.2
Revised process for Control of 
Type I Error
To align with revised 
order of objectives and 
endpoints
Synopsis – Statistical 
Methods
Section 9.7.1.6
Added WASO1H as a sleep 
architecture parameter
(efficacy)
Correction
Synopsis – Assessments
Section 9.5.1.3.1
Revised description of mornings 
sleepiness scale
Correction
Section 9.5.1.3.2
Revised age groups for analysis
In response to request 
from regulatory 
authorities
Section 9.7.1.4
Revised analysis covariate from 
country to region
To ensure adequate 
number of subjects per 
analysis group
Throughout
Revised Sponsor Signature Page
To reflect current 
sponsor signatories
Sponsor Signature Page


Clinical Study Protocol
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Revision History:
Previous Version (Amendment 01):  V4.0
Current Version (Amendment 02):  V5.0
Date of Revisions:  16 Feb 2017
Change
Rationale
Affected Protocol Sections
Revised approximate 
number of sites from 90 to 
105
To facilitate study 
enrollment
Synopsis – Site(s)
Section 6
Section 9.3
Revised text to allow 
Sleep Diary entries may be 
to be maintained in paper 
format as a backup to the 
electronic Sleep Diary, if 
necessary
To allow flexibility in diary 
data collection in the event 
electronic diary is not 
available
Synopsis – Assessments
Section 9.5.1.3.2
Revised to Screening Period 
from up to -28 days to up 
to -35 days
To allow flexibility in 
scheduling
Synopsis – Study Design
Section 9.1
Section 9.1.1.1
Figure 1
Table 4
Revised total number of 
expected screened subjects 
from 2100 to 2800
To reflect current screen 
failure rate
Synopsis – Number of 
Subjects
Section 9.3
Revised inclusion (#6) 
requirement for ISI at both 
V1 and V3 from “≥15” to 
“≥13”.
To more accurately target 
study population (those with 
chief complaint of sleep 
maintenance insomnia) for 
inclusion
Synopsis – Inclusion 
Criteria
Section 9.3.1
Revised inclusion (#9) 
requirements for time spent 
in bed requirement from “>9 
hours on more than 2 nights 
per week” to “>10 hours on 
more than 2 nights per week.
To permit broader inclusion 
of appropriate subjects
Synopsis – Inclusion 
Criteria
Section 9.3.1
Revised inclusion (#13) to 
eliminate the need for sleep 
efficiency component
For consistency throughout 
protocol
Synopsis – Inclusion 
Criteria
Section 9.3.1
Revised exclusion (#1) for 
ESS score “>10” to “>15” as 
an indicator of excessive 
daytime sleepiness and 
required that scores of 11-15 
require excessive daytime 
sleepiness to be recorded in 
subject's Medical History)
Based on ESS data in 
Study 304 to date, to record 
excessive sleepiness in 
medical history instead of 
excluding subjects
Synopsis – Exclusion 
Criteria
Section 9.3.2
Section 9.5.1.2.1
Revised exclusion (#3) for 
MUPS such that endorsing 
To allow investigatory 
follow-up and clinical 
Synopsis – Exclusion 
Criteria


Clinical Study Protocol
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Revision History:
Previous Version (Amendment 01):  V4.0
Current Version (Amendment 02):  V5.0
Date of Revisions:  16 Feb 2017
Change
Rationale
Affected Protocol Sections
item relating to a history of 
symptoms of Rapid Eye 
Movement (REM) Behavior 
Disorder or sleep related 
violent behavior is no longer 
automatically exclusionary 
and clarified requirements 
with regard to sleep-driving
judgment for subjects who 
endorse the item regarding a
history of “acting out 
dreams,” rather than
automatically excluding 
these subjects
Section 9.3.2
Revised exclusion (#19) for 
suicidal behavior as per the 
C-SSRS from a “lifetime” to 
“in the past 10 years”
To facilitate enrollment and 
align with other protocols in 
the program
Synopsis – Exclusion 
Criteria
Section 9.3.2
Revised window around 
Screening and Run-In Visits
To permit flexibility in 
scheduling of subjects
Synopsis – Study Design
Section 9.1.1.1
Section 9.1.1.2
Table 4
Revised timing for CDR 
posture training from 
“during” for “before” Visit 
2a
To permit training on the 
assessment at Visit 1
Table 4
Revised analyses for 
Rebound Insomnia 
To match final Study 303 
protocol per VHP review
Synopsis – Statistical 
Methods
Section 9.7.1.1.3
Section 9.7.1.6.3
Revised the detailed 
Inclusion/Exclusion Criteria 
Schedule (Appendix 2)
For clarity
Appendix 2
Revised List of Prohibited 
Concomitant Medications 
(Appendix 3)
To correct lists of strong and
moderate CYP3A inhibitors
and CYP3A inducers
Appendix 3
Deleted Zolpidem 
Prescribing Information
(Appendix 4)
To ensure sites always have 
the most current approved 
version (will be provided to 
sites outside the protocol)
Section 9.4.1
Appendix 4
Added the requirement for 
monitoring of seizures and 
falls
Per request of FDA
Synopsis – Study Methods
Section 9.2.5
Table 4
Revised text regarding ECG 
interpretation categories
For clarity
Section 9.7.1.8.5


Clinical Study Protocol
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E2006-G000-304
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Page v of xi
Revision History:
Previous Version (Amendment 01):  V4.0
Current Version (Amendment 02):  V5.0
Date of Revisions:  16 Feb 2017
Change
Rationale
Affected Protocol Sections
Revised T-BWSQ 
assessment description such 
that scores above 20 will not 
be considered clinically 
significant and that the 
symptoms will no longer be 
summarized separately from 
all other AEs.
For clarity
Synopsis – Study 
Assessments
Section 9.5.1.5.2
Revised Sponsor signature 
page
To reflect current Eisai 
personnel
Protocol Signature Page


Clinical Study Protocol
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E2006-G000-304
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FINAL: (v7.0), 05 Feb 2018
Confidential
Page vi of xi
Revision History:
Previous Version (Revised protocol):  V3.0
Current Version (Corrected protocol):  V4.0
Date of Revisions:  16 Jul 2016
Change
Rationale
Affected Protocol Sections
Corrected typographical 
errors in the list of exclusion 
criteria
For consistency and 
editorial quality.  No 
changes to content.
Section 9.3.2


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Page vii of xi
Revision History:
Previous Version (Revised protocol):  V2.0
Current Version (Amended protocol):  V3.0
Date of Revisions:  24 Jun 2016
Change
Rationale
Affected Protocol Sections
Stated in all relevant places 
in Study Design that 
subjects will rate their 
morning sleepiness at 1.5 
hours after waketime, and 
specified analysis methods 
for this assessment
For consistency with 
Schedule of Assessments 
and completeness of 
analysis methods
Synopsis – Study Design
Synopsis – Statistical 
Methods
Section 9.1.2.1
Section 9.5.1.3.1
Section 9.7.1.1.3
Section 9.7.1.6.3
Specified that exclusion 
criteria include current 
diagnosis of obstructive 
sleep apnea
Per VHP comment
Synopsis – Exclusion Criteria
Section 4
Section 9.3.2
Revised STOPBang score 
cutoff for exclusion from 
study
To avoid low specificity of 
more stringent criterion 
Synopsis – Exclusion Criteria
Section 9.3.2
Revised Epworth Sleepiness 
Scale score cutoff for 
exclusion from study
To avoid low specificity of 
more stringent criterion
Synopsis – Exclusion Criteria 
Section 9.3.2
Deleted “on a screening 
questionnaire” from 
exclusion criterion 
pertaining to screening for 
narcolepsy symptoms
No formal screening 
questionnaire is being 
utilized
Synopsis – Exclusion Criteria 
Section 9.3.2
Provided examples of 
clinically significant disease 
that would exclude the 
subject from the study
Per VHP review; to specify 
conditions for which 
zolpidem is contraindicated
Synopsis—Exclusion Criteria
Section 9.3.2
Stated that subjects taking 
sedating drugs that would 
interfere with occupation or 
activities will be excluded
Per VHP review; to exclude 
such individuals from the 
study for reasons of safety
Synopsis – Exclusion Criteria
Section 9.3.2
Revised the washout 
interval between taking a 
prohibited medication, 
including treatment for 
insomnia, and the first dose 
of study medication
For consistency and to 
account for medications or 
insomnia treatments with 
long half-lives
Synopsis – Exclusion Criteria
Section 9.3.2
Section 9.4.7.2
Prohibited strong CYP3A 
inhibitors from being used 
any time during study, even 
if intermittently
Per VHP review; based on 
known drug metabolism 
interactions with zolpidem 
Synopsis – Concomitant Drug 
Therapy
Section 9.3.2
Section 9.4.7.2


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Revision History:
Previous Version (Revised protocol):  V2.0
Current Version (Amended protocol):  V3.0
Date of Revisions:  24 Jun 2016
Change
Rationale
Affected Protocol Sections
Clarified that the MUPS to 
be used is an adapted 
version 
For accuracy
Synopsis – Assessments
Section 9.5.1.2.2
Added sleep onset latency 
as a PSG variable 
For completeness of PSG 
variable dataset 
Synopsis – Assessments
Section 9.5.1.3.1
Clarified definition of REM 
latency 
For accuracy
Synopsis – Assessments
Section 9.5.1.3.1
Changed wording such that 
sleep diary will ask, not 
determine, alcohol 
consumption
For accuracy
Synopsis – Assessments
Section 9.5.1.3.2
Allowed flexibility for the 
means of documenting the 
time and date of 2 most 
recent doses before each 
blood sample for 
pharmacokinetic analyses
Time and date are being 
documented by means other 
than in the electronic Case 
Report Form
Synopsis – Assessments
Section 9.5.1.4.1
Clarified details of the CDR 
posture assessment at 
screening
For accuracy
Synopsis  Assessments
Section 9.5.1.4.2
Deleted statement that all 
cognitive performance 
assessment batteries require 
Yes/No button response
For accuracy – some tasks 
do not require a Yes/No 
button response
Synopsis – Assessments
Section 9.5.1.4.2
Revised the expected 
completion time for the full 
PAB
For accuracy
Synopsis – Assessments
Section 9.5.1.4.2
Moved analysis of cognitive 
PAB tasks from Exploratory 
to Secondary Analyses
For accuracy
Synopsis – Statistical 
Methods
Section 9.7.1.6.3
Revised method for 
assessment of rebound 
insomnia
Per VHP review; to 
emphasize assessment of 
rebound insomnia at 
individual subject level
Synopsis – Statistical 
Methods
Section 9.7.1.6.3
Provided that for applicable 
countries, the year of birth 
will be collected instead of 
the date of birth
To meet requirements in 
some countries regarding 
personally identifying 
information
Section 9.5.1.1
Specified viral tests for 
hepatitis B and hepatitis C
To provide additional detail 
of screening assessments
Section 9.5.1.5.5
Table 4 (footnote “g”)


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Page ix of xi
Revision History:
Previous Version (Revised protocol):  V2.0
Current Version (Amended protocol):  V3.0
Date of Revisions:  24 Jun 2016
Change
Rationale
Affected Protocol Sections
Deleted alcohol and 
nicotine/ cotinine from 
screening for drugs of abuse
To correct an error, as these 
drugs are not being tested in 
the urine drug screen in this 
study 
Section 9.5.1.5.5
Corrected window of study 
days for Screening
To correct an error
Table 4
Clarified interval for 
reporting of follow-up SAE, 
pregnancy, or breastfeeding 
information
Per VHP review; for 
accuracy
Section 9.5.4.1
Added sentence 
distinguishing between 
definitions of “study 
completer” per protocol 
versus for statistical analysis 
purposes
For clarity
Section 9.5.5
Corrected statement 
referring to study visit at 
which randomization occurs
To correct an error
Section 9.5.5
Deleted reference to 
examples of source 
documents that will not be 
used in this study
For accuracy
Section 11.3
Deleted glucose-
metabolizing agents from 
list of 
prohibited/concomitant 
medications
This prohibition is 
considered unnecessary.
Appendix 3
Added Appendix 4 –
Prescribing Information for 
Ambien CR®
For reference
Section 9.4.1
Appendix 4
Revised signature sheet
Changes in corporate 
structure
Protocol signature page


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Revision History:
Previous Version (Original protocol):  V1.0
Current Version (Revised protocol):  V2.0
Date of Revisions:  04 Apr 2016
Change
Rationale
Affected Protocol Sections
Specify that an additional 
secondary objective will be 
the determination of whether
LEM5 or LEM10 or both 
LEM5 and LEM10 are 
superior to ZOL with respect 
to SE, WASO, TST, sSOL, 
sSE, sWASO, and sTST at 
defined time intervals.  
The previous description of 
these comparisons did not 
make reference to 
superiority.  
Synopsis – Objectives
Section 8.2.2
Add an additional secondary 
objective specifying the 
evaluation of whether LEM5 
or LEM10 or both LEM5 and 
LEM10 are superior to ZOL 
with respect to LPS, 
separately from comparisons 
of drug effects on other sleep 
measures.  
Previously, the comparison 
of LEM5 and LEM10 to 
ZOL on LPS was not a 
separate additional
secondary objective, and 
the previous description of 
these comparisons with 
regard to LPS did not make 
reference to superiority.   
Synopsis – Objectives
Synopsis – Statistical 
Methods
Section 8.2.2
Section 9.7.1.1.2
Section 9.7.1.6.2
Specify that an additional 
secondary objective will be 
the evaluation of whether 
LEM5 or LEM10 or both 
LEM5 and LEM10 are 
superior to ZOL with respect 
to the proportions of sleep 
onset and sleep maintenance 
responders as defined by LPS, 
WASO, sSOL, and sWASO.  
The previous description of 
these comparisons did not 
make reference to 
superiority.   
Synopsis – Objectives
Section 8.2.2
Specify that an additional 
secondary objective will be 
the evaluation of whether 
LEM5 or LEM10 or both 
LEM5 and LEM10 are 
superior to ZOL and PBO 
with respect to ISI and FSS
The previous description of 
these comparisons did not 
make reference to 
superiority.   
Synopsis – Objectives
Section 8.2.2


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Page xi of xi
Revision History:
Previous Version (Original protocol):  V1.0
Current Version (Revised protocol):  V2.0
Date of Revisions:  04 Apr 2016
Change
Rationale
Affected Protocol Sections
Add an additional secondary 
objective specifying the 
evaluation of whether LEM5 
or LEM10 or both LEM5 and 
LEM10 are superior to ZOL 
and PBO with respect to 
cognitive performance the 
morning after the first 2 nights 
of treatment.  
Previously, these 
comparisons were an 
exploratory objective, and 
the previous description of 
these comparisons did not 
make reference to 
superiority.   
Synopsis – Objectives
Section 8.2.2
State as a separate additional 
secondary endpoint, the 
change of mean LPS from 
baseline on Days 1, 2, 29, and 
30 of LEM5 and LEM10 
compared to ZOL
A separate additional 
secondary objective was 
added for the comparison 
of LEM versus ZOL on 
LPS.  Previously this 
endpoint for LPS was 
combined with other sleep 
variables.
Synopsis—Statistical 
Methods
Add the descriptor “potential” 
before cases in the paragraph 
describing the process to be 
followed regarding the 
Cataplexy Adjudication 
Committee.
For clarity.  It is possible 
that the Cataplexy 
Adjudication Committee 
may review cases that are 
adjudicated as events other 
than cataplexy, but all 
potential cases that may be 
adjudicated as events of 
cataplexy will be flagged 
for review.  
Section 9.2.5


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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-G000-304
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active 
Comparator, Parallel-Group Study of the Efficacy and Safety of 
Lemborexant in Subjects 55 Years and Older with Insomnia Disorder
Sponsor: 
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake,
New Jersey 07677
US
Eisai Ltd. 
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Investigational 
Product Name:
E2006/lemborexant
Indication:
Insomnia
Phase:
3
Approval Date:
V1.0
V2.0
V3.0
V4.0
V5.0
V6.0
V7.0
21 Mar 2016 (original protocol)
04 Apr 2016 (revised protocol)
24 Jun 2016 (per Amendment 01)
16 Jul 2016 (per Amendment 01, editorial corrections)
16 Feb 2017 (per Amendment 02)
16 Jun 2017 (per Amendment 03)
05 Feb 2018 (per Amendment 04)
IND Number:
111,871
EudraCT Number:
2015-004347-39
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or performing 
this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Parallel-Group Study of 
the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older with Insomnia Disorder
Investigator(s)
To be determined
Site(s)
Approximately 105 sites in North America and Europe (revised per Amendment 02)
Study Period and Phase of Development
Approximately 64 weeks 
Phase 3
Objectives
Primary Objective – US and Non-US (revised per Amendment 03)

Demonstrate using polysomnography (PSG) that lemborexant (LEM10 and LEM5) is superior to placebo 
(PBO) on objective sleep onset as assessed by latency to persistent to sleep (LPS) after the last 2 nights of 
1 month of treatment in subjects 55 years and older with insomnia disorder 
Key Secondary Objectives – US ONLY (revised per Amendment 03)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep maintenance as assessed 
by sleep efficiency (SE) after the last 2 nights of treatment

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep maintenance as assessed 
by WASO after the last 2 nights of treatment (revised per Amendments 03 and 04)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to zolpdiem tartrate extended release
6.25 mg (Ambien CR®; ZOL) on wake after sleep onset in the second half of the night (WASO2H) after 
the last 2 nights of treatment
Key Secondary Objectives – Non-US ONLY (revised per Amendment 03)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep maintenance as assessed 
by SE after the last 2 nights of treatment

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on wake after sleep onset (WASO) 
after the last 2 nights of treatment
Additional Secondary Objectives – US and Non-US (revised per Amendment 03)

Demonstrate that LEM5 or LEM10 or both LEM5 and LEM10 are superior to ZOL on postural stability in 
the morning after the first 2 nights of treatment

Determine whether the efficacy of LEM5 or LEM10 or both LEM5 and LEM10 is superior to that of ZOL 
on selected PSG variables after the first 2 nights and the last 2 nights of treatment and on selected Sleep 
Diary variables over the first 7 nights and the last 7 nights of treatment

Confirm the efficacy of LEM5 and LEM10 compared to placebo (PBO) on sleep as measured by PSG after 
the first 2 and last 2 nights of treatment and as measured by Sleep Diary over the first 7 and last 7 nights of 
treatment 

Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and LEM10 and 
determine whether they are superior to that of ZOL and PBO as defined by response on PSG LPS and 
WASO and Sleep Diary subjective sleep onset latency (sSOL) and subjective wake after sleep onset 
(sWASO)

Evaluate the safety and tolerability of lemborexant

Determine whether the efficacy of LEM5 or LEM10 or both LEM5 and LEM10 is superior to that of ZOL 
and PBO on daytime functioning as assessed by the Insomnia Severity Index (ISI) and Fatigue Severity 


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Scale (FSS) at the end of treatment

Determine whether the safety of LEM5 or LEM10 or both LEM5 and LEM10 is superior to that of ZOL 
and PBO as assessed by cognitive performance in the morning after the first 2 nights of treatment
Exploratory Objectives – US and Non-US (revised per Amendment 03)

Explore the effects of LEM5, LEM10, ZOL and PBO on:
o
Subjective quality of sleep
o
Postural stability in the morning after the last 2 nights of treatment
o
Cognitive performance after the last 2 nights of treatment
o
Rebound insomnia in the 2 weeks following 30 days of treatment
o
Subjective ratings of morning sleepiness during and following completion of treatment
o
Sleep architecture parameters and other PSG variables
o
Health outcomes on the Patient Global Impression - Insomnia (PGI-Insomnia) and EQ-5D-3L
o
Withdrawal symptoms after completion of treatment

Summarize plasma concentrations of lemborexant and its metabolites M4, M9, and M10

Conduct population pharmacokinetic (PK) modeling for lemborexant

Explore PK/pharmacodynamic (PK/PD) relationships between lemborexant concentrations and efficacy 
and safety variables
Study Design
E2006-G000-304 is a multicenter, randomized, double-blind, placebo-controlled, active comparator (ZOL), 
parallel-group study of 2 dose levels of lemborexant for 30 nights in approximately 950 subjects 55 years or 
older with insomnia disorder. Subjects will be males 65 years or older or females 55 years or older. 
Approximately 60% of the subjects will be age 65 years or older. (revised per Amendment 03)
The study will have 2 phases:
The Prerandomization Phase and the Randomization Phase. The 
Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 days: a Screening Period, 
a Run-in Period, and a Baseline Period. The Randomization Phase will comprise a Treatment Period during 
which subjects are treated for 30 nights, and a minimum 14-day Follow-up Period before an End of Study 
(EOS) Visit. (revised per Amendment 02)
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will undergo routine safety 
assessments at specified visits, including questioning regarding adverse events (AEs), 12-lead 
electrocardiograms (ECGs), vital signs, weight, height, clinical hematology and chemistry analysis and 
urinalysis, and suicidality. 
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At the first visit, 
informed consent will be obtained after the study has been fully explained to each subject and before the 
conduct of any screening procedures or assessments.  A medical, psychiatric, and sleep history interview will be 
conducted, and will include confirmation that the subject meets diagnostic criteria for insomnia disorder, and 
further that the subject complains of difficulties with sleep maintenance and/or early morning awakening.
Screening assessments will include the ISI, as well as the Epworth Sleepiness Scale (ESS), STOPBang, 
International Restless Legs Scale (IRLS), and Munich Parasomnia Scale (MUPS), collectively called the Sleep 
Disorders Screening Battery (SDSB). Other assessments administered will include the FSS and EQ-5D-3L.  
Additional eligibility criteria will be assessed and safety assessments including the electronic Columbia-Suicide 
Severity Rating Scale (eC-SSRS) will be conducted.  (revised per Amendment 02)
Eligible subjects will be provided with an electronic device on which they will complete the Sleep Diary.  
Subjects will be trained in the use of this device.  Site staff will instruct subjects to complete the diary each 
morning within 1 hour after morning waketime and will emphasize the importance of doing so.  The Sleep 
Diary entries will be reviewed by site staff at least weekly throughout the study to ensure subject compliance 
with completion of the Sleep Diary and to ensure that study restrictions are met pertaining to duration of time 
spent in bed, and use of alcohol.  Subjects will also be reminded of study restrictions pertaining to timing of 
meals and caffeine use.
After subjects have completed the Sleep Diary on at least 7 consecutive mornings, and provided that the Sleep 


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Diary entries indicate continued eligibility with regard to sleep timing, duration of time spent in bed, and 
frequency of nights with symptoms of insomnia, subjects will undergo the second screening visit.  (Subjects 
who are not eligible based on Sleep Diary entries will return to the clinic for debriefing purposes and to return 
study equipment.) This visit must occur between Day -17 and Day -10.  On this and all nights on which PSG is
recorded, subjects will arrive at the clinic in the evening with sufficient time before bedtime to complete check-
in procedures, any scheduled assessments, and preparations (eg, electrode montage placement) for the PSG 
recordings. In addition, at check-in before all visits at which PSG is to be recorded, subjects will undergo a 
urine drug test. (revised per Amendment 02)
After check-in has been completed, study personnel will familiarize subjects with the postural stability 
assessment (Cognitive Drug Research [CDR] posture assessment) and will also conduct a minimum of 2 
training sessions for the cognitive performance assessment battery (PAB).  Subjects will then undergo an 
8-hour PSG recording, to start at the median habitual bedtime (MHB) as calculated from the Sleep Diary 
entries.  The PSG recording will include channels in the electrode montage to screen for symptoms of sleep 
apnea and periodic limb movement disorder.  Within 5 minutes of morning waketime, the CDR posture and 
PAB assessments will be administered under the same conditions (eg, timing of assessments relative to 
waketime, ambient lighting), as will be employed during the testing sessions.  The CDR posture and PAB 
assessments at this time are for familiarization purposes only.  At 1.5 hours after waketime, subjects will rate 
their morning sleepiness level.  The PSG will be reviewed for exclusion criteria related to symptoms of sleep 
apnea and/or periodic limb movement disorder.  Subjects who continue to meet the eligibility criteria will then 
be dispensed PBO tablets (single-blind) and will enter the Run-in Period.
Run-in Period
The Run-in Period will begin when eligible subjects are dispensed PBO tablets and will continue until the 
Baseline Period on Day 1.  During the Run-in Period subjects will take PBO each night immediately (ie, within 
5 minutes) before bedtime (defined as the time the subject intends to try to fall asleep).  They will be reminded 
that they must remain in bed for at least 7 hours each night and maintain a regular bedtime and waketime 
throughout the study, according to the schedule determined by the study site and the subject. They will also be 
reminded that they must follow study restrictions with regard to timing of meals and use of caffeine and 
alcohol.  
When subjects have completed the Sleep Diary on at least 7 consecutive mornings during the Run-in Period, the 
diary will be reviewed for continued eligibility with regard to whether the subject continues to report sWASO 
≥60 minutes on at least 3 of the 7 nights, as well as the schedule and duration of time spent in bed.  Subjects 
who are still eligible will return to the clinic for the first of 2 consecutive nights on which PSG will be recorded. 
The first of these 2 nights must be between Day -10 and Day -4.  In the evening, before the PSG recording, the 
ISI, FSS, and EQ-5D-3L will be assessed.  The ISI score will be reviewed for eligibility, and safety assessments 
will be conducted.  Study personnel will administer study drug to subjects within 5 minutes before their
scheduled bedtime, which will be at the same MHB as used for the second screening visit.  Subjects will 
undergo an 8-hour PSG.  The next morning, subjects will undergo assessments including the CDR posture and 
PAB assessments, will complete the Sleep Diary, and will rate their morning sleepiness level at 1.5 hours after 
waketime. (revised per Amendment 01)  The PSG recording will be reviewed for continued eligibility and 
subjects may then leave the clinic only after the investigator determines that is safe for them to do so.  (revised 
per Amendment 02)
Subjects will return to the clinic that evening.  Study personnel will administer study drug to subjects within 
5 minutes before the scheduled bedtime.  A PSG will be recorded overnight.  The following morning subjects
will undergo postural stability and PAB assessments and will complete the Sleep Diary.  At 1.5 hours after 
waketime, subjects will rate their morning sleepiness level.  The PSG recording will be reviewed for continued 
eligibility, and both PSGs during the Run-in Period will also serve as the baseline for PSG-derived endpoints 
for subjects who are randomized. Subjects may then leave the clinic after the investigator determines that is 
safe for them to do so.
Subjects will continue to take study drug at home within 5 minutes before bedtime and they will continue to 
complete the Sleep Diary each morning within 1 hour after morning waketime.  They will again be reminded 
that they must remain in bed for at least 7 hours each night, maintain a regular bedtime throughout the study,
and follow study restrictions with regard to timing of meals and use of caffeine and alcohol.
Baseline Period


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After a minimum of 2 nights following the baseline PSGs, the Run-in Period will end and the Baseline Period 
will take place.  On Day 1, subjects will be admitted to the clinic and the ISI, FSS, and EQ-5D-3L will be 
administered.  Blood and urine samples will be collected for routine safety assessments, an ECG will be 
performed, and vital signs and weight will be assessed.  The eC-SSRS will be administered.  Subjects who 
complete the Baseline Period and continue to meet the eligibility criteria will be randomized, and will begin the 
Treatment Period.  (revised per Amendment 02)
Treatment Period
The Treatment Period will begin on Day 1 and will continue until Day 31.  Subjects will be randomized in a 
double-blind manner, to receive LEM5, LEM10, ZOL, or PBO. (revised per Amendment 02)
Within 5 minutes before the subject’s MHB, study drug will be administered and an 8-hour overnight PSG will 
be initiated.  At completion of the PSG recording the following morning (Day 2), postural stability will be 
assessed and the PAB will be conducted immediately thereafter.  Subjects will complete the Sleep Diary. At 
1.5 hours after waketime, subjects will rate their morning sleepiness level.  (revised per Amendment 01)  They 
may leave the clinic after the investigator determines that is safe for them to do so.
On the evening of Day 2, subjects will return to the clinic.  A PK blood sample will be collected predose and
study drug will be administered within 5 minutes before the subject’s MHB, followed by an overnight PSG.  
The next morning (Day 3), CDR posture and PAB assessments will be conducted and a PK sample will be 
obtained.  Subjects will complete the Sleep Diary. The eC-SSRS will be administered. At 1.5 hours after 
waketime, subjects will rate their morning sleepiness level.  Subjects may then leave the clinic after the 
investigator determines that is safe for them to do so. Study drug will be dispensed and subjects will be 
provided with instructions to continue completing the Sleep Diary each morning within 1 hour of waketime and 
taking study drug daily at home according to the same schedule and with the same instructions as during the 
Run-in Period.
On Day 29, subjects will return to the clinic.  Study drug will be administered within 5 minutes before the 
subject’s MHB, followed immediately by a PSG.  On the morning of Day 30, CDR posture and PAB 
assessments will be conducted.  At 1.5 hours after waketime, subjects will rate their morning sleepiness level.  
Subjects may leave the clinic after the investigator determines that is safe for them to do so.  
On the evening of Day 30, subjects will return to the clinic.  A PK blood sample will be collected predose and 
study drug will be administered within 5 minutes before the subject’s MHB, followed by a PSG.  On the 
morning of Day 31, CDR posture and PAB assessments will be conducted and a PK sample will be obtained.  
Then the ISI, FSS, EQ-5D-3L and PGI-Insomnia will be administered.  Blood and urine samples will be 
collected for routine safety assessment. An ECG will be performed, and vital signs and weight will be assessed.  
The eC-SSRS will be administered. At 1.5 hours after waketime, subjects will rate their morning sleepiness 
level.  Then, after the investigator determines that it is safe for them to do so, subjects will be discharged from 
the clinic.  
Follow-up Period
The Follow-up Period will begin when the subjects leave the clinic at the end of the Treatment Period.  Subjects 
will cease to take study drug but will continue to complete the Sleep Diary each morning until the EOS Visit.
At least 14 days but no more than 18 days after completion of the Treatment Period subjects will return to the 
clinic for the EOS Visit.  The Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (T-BWSQ) and 
eC-SSRS will be administered, and routine safety assessments will be conducted.
A subject who prematurely discontinues taking study drug should return to the clinic as soon as practicable after 
discontinuing study drug, to complete an Early Termination (ET) Visit.  If the subject discontinues from the 
study due to an AE, the subject must complete an ET Visit and the AE must be followed to resolution or for 2
weeks, whichever comes first. In addition, subjects who withdraw due to an AE should undergo a urine drug 
test.
Interim Analysis
An interim analysis is planned to be conducted after approximately 50% of subjects (approximately 
475 subjects) have been randomized and either completed Day 31 assessments or discontinued from the study, 
which is anticipated to occur by the end of July 2017. This interim analysis will be conducted for administrative 
reasons as detailed in the separate Interim Analysis charter. (revised per Amendment 03)
Adjudication Committee (revised per Amendment 02)


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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 [SMQ narrow and broad], atypical 
migraine, loss of consciousness, decreased consciousness, myoclonus, syncope, transient global amnesia, 
lipothymia, 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 personnel will be instructed to query 
subjects who report any of the above events for supplemental information about the events, using a 
questionnaire for events potentially related to cataplexy and the SAE form for any of the above events 
considered serious. (revised per Amendment 02)
End of Study
Estimates for End of Study are as follows: 

The study will begin in approximately April 2016 

The end of the study will be the date of the last study visit for the last subject in the study.
The estimated duration for each subject on study is anticipated to be a maximum of 81 days (11.5 weeks)
consisting of the Screening Period plus Run-in Period plus Baseline Period maximum of 35 days plus 
Treatment Period plus Follow-up Period and EOS Visit maximum of 53 days.  A subject who completes the 
Treatment Period (assessments through discharge from clinic on the morning of Day 31) will be considered to 
have completed the study. (revised per Amendment 02)
Number of Subjects
Approximately 2800 subjects will be screened to provide approximately 950 randomized subjects. Subjects 
will be randomized to one of the following treatment arms: LEM5, LEM10, ZOL, or PBO, in an approximate 
5:5:5:4 ratio (n=250:250:250:200).  Randomization will be stratified by country and age group (55 to 64 years 
old; 65 years or older). Approximately 60% of the subjects will be age 65 years or older.  (revised per 
Amendments 02 and 03)
Inclusion Criteria
1.
Male age 65 years or older or female age 55 years or older at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for Insomnia 
Disorder, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep and/or 
awakening earlier in the morning than desired despite adequate opportunity for sleep (Note that if the 
complaint is limited to difficulty initiating sleep, the subject is not eligible)

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
At Screening:  History of subjective WASO (sWASO) typically ≥ 60 minutes on at least 3 nights per week 
in the previous 4 weeks
4.
At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours 
5.
At Screening: Reports habitual bedtime, defined as the time the subject attempts to sleep, between 21:00 
and 24:00 and habitual waketime between 05:00 and 09:00 
6.
At Screening and at check-in before the first PSG during the Run-in Period: ISI score ≥13 (revised per 
Amendment 02)
7.
Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary on the 7 
most recent mornings (minimum 5 of 7 for eligibility) before the second screening visit, such that sWASO
≥ 60 minutes on at least 3 of the 7 nights
8.
Confirmation of regular bedtime and waketime as determined from responses on the Sleep Diary on the 7 
most recent mornings before the second screening visit, such that neither bedtime, (defined as the time the 
subject attempts to try to sleep), nor waketime (defined as the time the subject gets out of bed for the day)
deviates more than 1 hour on more than 2 nights from the calculated MHB or median habitual waketime


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(MHW), respectively, from the screening Sleep Diary entries
9.
Confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary 
on the 7 most recent mornings before the second screening visit, such that there are no more than 2 nights
with time spent in bed duration < 7 hours or > 10 hours (revised per Amendment 02)
10. During the Run-in Period: Reconfirmation of insomnia symptoms, as determined from responses on the 
Sleep Diary on the 7 most recent mornings before the first PSG during the Run-in Period, such that 
sWASO ≥ 60 minutes on at least 3 of the 7 nights 
11. During the Run-in Period: Reconfirmation of regular bedtimes and waketimes as defined in Inclusion 
Criterion 8
12. During the Run-in Period: Reconfirmation of sufficient duration of time spent in bed as defined in 
Inclusion Criterion 9 (revised per Amendment 02)
13. During the Run-in Period: Objective (PSG) evidence of insomnia as follows:  WASO average ≥ 60 
minutes on the 2 consecutive PSGs, with neither night < 45 minutes (revised per Amendment 02)
14. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours 
each night
15. Willing not to start a behavioral or other treatment program for the treatment of insomnia during the 
subject’s participation in the study
Exclusion Criteria
1.
A current diagnosis of sleep-related breathing disorder including obstructive sleep apnea (with or without 
continuous positive airway pressure [CPAP] treatment), periodic limb movement disorder, restless legs 
syndrome, circadian rhythm sleep disorder, or narcolepsy, or an exclusionary score on screening 
instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia as 
follows:  (revised per Amendment 01)
a.
STOPBang score ≥5
b.
International Restless Legs Scale score ≥16
c.
Epworth Sleepiness Scale score >15 (Scores of 11-15 require excessive daytime sleepiness to be 
recorded in subject's Medical History) (revised per Amendments 01 and 02)
2.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator indicates 
the need for referral for a diagnostic evaluation for the presence of narcolepsy
3.
On the MUPS, endorsed the item that corresponds to a history of sleep-eating or reports a history of sleep-
related violent behavior, sleep-driving, or symptoms of another parasomnia that in the investigator's 
opinion make the subject unsuitable for the study (revised per Amendment 02)
4.
Apnea-Hypopnea Index > 15 or Periodic Limb Movement with Arousal Index >15 as measured on the PSG 
at the second screening visit
5.
Beck Depression Inventory – II (BDI-II) score  >19 at Screening
6.
Beck Anxiety Index (BAI) score >15 at Screening
7.
Habitually naps during the day more than 3 times per week
8.
Is a female of childbearing potential  
Note:  All females will be considered to be of childbearing potential unless they are postmenopausal 
(defined as amenorrheic for at least 12 consecutive months, and are postmenopausal without other known 
or suspected cause), or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing).
9.
Excessive caffeine use that in the opinion of the investigator contributes to the subject’s insomnia, or 
habitually consumes caffeine-containing beverages after 18:00 and is unwilling to forego caffeine after 
18:00 for the duration of his/her participation in the study
10. History of drug or alcohol dependency or abuse within approximately the previous 2 years
11. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or more than


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21 drinks containing alcohol per week (males), or unwilling to limit alcohol intake to no more than 2 drinks 
per day or forego having alcohol within the 3 hours before bedtime for the duration of his/her participation 
in the study
12. Known to be positive for human immunodeficiency virus
13. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
14. A prolonged QT/QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at Screening 
(repeated only if initial ECG indicates a QTcF interval >450 ms) 
15. Current evidence of clinically significant disease (eg, cardiac; respiratory including chronic obstructive 
pulmonary disease, acute and/or severe respiratory depression; gastrointestinal; severe hepatic impairment;
renal including severe renal impairment; neurological including myasthenia gravis; psychiatric disease; or 
malignancy within the past 5 years other than adequately treated basal cell carcinoma) or chronic pain that 
in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments, 
including the ability to perform tasks on the cognitive PAB.  Subjects for whom a sedating drug would be 
contraindicated for safety reasons because of the subject’s occupation or activities are also excluded.  
(revised per Amendment 01)
16. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the night
17. Any history of a medical or psychiatric condition that in the opinion of the investigator(s) could affect the 
subject’s safety or interfere with the study assessments, including the ability to perform the PAB.
18. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months before the 
eC-SSRS administration during the Prerandomization Phase (ie, answering “Yes” to questions 4 or 5 on the 
Suicidal Ideation section of the eC-SSRS)
19. Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the eC-SSRS) (revised per 
Amendment 02)
20. Scheduled for surgery during the study
21. Used any prohibited prescription or over-the-counter concomitant medications within 1 week or 5 half-
lives, whichever is longer, before the first dose of study medication (Run-in Period). (A list of prohibited 
concomitant medications is presented in Appendix 3 of the protocol) (revised per Amendment 01)
22. Used any modality of treatment for insomnia, including cognitive behavioral therapy or marijuana within 1 
week or 5 half-lives, whichever is longer, before the first dose of study medication (Run-in Period) (revised 
per Amendment 01)
23. Failed treatment with suvorexant (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 in the 2 weeks before Screening, or between Screening 
and Baseline, or plans to travel across more than 3 time zones during the study
25. A positive drug test at Screening, Run-In, or Baseline, or unwilling to refrain from use of recreational drugs 
during the study
26. Hypersensitivity to lemborexant or zolpidem or to their excipients 
27. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5× 
the half-life, whichever is longer preceding informed consent
28. Previously participated in any clinical trial of lemborexant
Study Treatment(s)
Test drug
Lemborexant 5 mg or 10 mg, or lemborexant-matched placebo taken orally in tablet form each night for 
30 consecutive nights immediately before the time the subject intends to try to sleep
Comparator drug
Zolpidem tartrate extended release 6.25 mg or zolpidem-matched placebo taken orally in tablet form each night 
for 30 consecutive nights immediately before the time the subject intends to try to sleep
Run-in Period


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All subjects will receive 1 lemborexant-matched placebo tablet and 1 zolpidem-matched PBO tablet in a single-
blind manner during the Run-in Period
Treatment Period
During the Treatment Period, all subjects will receive 2 tablets as described below according to the treatment 
arm to which the subject has been randomized: 
LEM5:  1 zolpidem-matched placebo tablet and 1 lemborexant 5 mg tablet 
LEM10:  1 zolpidem-matched placebo tablet and 1 lemborexant 10 mg tablet 
ZOL:  1 zolpidem 6.25 mg tablet and 1 lemborexant-matched placebo tablet 
PBO:  1 zolpidem-matched placebo tablet and 1 lemborexant-matched placebo tablet  
Duration of Treatment
A maximum of approximately 7.5 weeks:  Up to 17 days of PBO during the Run-in Period and up to 35 days of 
randomized treatment
Concomitant Drug/Therapy
Caffeine will be permitted in limited quantities during the study.  Subjects will be advised to limit caffeine 
consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg caffeine per day.  They will be instructed 
to avoid caffeine after 13:00 on days when they are scheduled for a PSG recording and after 18:00 on all other 
days during the study.  
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a maximum of 
2 alcoholic drinks on any day during the study, but will be instructed not to consume any alcohol within 3 hours 
before bedtime. They must not consume any alcohol on days when they are scheduled for a PSG recording. 
Compliance with these restrictions will be monitored by specific questions on the Sleep Diary.
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A inducers.  Prohibited 
therapies also include any treatment for insomnia disorder, including any drugs or non-pharmacological 
treatment such as cognitive behavioral therapy; medications that are used for the purpose of inducing sleep 
(hypnotics) or inducing wakefulness (stimulants; except caffeine; see above) and medications that have known 
sedating effects or alerting effects. The prohibition applies even if the entire class to which that medication 
belongs is not prohibited (eg, anticonvulsants).  
If a medication is not on the list of prohibited medications but in the opinion of the investigator causes or 
exacerbates the subject’s insomnia, it must not be used throughout the study.  If a medication is not specified as 
prohibited but is in the same class as a medication that is listed in Appendix 3 of the protocol, and if the 
investigator is uncertain whether the medication has known sedating or alerting effects, the Medical Monitor 
must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue from the 
study, with the exception that certain prohibited medications may be used for a short duration (not to exceed 
2 weeks) to treat an acute condition if this is agreed with the Medical Monitor. Note that strong CYP3A 
inhibitors will not be permitted at any time for any duration during the study. (revised per Amendment 01)
Assessments
Screening Assessments (administered only at first screening visit)
Sleep Disorders Screening Battery
The SDSB will include the:

StopBANG:  a list of eight questions to be answered Yes or No, which screens subjects for obstructive 
sleep apnea

IRLS:  a subjective scale comprising ten questions, which measures severity of symptoms of restless legs 
syndrome

ESS:  a questionnaire that asks the subject to rate their probability of falling asleep, on a scale of increasing 
probability from 0 to 3 for eight different situations that most people engage in during their daily lives, 
which assesses the severity of daytime sleepiness

MUPS (adapted version):  a scale comprising 21 questions asking whether the subject has experienced 


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phenomena related to the International Classification of Sleep Disorders Version 2 classified parasomnias 
(eg, enuresis, sleepwalking, sleep paralysis) along with a time frame for occurrence of these experiences 
ranging from within past month to lifetime and frequency within the time frame ranging from occasionally 
to almost every night. (revised per Amendment 01)
Beck Depression Inventory – II
The BDI-II is a 21-question multiple-choice self-report questionnaire that subjects will use to rate the presence, 
frequency, and severity of symptoms of depression using a 4-point Likert scale.  Scores on the BDI-II may 
range from 0 to 63, with higher scores indicating higher levels of depressive symptoms.  Subjects with BDI-II 
scores greater than 19 will be excluded from participation.
Beck Anxiety Inventory
The BAI is a 21-question multiple-choice self-report inventory that subjects will use to rate the presence, 
frequency, and severity of symptoms of anxiety using a 4-point Likert scale.  Scores on the BAI may range 
from 0 to 63, with higher scores indicating higher levels of anxiety symptoms.  Subjects with scores on the BAI 
greater than 15 will be excluded from participation.
Efficacy Assessments
Polysomnography (PSG)
Each PSG recording will include an electrode montage with electroencephalography (EEG), electromyography 
(EMG), electrooculography, and ECG channels, for scoring of sleep parameters and sleep architecture via 
standard sleep scoring criteria.  In addition, the first PSG will include channels for assessment of symptoms of 
sleep apnea and periodic limb movement disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard criteria.  The PSG at the 
second screening visit will be used only to calculate the Apnea-Hypopnea Index and the Periodic Limb 
Movements with Arousal Index for evaluation of eligibility criteria; sleep parameters and sleep architecture will 
not be evaluated from this PSG.  The 2 PSGs obtained during the Run-in Period will be used to a) determine 
eligibility and b) derive baseline PSG parameters for those subjects who are randomized.
All PSG parameters will be obtained separately for each PSG recording and averaged across the pairs of 
consecutive PSG nights.
The following parameters will be derived from all PSGs:

LPS:  minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness

SE:  proportion of time spent asleep per time in bed (TIB), calculated as TST/interval from lights off until 
lights on

WASO:  minutes of wake from the onset of persistent sleep until lights on 

WASO2H:  minutes of wake during the interval from 240 minutes after lights off until lights on 

TST:  minutes of sleep from sleep onset until terminal awakening 

Mean duration of long awakenings (DurLongAw):  average duration of all long awakenings (with long 
awakening defined as 10 or more consecutive epochs [ie, 5 minutes or longer] scored as wake or N1, 
initiated with at least one epoch of wake, after onset of persistent sleep, and including any terminal 
awakening)
Additional sleep architecture parameters will also be calculated from each PSG, including:

Sleep onset latency: minutes from lights off to the first epoch of any stage of sleep (N1, N2, N3, REM)
(revised per Amendment 01)

Number of awakenings after persistent sleep, with an awakening defined as at least 2 consecutive epochs 
of wakefulness; an awakening cannot be interrupted by stage N1, but must be interrupted by stage N2, N3, 
or REM

Number of long awakenings

WASO1H (wake after sleep onset in the first half of the night): minutes of wake during the interval from 
onset of persistent sleep until 240 minutes after lights off (revised per Amendment 03)

Percentage of sleep stages per TIB:  wake, non-REM (NREM) sleep (stages N1, N2, N3 separately and 


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combined), REM sleep 

Minutes of sleep stages per TIB:  wake, NREM sleep (stages N1, N2, N3), REM sleep 

Percentage of sleep stages per TST: wake, NREM sleep (stages N1, N2, N3 separately and combined), 
REM sleep 

Minutes of sleep stages per TST:  wake, NREM sleep (stages N1, N2, N3), REM sleep

REM episode frequency and duration

Mean REM/NREM cycle duration

REM latency:  minutes from first epoch of sleep (N1, N2, N3) to first epoch of REM (revised per 
Amendment 01)
Each of these PSG-derived variables, with the exceptions of SE, REM episode frequency and duration, mean 
REM/NREM cycle duration, and REM latency, will also be calculated by hour and half of the 8-hour TIB.  
Electronic Sleep Diary
The Sleep Diary will be completed within an hour of morning waketime on each morning of the study from 
Screening through the end of the study.  Sleep Diary entries may be maintained in paper format as a backup to 
the electronic Sleep Diary, if necessary.  This Sleep Diary will yield several self-reported measures of sleep that 
will be used to determine eligibility, as well as to assess efficacy and safety.  In addition, the Sleep Diary will 
include questions that relate to morning sleepiness and to alcohol consumption.  (revised per Amendment 02)
Sleep parameters:

Subjective Sleep Onset Latency (sSOL):  estimated minutes from the time that the subject attempts to sleep 
until sleep onset 

Subjective Wake After Sleep Onset (sWASO):  sum of estimated minutes of wake during the night after 
initial sleep onset until the time that the subject stopped trying to sleep for the night

Subjective Total Sleep Time (sTST):  derived minutes of sleep from sleep onset until the time the subject 
stopped trying to sleep for the night

Subjective Sleep Efficiency (sSE):  proportion of sTST per subjective time spent in bed, calculated as the 
interval from the time the subject reported attempting to sleep until the time the subject stopped trying to 
sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO
Quality of Sleep:
The Sleep Diary will also be used to assess the subject’s perception of the quality of sleep on the previous night 
with the following question, “How would you rate the quality of your sleep last night?”  Subjects will rate the 
quality of their sleep on a scale from 1 to 9 with 1 being extremely poor and 9 being extremely good.
Morning Sleepiness:
The Sleep Diary will also be used to assess subjective ratings of morning sleepiness with the following 
question: “How sleepy/alert do you feel this morning?”  Subjects will rate their sleepiness/alertness level on a 
scale from 1 to 9, with 1 being extremely sleepy, and 9 being extremely alert.
The morning sleepiness question that is part of the electronic Sleep Diary will also be asked verbatim, using a 
paper-and-pencil format, at 1.5 hours after waketime each morning the subject is in the clinic following a PSG 
recording.  The rating on this question will be taken into consideration by the investigator when making the 
determination about whether it is safe for the subject to be discharged from the clinic.
Alcohol Consumption:
The Sleep Diary will include questions to ask whether the subject consumed alcohol the previous day within 3 
hours before bedtime, or exceeded the daily maximum of 2 alcoholic drinks, or both.
(revised per 
Amendment 01)
Insomnia Severity Index 
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia. The 
dimensions evaluated are severity of sleep onset, sleep maintenance, early-morning awakening problems; sleep 
dissatisfaction; interference of sleep difficulties with daytime functioning, noticeability of the sleep problems 
by others; and distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each item (from 
0 = no problem to 4 = very severe problem), yielding a total score from 0 to 28.


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Fatigue Severity Scale
The FSS is a self-report scale on which subjects are instructed to choose a number from 1 to 7 that indicates 
their degree of agreement with each of 9 statements about their fatigue where “1” indicates strongly disagree 
and “7”, strongly agree. The FSS score is the sum of all responses to the 9 questions.  Higher scores indicate 
greater fatigue. 
Pharmacokinetic Assessments
A single blood sample for plasma concentrations of lemborexant and its metabolites M4, M9 and M10 or 
zolpidem will be taken at predefined visits.  The time and date of the 2 most recent doses before each sample 
will be documented.
Pharmacodynamic Assessments
Postural Stability using the CDR Posture Assessment
Postural stability will be assessed using an apparatus similar to the Wright ataxiameter, and referred to as the 
CDR posture device.  The CDR posture device measures directional trunk movements (ie, body sway) through 
a cord placed around the subject’s waist and connected to the ataxiameter.  On the evening of the Screening 
PSG visit, subjects will be introduced to the CDR posture assessment.  Subjects will stand on a firm surface 
with feet comfortably apart, either barefoot or wearing socks.  The standing position (inside heel-to-inside heel 
distance) and barefoot/socks conditions will be documented to ensure they remain the same for a given subject 
at each postural stability assessment timepoint.  They will be instructed to stand as still as possible with eyes 
closed for 1 minute.  (revised per Amendment 01)
On the morning after the Screening PSG, subjects will 
complete a CDR posture assessment session for familiarization purposes only; no data from this session will be 
used for analyses.  This session must be conducted under the same conditions (eg, starting within 5 minutes of 
morning waketime, at bedside) as during the testing sessions at subsequent visits.
Body sway is detected through the cable around the subject’s waist by the ataxiameter and these data are 
transmitted to a laptop. Body sway is measured in units of 1/3° of the angle of arc. For ease in reporting these 
will be called arbitrary units, with a higher number indicating more body sway (less postural stability). 
Cognitive Performance Assessment Battery
A computerized PAB will be administered on a laptop computer after the postural stability test.  (revised per 
Amendment 01)  While completing the PAB, subjects will be in bed and ambient lighting will be maintained at 
a level of 80 – 100 lux at the subject’s eye level.  On the evening of the Screening PSG visit, before bedtime, 
subjects will be introduced to the PAB tasks and will undergo a minimum of 2 training sessions. If subjects 
cannot adequately perform the tasks during the training sessions, they will be excluded from further 
participation.  On the morning after the Screening PSG, subjects will complete a session of the cognitive PAB 
for familiarization purposes only; no data from this session will be used for analyses.  This session must be 
conducted under the same conditions (eg, lighting, subject in bed) as during the testing sessions at subsequent 
visits.
The PAB comprises 9 tasks including Simple Reaction Time, Choice Reaction Time, Digit Vigilance, 
Immediate Word Recall, Delayed Word Recall, Numerical Working Memory, Spatial Working Memory, Word 
Recognition, and Picture Recognition.  The full PAB will take approximately 18 to 30 minutes to complete.  
Four composite domain factor scores are calculated by combining outcome variables from the various tests.  
The four domain factor scores are Power of Attention, Continuity of Attention, Quality of Memory, and Speed 
of Memory Retrieval.

Power of Attention
o
A composite score from the speed scores of 3 tests of attention
o
Reflects the ability to focus attention and process information

Continuity of Attention
o
A composite score created by combining the accuracy scores from the tests of attention 
o
Reflects the ability to sustain attention (vigilance)

Quality of Memory
o
A composite score created by combining the accuracy measures from the two tests of working memory 
and the four tests of episodic memory 


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o
Reflects the ability to store information in memory and subsequently retrieve it

Speed of Memory Retrieval
o
A composite score created by combining the reaction time scores from the two working memory tests 
and the two episodic recognition tests
o
Reflects time taken to retrieve information held in both working and episodic memory
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; regular laboratory evaluation for 
hematology, blood chemistry, and urine values; periodic measurement of vital signs, weight and ECGs; and the 
performance of physical examinations.  Safety will be assessed at every clinic visit throughout the study, and at 
the EOS Visit.
Columbia - Suicidality Severity Rating Scale
Suicidality will be assessed using a self-rated electronic version of the C-SSRS (eC-SSRS).  The eC-SSRS 
assesses an individual’s degree of suicidality, including both suicidal ideation and suicidal behavior. 
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire 
An assessment of withdrawal symptoms will be made using the T-BWSQ completed at the EOS Visit. Subjects 
will be asked about the presence/absence and severity of the symptoms listed in the questionnaire.  For each 
listed symptom, the subject is to respond “No” (Score = 0), “Yes –moderate” (Score = 1) or “Yes – severe” 
(Score = 2).  The sum of responses will be the subject’s score. (revised per Amendment 02)
Other Assessments
EQ-5D-3L
The EQ-5D-3L 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 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”).
Patient Global Impression – Insomnia 
The PGI-Insomnia is a self-report assessment asking about subjects’ perceptions of the effects of the study 
medication on their sleep relative to their sleep before entering in the study.  As such, the PGI-Insomnia does 
not have a baseline and the outcome is not change from baseline, but rather the global impression of the study 
medication’s effects at the end of treatment. The PGI-Insomnia has 3 items related to study medication effects 
(a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) increased/decreased total sleep time,
and 1 item related to perceived appropriateness of study medication strength.  The first 3 items are answered on 
a 3-point scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and 
the last item on a different 3-point scale (medication: 1=too strong, 2=just right, 3=too weak).
Bioanalytical Methods
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10) and zolpidem (as needed), will 
be measured using validated liquid chromatography-tandem mass spectrometry assay methods.
Statistical Methods
All statistical tests will be based on the 5% level of significance (2-sided).
Study Endpoints
Primary Endpoint(s)
The primary endpoint is:

Change from baseline of mean LPS on Days 29 and 30 of LEM10 and LEM5 compared to PBO (revised 
per Amendment 03)
Secondary Endpoint(s)
Key Secondary Endpoints: US ONLY (revised per Amendment 03)

Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to PBO

Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5 compared to PBO (revised 
per Amendment 04)


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
Change from baseline of mean WASO2H on Days 29 and 30 of LEM10 and LEM5 compared to ZOL
Key Secondary Endpoint(s): Non-US ONLY (revised per Amendment 03)

Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to PBO

Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5 compared to PBO
Additional Secondary Endpoints:  US and Non-US (revised per Amendment 03)

Change from baseline on the postural stability test of mean units of body sway on Days 2 and 3 of LEM5 
and LEM10 compared to ZOL

Change from baseline of mean LPS, WASO, and TST on Days 1 and 2 and Days 29 and 30 of  LEM5 and 
LEM10 compared to ZOL 

Change from baseline mean of subjective Sleep Diary variables including  sSOL, sWASO, sSE and sTST 
over the first 7 and last 7 nights of the Treatment Period of LEM5 and LEM10 compared to ZOL

Change from baseline of mean LPS, SE, WASO, WASO2H, and TST on Days 1 and 2 of LEM5 and 
LEM10 compared to PBO

Change from baseline of mean WASO2H and TST on Days 29 and 30 of LEM5 and LEM10 compared to 
PBO

Change from baseline mean of subjective Sleep Diary variables including  sSOL, sWASO, sSE and sTST 
over the first 7 and last 7 nights of the Treatment Period of LEM5 and LEM10 compared to PBO 

Proportion of responders after Days 1 and 2 and Days 29 and 30 (PSG), and over the first 7 nights and last 
7 nights of treatment (Sleep Diary), to LEM5 and LEM10 compared to ZOL and PBO, such that:
o
Objective sleep onset response is defined as LPS ≤20 minutes (provided mean baseline LPS 
was > 30 minutes)
o
Subjective sleep onset response is defined as sSOL ≤ 20 minutes (provided mean baseline 
sSOL was > 30 minutes)
o
Objective sleep maintenance response is defined as WASO ≤ 60 minutes (provided mean 
baseline WASO was > 60 minutes and is reduced by > 10 minutes compared to baseline)
o
Subjective sleep maintenance response is defined as sWASO ≤ 60 minutes  (provided mean 
WASO was > 60 minutes and is reduced by > 10 minutes compared to baseline)

Safety and tolerability of LEM

Change from baseline of the score from items 4 to 7 on the ISI at Day 31 of LEM5 and LEM10 compared 
to ZOL and PBO

Change from baseline on the FSS score at Day 31 of LEM5 and LEM10 compared to ZOL and PBO

Change from baseline of mean power of attention, mean continuity of attention, mean quality of memory, 
and mean speed of memory retrieval on Days 2 and 3
Exploratory Endpoints
The change from baseline of WASO2H for LEM5 and LEM10 compared to ZOL will be considered as 
exploratory for all non-US submissions. The following endpoints will also be explored for LEM5 and LEM10.  
Except for PK endpoints, comparisons to ZOL and PBO will be made.   (revised per Amendment 03)

Change from baseline of the mean rating on the Quality of Sleep question from the Sleep Diary of the first 
7 days and last 7 days of the Treatment Period 

Change from baseline of mean power of attention, mean continuity of attention, mean quality of memory, 
and mean speed of memory retrieval on Days 30 and 31 

From the postural stability test, change from baseline of mean units of body sway after the first 2 nights of 
the Treatment Period compared to PBO and the last 2 nights of the Treatment Period compared to ZOL and 
PBO

Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up Period
o
Change from baseline of sSOL at the following timepoints during the Follow-up Period: each 
of the first 3 nights, mean of the first 3 nights, mean of the first 7 nights, mean of the second 7 
nights(revised per Amendment 03)


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o
Change from baseline of sWASO at the following timepoints during the Follow-up Period:  
each of the first 3 nights, mean of the first 3 nights, mean of the first 7, mean of the second 7 
nights (revised per Amendment 03)
o
Proportion of subjects whose sSOL is longer than at Screening at the following timepintgs 
during the the Follow-up Period:  each of the first 3 nights, mean of the first 3 nights, mean 
for first 7 nights, mean of the second 7 nights (revised per Amendments 02 and 03)
o
Proportion of subjects whose sWASO is higher than at Screening at the following timepoints 
during the Follow-up Period:  each of the first 3 nights, mean of the first 3 nights, mean for 
the first 7 nights, for thesecond 7 nights (revised per Amendments 02 and 03)

Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings and last 7 mornings 
of the Treatment Period 

Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings and second 7 
mornings of the Follow-up Period 

Change from baseline of mean morning sleepiness ratings assessed at 1.5 hours after waketime when 
subjects are in clinic on Days 1 and 2, and Days 29 and 30 (revised per Amendment 01)

Change from baseline of mean minutes and mean percentage (a) per TIB and (b) per TST of sleep stage 
N1, N2, N3 (separately and combined) and REM on Days 1 and 2 and Days 29 and 30 

Change from baseline of mean REM latency, mean number of awakenings, and mean number of long 
awakenings on Days 1 and 2 and Days 29 and 30 (revised per Amendment 03)

Number and percentage of subjects with a rating of a positive medication effect on each PGI-Insomnia item
at Day 31

Change from baseline on the EQ-5D-3L at Day 31

Mean score on the T-BWSQ of LEM5 and LEM10 compared to ZOL and PBO at end of study

Proportion of subjects who score ≥ 3 on the T-BWSQ of LEM5 and LEM10 compared to ZOL and PBO at 
end of study

PK of lemborexant and its metabolites M4, M9, and M10

Relationships between lemborexant PK, efficacy, and/or safety variables using PK/PD modeling 
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 primary efficacy measurement.
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with the protocol.  
Details of the evaluability criteria will be determined before database lock and treatment unblinding and will be 
specified in the Statistical Analysis Plan (SAP).
The PK Analysis Set is the group of subjects who have at least one quantifiable plasma concentration of 
lemborexant or its metabolites, or zolpidem, 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 
one quantifiable lemborexant concentration data point as per the PK Analysis Set.
Efficacy Analyses
Definitions of Baseline
Baseline is defined as the means from the 2 PSGs during the Run-in Period for PSG-derived variables and the 
mean of the last 7 mornings before the first baseline PSG during the Run-in Period for Sleep Diary variables. 
For other endpoints, baseline data are captured during the Run-in Period and Baseline Period.  Details will be 
specified in the SAP.
Control of Type I Error (revised per Amendment 03)
A sequential gate-keeping procedure will be used for the primary and the key secondary endpoint comparisons 
to control for the overall type I error at the 0.05 significance level.  The first endpoint comparison will be tested 


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at the 0.05 significance level.  If the testing is found to be statistically significant, then proceed to the next 
endpoint testing at significance level of 0.05, otherwise stop testing.  
The primary endpoints will be tested in the following order:

Change from baseline of the mean LPS of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean LPS of Days 29 and 30 of LEM5 compared to PBO
The key secondary endpoints will only be tested if both primary analyses are statistically significant at the 0.05 
level.  The key secondary endpoints will be tested in the following order:
US Only

Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO

Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to PBO (revised per 
Amendment 04)

Change from baseline of the mean WASO2H of Days 29 and 30 of LEM10 compared to ZOL 

Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to PBO (revised per 
Amendment 04)

Change from baseline of the mean WASO2H on Days 29 and 30 of LEM5 compared to ZOL
Non-US Only

Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO

Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to PBO 

Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to PBO
No multiplicity adjustment will be done on other efficacy analyses.
Analysis for the Primary Endpoint
Null Hypothesis:  No difference exists in the mean change from baseline of the mean LPS of Days 29 and 30 
for treatment with LEM10 (or LEM5) as compared with PBO. (revised per Amendment 03)
Alternative Hypothesis:  A difference exists in the mean change from baseline of the mean LPS of Days 29 and 
30 for LEM10 (or LEM5) compared to PBO.  (revised per Amendment 03)
The LPS change from baseline (the mean of Days 1 and 2, and the mean of Days 29 and 30) will be analyzed 
using the mixed effect model repeated measurement analysis (MMRM) on the FAS. The model will include all 
data and will be adjusted for the corresponding baseline value (the means from the 2 PSG recordings during the 
Run-in Period), region, age group (55 <65 years; 65 years or older), treatment, time (Days 1/2, and Days 
29/30), and the interaction of treatment by time (revised per Amendment 04).  Since LPS is known to be non-
normally distributed, a log-transformation will be used in the analysis. An unstructured covariance matrix will 
be used, and if the model fails to converge, then an autoregressive matrix will be used. The missing values will 
be imputed using a pattern mixture model utilizing multiple imputations (MI) assuming the missing values are 
missing not at random (MNAR) utilizing the complete case missing value pattern (CCMV - subjects who 
completed primary efficacy assessments without missing values) (revised per Amendment 04).  The missing 
values for a given visit will be imputed using all available values including the retrieved measurement from the 
post-discontinuation data. The treatment comparison will be performed using contrasts. The p-value, least 
square (LS) means and the 95% confidence interval (CI) for the treatment difference will also be provided.  
(revised per Amendment 03)
Subgroup analyses and additional sensitivity analysis will be performed as appropriate.  
The following analyses will be considered as sensitivity analyses: 

PP analysis: The same primary efficacy analyses described above will be repeated based on PP analysis set. 

Completer analysis: The same primary efficacy analyses described above will be repeated on subjects who 
completed all efficacy assessments and have no missing values.

As-treated analysis: The same primary efficacy analyses (MMRM analysis with MI for missing value 
imputation) will be repeated based on the actual treatment the subject received regardless of randomization.


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
MMRM analysis assuming missing at random (MAR): The same primary endpoint analysis described 
above will be analyzed using MMRM assuming the missing values are MAR.

MI Imputation assuming MNAR utilizing CCMV-4: The same MMRM method used in the primary 
analysis will be applied utilizing CCMV-4 (ie, up to 4 monotone missing patterns will be used for missing 
value imputation as follows): (revised per Amendment 04)
Study days where results are available
1
2
29
30
Pattern 1
x
x
x
x
Pattern 2
x
x
x
.
Pattern 3
x
x
.
.
Pattern 4
x
.
.
.
x = result present; . = result missing

Tipping point analysis: A range of shifts will be used in the multiple imputation of missing data assuming 
MNAR to identify the specific shift and treatment effect that will tip the results from statistically 
significant to non-significant. (revised per Amendment 04)
Secondary Efficacy Analyses 
Key Secondary Efficacy Analysis (revised per Amendments 03 and 04)
Changes from baseline of mean SE, WASO2H, and WASO of Days 1 and 2 and the mean of Days 29 and 30 
will be analyzed using a pattern mixture model utilizing MI assuming MNAR.  The treatment comparison will 
be performed using contrasts.  The p-value, LS means and the 95% CI of the treatment differences will also be 
provided. The comparison of LEM10 and LEM5 to ZOL on WASO2H will be considered as exploratory for all 
non-US submissions. (revised per Amendment 03)
Other Secondary Efficacy Analyses (revised per Amendment 03)
The other secondary efficacy endpoints (change from baseline of the mean of the following endpoints:  LPS, 
SE, WASO2H, and WASO of the mean of Days 1 and 2; TST of the mean of Days 1 and 2 and of the mean of 
Days 29 and 30; sSOL, sWASO, sSE, and sTST for the mean of the first 7 and last 7 days of the Treatment 
Period) will be analyzed using MMRM assuming MAR. (revised per Amendment 03)
The proportion of responders will be analyzed using the Cochran-Mantel-Haenszel test, controlled for region
and age group, for each dose of lemborexant compared to PBO and ZOL. The analysis will be similarly 
repeated for responder analysis based on Sleep Diary variables (sSOL and sWASO) over the first 7 and last 
7 nights of treatment. (revised per Amendment 03)
The change from baseline of the ISI total of four items on daytime functioning at Day 31 and the FSS score at 
Day 31 will be analyzed using analysis of covariance (ANCOVA), adjusted for the corresponding baseline 
value, age group, region, and treatment. (revised per Amendment 03)
Changes from baseline in mean power of attention, mean continuity of attention, mean quality of memory, and 
mean speed of memory retrieval for the PAB tasks will be analyzed using MMRM assuming MAR. (revised 
per Amendments 01 and 03)
Secondary endpoints may also be presented graphically or analyzed by modeling methods if warranted.
(revised per Amendment 03)
No multiplicity adjustment or missing values imputation is planned for other secondary analyses. (revised per 
Amendment 03)
Exploratory and Pharmacodynamic Analyses  
The change from baseline mean score of the quality of sleep item on the Sleep Diary for the means of the first 
7 days and last 7 days of the Treatment Period will be analyzed using MMRM assuming MAR.  (revised per 
Amendment 03)
Rebound insomnia is defined as worsened sleep relative to Screening after study drug treatment is completed.  
Sleep Diary data from the Follow-up Period will be compared to Sleep Diary data from the Screening Period to 
assess whether subjects experience rebound insomnia.  Specifically, a higher value for sSOL or sWASO during 


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the Follow-up Period compared to the mean sSOL or sWASO value during the Screening Period will be 
considered worsened sleep. (revised per Amendment 02)
To assess rebound insomnia, both categorical analysis at the subject level and continuous analysis at the group 
mean level will be performed.  For each of the first 3 nights, the mean of the first 3 nights, and the mean of each 
of the 2 weeks of the Follow-up Period the proportion of subjects whose corresponding value for sSOL or 
sWASO exceeds the corresponding Screening Period value by 5 minutes will be summarized by treatment 
group and compared to placebo. The percentage of ‘rebounders’ between each treatment and placebo group 
will be analyzed using a CMH test.  (revised per Amendments 01, 02, and 03)
To assess statistical significance using the continuous data at the group mean level, the data will be analyzed 
using ANCOVA, adjusted for region, age group and treatment.  The LS mean of each of the first 3 nights and 
each week of the Follow-up Period will be compared to the Screening Period between each treatment group and 
placebo.  If the lower bound of the 95% CI of sSOL or sWASO for each of the first 3 nights and the mean of 
each week of the Follow-Up Period exceeds the upper bound of a 95% CI for the values during the Screening 
Period in the given treatment group, it will be considered strong evidence for rebound insomnia. If the LS 
means for sSOL and sWASO for the Follow-up Period are all lower than for the Screening Period, then no 
rebound insomnia is suggested.    (revised per Amendments 01 and 03)
To evaluate morning residual sleepiness during study treatment and following completion of treatment, the 
change from baseline of the mean of morning sleepiness item on the Sleep Diary for the first 7 mornings of the 
Treatment Period, the last 7 mornings of the Treatment Period, as well as the means of the first 7 days and 
second 7 days of the Follow-up Period will be analyzed using MMRM assuming MAR.  Change from baseline 
of the mean morning sleepiness ratings assessed at 1.5 hours after waketime when subjects are in clinic on days 
1 and 2 and days 29 and 30 will be similarly analyzed using MMRM assuming MAR.  (revised per 
Amendments 01 and 03)
The change from baseline of the mean of Days 1 and 2 and of the mean of Days 29 and 30 for the sleep 
architecture and other PSG endpoints (WASO1H minutes and percentage [a] per TIB and [b] per TST of sleep 
stage N1, N2, N3, total NREM and REM; REM latency, DurLongAW, number of awakenings, number of long 
awakenings, REM episode frequency and duration, and mean REM/NREM cycle duration) will be summarized.  
(revised per Amendment 03)  
Each item on the PGI-Insomnia at Day 31 will be analyzed separately by calculating the number and 
percentages of subjects for each response category (eg, negative [3], neutral [2], positive [1] medication effect).  
The percentage of positive responses will be compared between treatment groups using the chi-square test, and 
repeated for age subgroups.
The change from baseline in the EQ-5D-3L score at Day 31 will be analyzed using ANCOVA, adjusted for
region, age group and treatment.  (revised per Amendment 03)
No multiplicity adjustment or missing value imputation is planned for exploratory and pharmocodynamic 
analyses.  (revised per Amendment 03)
Pharmacokinetic Analysis 
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, and M10, as well 
as zolpidem plasma concentration listings. The PK Analysis Set will be used for summaries of lemborexant and 
its metabolites M4, M9, and M10, as well as zolpidem plasma concentrations by dose, time, and day.
A population PK approach will be used to characterize the PK of lemborexant. For this approach, PK analysis 
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 covariates (ie, demographics) on the PK of lemborexant will be evaluated. The PK 
model will be parameterized for apparent total clearance following extravascular administration (CL/F) and 
volumes of distribution. Derived exposure parameters such as area under the concentration-time curve (AUC), 
maximum lemborexant 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. 
Pharmacodynamic Analysis
These analyses are described in the Secondary Efficacy Analyses, and Exploratory and Pharmacodynamic 
Analyses sections (above).
Pharmacokinetic/Pharmacodynamic Analysis
The PK/PD relationship between exposure to lemborexant and efficacy variables including but not limited to 


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LPS and WASO, and safety variables including but not limited to morning sleepiness and frequently occurring 
treatment-emergent adverse events (TEAEs), will be explored graphically.  Any emergent PK/PD relationships 
will be evaluated by population PK/PD modeling. The population PK/PD analysis plan will be described and 
results will be reported in a separate document. 
Population PK and PK/PD 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, out-of-
normal-range laboratory safety test variables, abnormal ECG findings, out-of-range vital signs and weight, 
suicidality (eC-SSRS), and T-BWSQ (including frequency and percentage of subjects with T-BWSQ score ≥3), 
along with change from baseline in laboratory safety test variables, ECGs, and vital sign and weight 
measurements, will be summarized by treatment group using descriptive statistics.
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed by modeling 
methods if warranted.
Although ZOL is included in the study as an active comparator, comparison of ZOL to PBO, and comparison 
between LEM10 and LEM5 may be made to facilitate evaluation of study results.
Interim Analyses
An interim analysis is planned to be conducted after approximately 50% of subjects (approximately 
n=475 subjects) have been randomized and either completed Day 31 assessments or discontinued from the 
study.  This interim analysis will be conducted for administrative reasons as detailed in the separate Interim 
Analysis charter.  When the specified number of subjects has completed the Day 31 assessments, an 
independent statistician external to the Sponsor will be provided with the relevant PSG dataset and will be 
unblinded to the primary endpoint, ie, change from baseline in WASO2H for the mean of Days 29 and 30.  A 
conditional power will be calculated to predict the probability that the trial will achieve a significant treatment 
effect for WASO2H in the LEM10 versus ZOL arms at the end of the study, given what is observed at the time 
of interim analysis. The interim analysis will be limited to the comparison of LEM10 versus ZOL on the 
change from baseline in WASO2H for the mean of Days 29 and 30.  No other endpoints, dose groups, or 
timepoints will be analyzed at the interim analysis. The study will not be terminated for either futility or 
efficacy.  Therefore no impact to the type I error rate is expected.  
The method of calculating the conditional power will be detailed in the Interim Analysis charter, along with 
operational procedures, unblinding procedures, procedures for communicating the results of the conditional 
power calculation and recipients of this information.  To preclude potential influence on the conduct of the 
remainder of the study, disclosure of the conditional power will be limited to a prespecified set of executive-
level individuals at the sponsor and sponsor's co-development partner. No individuals involved with the 
conduct of the study will have access to the interim data or the results of the interim analysis (i.e., the 
conditional power of LEM10 versus ZOL on the change from baseline in WASO2H for the mean of Days 29 
and 30).
Enrollment of subjects will not be stopped during the interval during which the interim analysis is conducted.  
The interim analysis may be waived or otherwise not conducted, for reasons including but not limited to a 
higher than anticipated enrollment rate which would make the interim analysis unnecessary as the majority of 
subjects would have been enrolled by the time the interim analysis was concluded.   
Sample Size Rationale
The sample size was estimated for each comparison of LEM10 vs. PBO, and LEM5 vs PBO with respect to the 
mean change from baseline of LPS at Month 1, on the basis of a 2-sided t-test at the 0.05 α-level for each 
treatment comparison.  (revised per Amendment 03)
On the basis of the dose finding study E2006-G000-201 (Study 201), across various lemborexant doses (1 to 
25 mg) at Days 14 and 15, the standard deviation (SD) of change from baseline for log-transformed LPS is 
assumed to be 0.9. The LS mean treatment difference at Days 14/15 from Study 201 for log-transformed LPS of 
LEM10 and LEM5 compared with PBO was 0.75 and -1.15, respectively.  Therefore, a sample size of 250 
subjects for LEM5, 250 subjects for LEM10, and 200 subjects for PBO has at least 95% power for each 
treatment comparison, LEM10 with PBO, and LEM5 with PBO, based on 2-sided, 2-sample t-test at 5% 
significance level. (revised per Amendment 03)
Power is also estimated for the key secondary objectives, the comparison of LEM10 and LEM5 to PBO on 


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change from baseline of SE and WASO, and LEM10 and LEM5 to ZOL on WASO2H.  A sample size of 250 
subjects each for LEM5, LEM10, and ZOL, and 200 subjects for PBO has at least 95% power for detecting a 
statistically significant difference between LEM and PBO for change from baseline in SE, at least 80% power 
for detecting a statistically significant difference between LEM10 and ZOL/PBO for change from baseline in 
WASO/WASO2H based on 2-sided 2-sample t-test at 5% significance level. (revised per Amendments 03 and 
04)
Endpoint (Test)
Estimated Treatment Difference
Estimated SD
Power
Log(LPS) (LEM5 vs PBO)
-0.75
0.9
>95%
Log(LPS) (LEM10 vs PBO)
-1.15
0.9
>95%
SE (LEM5 vs PBO)
5%
14%
>95%
SE (LEM10 vs PBO)
7%
14%
>95%
WASO (LEM5 vs PBO)
-10 min
55 min
48%
WASO (LEM10 vs PBO)
-15 min
55 min
81%
WASO2H (LEM5 vs ZOL)
-8 min
38 min
65%
WASO2H (LEM10 vs ZOL)
-11 min
38 min
89%
Estimated treatment difference and SD are based on Study 201.


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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................21
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................26
5
ETHICS............................................................................................................................29
5.1
Institutional Review Boards/Independent Ethics Committees ..............................29
5.2
Ethical Conduct of the Study.................................................................................29
5.3
Subject Information and Informed Consent...........................................................30
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................31
7
INTRODUCTION ...........................................................................................................32
7.1
Indication ...............................................................................................................32
7.1.1
Current Therapeutic Options........................................................................32
7.1.2
Lemborexant (E2006)..................................................................................32
7.1.2.1
Mechanism of Action...........................................................................32
7.1.2.2
Clinical Experience with Lemborexant ...............................................32
7.1.2.2.1
Phase 1 ...........................................................................................32
7.1.2.2.2
Phase 2 ...........................................................................................34
7.2
Study Rationale......................................................................................................34
8
STUDY OBJECTIVES....................................................................................................36
8.1
Primary Objective – US and Non-US (revised per Amendment 03).....................36
8.2
Secondary Objectives.............................................................................................36
8.2.1
Key Secondary Objectives – US ONLY (revised per Amendment 03).......36
8.2.2
Key Secondary Objectives – Non-US ONLY (revised per Amendment 
03) ................................................................................................................36
8.2.3
Additional Secondary Objectives – US and Non-US (revised per 
Amendment 03) ...........................................................................................36
8.3
Exploratory Objectives – US and Non-US (revised per Amendment 03).............37
9
INVESTIGATIONAL PLAN..........................................................................................38
9.1
Overall Study Design and Plan..............................................................................38
9.1.1
Prerandomization Phase...............................................................................40
9.1.1.1
Screening Period..................................................................................40
9.1.1.2
Run-in Period.......................................................................................41
9.1.1.3
Baseline Period ....................................................................................42
9.1.2
Randomization Phase...................................................................................42
9.1.2.1
Treatment Period..................................................................................42
9.1.2.2
Follow-up Period .................................................................................43
9.2
Discussion of Study Design, Including Choice of Control Groups.......................43


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9.2.1
Randomization.............................................................................................43
9.2.2
Run-In ..........................................................................................................43
9.2.3
Efficacy Assessments...................................................................................44
9.2.4
Morning Residual Effects on Postural Stability and Cognitive 
Performance.................................................................................................44
9.2.5
Adjudication Committee (revised per Amendment 02)...............................45
9.2.6
Study Duration.............................................................................................45
9.2.7
Age Group....................................................................................................45
9.2.8
Time of Dosing ............................................................................................46
9.2.9
Interim Analysis...........................................................................................46
9.3
Selection of Study Population................................................................................47
9.3.1
Inclusion Criteria .........................................................................................47
9.3.2
Exclusion Criteria ........................................................................................48
9.3.3
Removal of Subjects From Therapy or Assessment....................................50
9.4
Treatment(s)...........................................................................................................51
9.4.1
Treatment(s) Administered..........................................................................51
9.4.2
Identity of Investigational Product(s) ..........................................................51
9.4.2.1
Chemical Name, Structural Formula of E2006/Lemborexant.............52
9.4.2.2
Comparator Drug .................................................................................52
9.4.2.3
Labeling for Study Drug......................................................................52
9.4.2.4
Storage Conditions...............................................................................52
9.4.3
Method of Assigning Subjects to Treatment Groups...................................53
9.4.4
Selection of Doses in the Study...................................................................53
9.4.5
Selection and Timing of Dose for Each Subject..........................................54
9.4.6
Blinding........................................................................................................54
9.4.7
Prior and Concomitant Therapy...................................................................54
9.4.7.1
Drug-Drug Interactions........................................................................54
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................54
9.4.8
Treatment Compliance.................................................................................55
9.4.9
Drug Supplies and Accountability...............................................................56
9.5
Study Assessments.................................................................................................57
9.5.1
Assessments.................................................................................................57
9.5.1.1
Demography.........................................................................................57
9.5.1.2
Baseline Assessments ..........................................................................58
9.5.1.2.1
Medical History and Physical Examinations.................................58
9.5.1.2.2
Sleep Disorders History and Screening Battery.............................58
9.5.1.2.3
Beck Depression Inventory - II......................................................58
9.5.1.2.4
Beck Anxiety Inventory.................................................................59


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9.5.1.3
Efficacy Assessments...........................................................................59
9.5.1.3.1
Polysomnography ..........................................................................59
9.5.1.3.2
Electronic Sleep Diary...................................................................60
9.5.1.3.3
Insomnia Severity Index ................................................................61
9.5.1.3.4
Fatigue Severity Scale....................................................................62
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................62
9.5.1.4.1
Pharmacokinetic Assessments .......................................................62
9.5.1.4.2
Pharmacodynamic Assessments ....................................................62
9.5.1.4.3
Pharmacogenomic Assessments ....................................................63
9.5.1.4.4
Other Biomarker Assessments.......................................................63
9.5.1.5
Safety Assessments..............................................................................64
9.5.1.5.1
Columbia-Suicide Severity Rating Scale.......................................64
9.5.1.5.2
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire ........64
9.5.1.5.3
Adverse Events ..............................................................................64
9.5.1.5.4
Serious Adverse Events and Events Associated With Special 
Situations........................................................................................66
9.5.1.5.5
Laboratory Measurements .............................................................67
9.5.1.5.6
Vital Signs and Weight Measurements..........................................69
9.5.1.5.7
Physical Examinations...................................................................69
9.5.1.5.8
Electrocardiograms ........................................................................69
9.5.1.5.9
Other Assessments.........................................................................70
9.5.2
Schedule of Procedures/Assessments ..........................................................70
9.5.2.1
Schedule of Procedures/Assessments ..................................................70
9.5.2.2
Description of Procedures/Assessments Schedule...............................75
9.5.3
Appropriateness of Measurements...............................................................75
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................75
9.5.4.1
Reporting of Serious Adverse Events..................................................75
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................76
9.5.4.3
Reporting of Events Associated with Special Situations.....................77
9.5.4.4
Expedited Reporting ............................................................................77
9.5.4.5
Breaking the Blind...............................................................................78
9.5.4.6
Regulatory Reporting of Adverse Events ............................................78
9.5.5
Completion/Discontinuation of Subjects.....................................................78
9.5.6
Abuse or Diversion of Study Drug ..............................................................79
9.5.7
Confirmation of Medical Care by Another Physician .................................79
9.6
Data Quality Assurance .........................................................................................79


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9.6.1
Data Collection ............................................................................................79
9.6.2
Clinical Data Management ..........................................................................80
9.7
Statistical Methods.................................................................................................80
9.7.1
Statistical and Analytical Plans....................................................................80
9.7.1.1
Study Endpoints...................................................................................80
9.7.1.1.1
Primary Endpoint(s).......................................................................80
9.7.1.1.2
Secondary Endpoint(s)...................................................................80
9.7.1.1.3
Exploratory Endpoint(s) – US and Non-US (revised per 
Amendment 03) .............................................................................82
9.7.1.2
Definitions of Analysis Sets.................................................................83
9.7.1.3
Subject Disposition..............................................................................83
9.7.1.4
Demographic and Other Baseline Characteristics ...............................84
9.7.1.5
Prior and Concomitant Therapy...........................................................84
9.7.1.6
Efficacy Analyses ................................................................................84
9.7.1.6.1
Primary Efficacy Analysis.............................................................86
9.7.1.6.2
Secondary Efficacy Analyses ........................................................88
9.7.1.6.3
Exploratory Efficacy and Pharmacodynamic Analyses.................89
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................90
9.7.1.7.1
Pharmacokinetic Analyses.............................................................90
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................90
9.7.1.8
Safety Analyses....................................................................................91
9.7.1.8.1
Extent of Exposure.........................................................................91
9.7.1.8.2
Adverse Events ..............................................................................91
9.7.1.8.3
Clinical Laboratory Values............................................................92
9.7.1.8.4
Vital Signs, Height, and Weight ....................................................93
9.7.1.8.5
Electrocardiograms ........................................................................93
9.7.1.8.6
Other Safety Analyses....................................................................94
9.7.1.9
Other Analyses.....................................................................................94
9.7.2
Determination of Sample Size .....................................................................94
9.7.3
Interim Analysis...........................................................................................95
9.7.4
Procedure for Revising the Statistical Analysis Plan...................................96
10
REFERENCE LIST .........................................................................................................97
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......99
11.1
Changes to the Protocol .........................................................................................99
11.2
Adherence to the Protocol......................................................................................99
11.3
Monitoring Procedures...........................................................................................99
11.4
Recording of Data................................................................................................100


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11.5
Identification of Source Data...............................................................................100
11.6
Retention of Records............................................................................................100
11.7
Auditing Procedures and Inspection....................................................................101
11.8
Handling of Study Drug.......................................................................................101
11.9
Publication of Results ..........................................................................................101
11.10 Disclosure and Confidentiality ............................................................................102
11.11 Discontinuation of Study .....................................................................................102
11.12 Subject Insurance and Indemnity.........................................................................102
12
APPENDICES ...............................................................................................................103
LIST OF IN-TEXT TABLES
Table 1
Treatment Effect for Lemborexant versus Placebo (Study 201) ...............46
Table 2
Clinical Laboratory Tests...........................................................................68
Table 3
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments...............................................................................................68
Table 4
Schedule of Procedures/Assessments in Study E2006-G000-304.............71
Table 5
Vital Sign Criteria......................................................................................93
Table 6:
Power and Sample Size Calculation for Change from Baseline of LPS, 
SE, WASO2H, and WASO........................................................................95
LIST OF IN-TEXT FIGURES
Figure 1
Schematic Diagram of E2006-G000-304 Study Design............................39
Figure 2
Flow Chart of Gate Keeping Testing Procedure – Study E2006-G000-
304 (revised per Amendment 04) ..............................................................86
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................104
Appendix 2
Inclusion/Exclusion Criteria Schedule.....................................................106
Appendix 3
List of Prohibited Concomitant Medications...........................................107


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve extrapolated from zero time to infinite 
time
BAI
Beck Anxiety Inventory
BDI-II
Beck Depression Inventory - II
BMI
body mass index
BP
blood pressure
CDR
Cognitive Drug Research
CFR
Code of Federal Regulations
CI
confidence interval
CL
total clearance
CL/F
apparent total clearance following extravascular administration
CPAP
continuous positive airway pressure (revised per Amendment 01)
Cmax
maximum observed concentration
CPMP
Committee for Proprietary Medicinal Products,
CRA
clinical research associate
CRF
case report form
CRO
Contract Research Organization
DORA
dual orexin receptor antagonist
EASS
events associated with special situations
ECG
electrocardiogram
eCRF
electronic case report form
eC-SSRS
electronic Columbia-Suicide Severity Rating Scale
EEG
electroencephalogram
EMG
electromyography
EOS
end of study
ESS
Epworth Sleepiness Scale
ET
early termination
EU
European Union
FAS
Full Analysis Set


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Abbreviation
Term
FDA
Food and Drug Administration
FSS
Fatigue Severity Scale
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Institutional Ethics Committee
IR
immediate release
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
ISI
Insomnia Severity Index
IxRS
an interactive voice and web response system 
KSS
Karolinska Sleepiness Scale
LDA
longitudinal data analysis
LEM5
lemborexant, 5-mg dose
LEM10
lemborexant, 10-mg dose
LNH
low-normal-high
LPS
latency to persistent sleep
LS
least square
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MHB
median habitual sleep time
MI
multiple imputations
M-MSLT
modified multiple sleep onset latency test
MNAR
missing not at random
MUPS
Munich Parasomnia Scale
NREM
non-REM sleep
PAB
performance assessment battery
PBO
placebo
PD
pharmacodynamic(s)
PGI
Patient Global Impression
PI
principal investigator
PK
pharmacokinetic(s)
PSG
polysomnography
PT
preferred term
QTcF
QT interval corrected for heart rate by Fridericia’s formula


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Abbreviation
Term
RBC
red blood cells
REM
rapid eye movement (sleep stage)
SAE
serious adverse event
SAP
statistical analysis plan
SDSB
Sleep Disorders Screening Battery
SE
sleep efficiency
SOC
system organ class
sSE
subjective sleep efficiency
sSOL
subjective sleep onset latency
sTST
subjective total sleep time
sWASO
subjective wake after sleep onset
T-BWSQ
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire
TEAE
treatment-emergent adverse event
TIB
time in bed
TST
total sleep time
US
United States
WASO
wake after sleep onset
WASO1H
wake after sleep onset in the first half of the night
WASO2H
wake after sleep onset in the second half of the night
WBC
white blood cells
ZOL
zolpidem tartrate extended release 6.25 mg (Ambien CR®)


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) E6 (Good Clinical Practice; GCP), Section 3, and any local regulations.  
Any protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for 
review and approval, except for changes involving only logistical or administrative aspects of 
the study (eg, change in clinical research associates [CRAs], 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 (PI) (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 
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 Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:


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o
Principles of the World Medical Association Declaration of Helsinki 
o
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
o
Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) 
regarding clinical studies, including Part 50 and Part 56 concerning informed subject 
consent and IRB regulations and applicable sections of US 21 CFR Part 312
o
European Good Clinical Practice 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.
o
Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator (or designee) must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document. After the ICF and any other 
written information to be provided to subjects is read and explained to the subject, and after 
the subject has orally consented to the subject’s participation in the study and, if capable of 
doing so, has signed and personally dated the ICF, the witness should sign and personally 
date the consent form.  The subject will be asked to sign an ICF before any study-specific 
procedures are performed.  No subject can enter the study before his/her informed consent 
has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  The form must be signed and dated by the 
appropriate parties.  The original, signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site.
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 105 investigational sites in North America and Europe. (revised 
per Amendment 02)
The name and telephone and fax numbers of the Medical Monitor and other contact 
personnel at the sponsor and of the contract research organization(s) (CRO[s]) are listed in 
the Investigator Study File provided to each site.


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7
INTRODUCTION
7.1
Indication 
7.1.1
Current Therapeutic Options 
Insomnia is a sleep disorder characterized by difficulties with sleep onset, sleep maintenance, 
or early morning awakening, in association with a complaint of impairment during the 
daytime.  Insomnia is a widespread problem in industrialized nations, with approximately 
30% of the population having symptoms and at least 6% meeting diagnostic criteria for 
insomnia meriting treatment.  Currently available pharmacological treatments used for 
insomnia include benzodiazepines, non-benzodiazepine γ-aminobutyric acid (GABA)
receptor agonists (GABAergics), a recently approved dual orexin receptor antagonist 
(DORA), sedating antidepressants, melatonin and melatonin agonists, antihistamines, and 
other prescription and non-prescription medications with sedative properties.  
The current commercial environment is generic, with the non-benzodiazepine, zolpidem 
(Ambien®), leading in prescriptions in the US. Other so-called “z-drugs” including zaleplon 
and eszopiclone, contribute substantially to market share as well.   However, there are 
efficacy and safety concerns associated with the use of z-drugs, particularly zolpidem, 
particularly in older patients.  This limited efficacy is characteristic of short-acting non-
benzodiazepine hypnotics and represents an important unmet medical need, as sleep 
maintenance insomnia is the most prevalent type of insomnia experienced in aging. Up to 
50% of individuals over age 55 report difficulty maintaining sleep.  The recently approved 
DORA, suvorexant, was shown in clinical trials to significantly improve sleep maintenance 
insomnia, but at the starting dose approved for use, showed suboptimal efficacy.
7.1.2
Lemborexant (E2006)
7.1.2.1
Mechanism of Action
Lemborexant, 
E2006, 
(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide
belongs 
to 
the 
pharmacologic class of orexin receptor antagonists.
Orexin neuropeptides (orexin-A and orexin-B) have been recognized as critical upstream 
controllers of most wake-promoting neurotransmitters via two G protein-coupled receptors, 
the orexin-1 receptor and the orexin-2 receptor.  Small-molecule antagonists of orexin 
receptors, such as suvorexant, have recently emerged as a new class of chemical compounds 
that represents a novel alternative approach to treat insomnia disorder. 
7.1.2.2
Clinical Experience with Lemborexant
7.1.2.2.1
PHASE 1
E2006-A001-001 (Study 001):  single ascending dose study.  This study included healthy 
subjects and otherwise healthy subjects with primary insomnia.  In addition to determining 


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the safety and tolerability of single doses, the study provided preliminary evidence of 
efficacy in the target patient population.
E2006-A001-002 (Study 002):  multiple ascending dose study.  This study enrolled healthy 
adult and elderly subjects, each of whom was dosed with lemborexant or placebo at night.  In 
addition to determining the safety and tolerability of multiple doses, the study also provided 
preliminary evidence of a lack of important differences in exposure between adult and 
elderly subjects.  
E2006-A001-003 (Study 003):  A multiple dose study to bridge pharmacokinetics (PK), 
pharmacodynamics (PD), safety and tolerability between Japanese and white healthy 
subjects.  This study provided evidence of a lack of important differences in exposure and 
safety between Japanese and white subjects.
E2006-A001-004 (Study 004):  metabolism-based inducer/inhibitor study.  This study 
provided data demonstrating (1) strong inhibitors of CYP3A lead to higher plasma 
concentrations of lemborexant; and (2) strong inducers of CYP3A lead to notably lower 
plasma concentrations of lemborexant. The study also demonstrated a weak effect of 
lemborexant on CYP2B6 activity and no effect on CYP3A activity.
E2006-A001-005 (Study 005):  relative bioavailability study of capsules vs tablet 
formulations.  This study demonstrated that the capsules and tablets provided similar 
exposure (maximum observed concentration [Cmax] and area under the concentration-time 
curve [AUC]), thus allowing the tablet formulation to be used in future clinical trials.
E2006-A001-007 (Study 007):  human mass balance absorption, distribution, metabolism, 
and excretion study to characterize the route and extent of excretion of lemborexant. This 
study demonstrated that elimination takes place by fecal (57%) and urinary excretion (29%) 
based on total recovery (86.5%) of radioactivity following a single dose of radiolabeled 
lemborexant. In addition, there were no human-specific metabolites and the only major 
(12%) metabolite was M10.  The blood-to-plasma ratio was approximately 0.65.
E2006-A001-008 (Study 008):  food effect study.  This study demonstrated a mild food 
effect.  The Cmax was decreased by 23% and the area under the concentration-time curve from 
zero time extrapolated to infinite time (AUC[0-inf]) was increased by 18% following 
consumption of a high fat meal.
E2006-A001-107 (Study 107):  This Phase 1 study was conducted to evaluate the effects of 
the 5 and 10 mg doses on next-morning residual sleepiness in subjects with insomnia 
disorder.  The study design was randomized, double-blind, and placebo (PBO)-controlled
with a 3-way crossover.  Next-morning residual sleepiness was measured on a modified 
multiple sleep onset latency test (M-MSLT).  An active comparator, flurazepam 30 mg, was 
included to confirm assay sensitivity.  Results showed that for neither 5 mg nor 10 mg was 
the lower bound of the 95% confidence interval (CI) of the treatment difference in change 
from baseline of average sleep onset latency on the M-MSLT more than -6 minutes, which 
was the prespecified criterion defining clinically meaningful next-morning residual 
sleepiness.  That is, neither dose level of E2006 resulted in a clinically meaningful reduction 


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in average time to sleep onset in the morning hours, supporting the safety of these doses and 
their use in Phase 3 studies.
7.1.2.2.2
PHASE 2
A dose-finding study (E2006-G000-201; Study 201) was conducted in subjects who had
insomnia disorder, with the primary objectives of identifying doses that resulted in efficacy 
but did not result in significant next-day residual sleepiness. The doses evaluated were 1, 
2.5, 5, 10, 15, and 25 mg, administered once daily for 15 days. The study was stopped early 
for efficacy after the prespecified success criterion for 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 (LPS) and wake after sleep onset (WASO).  These changes 
were largely maintained over 15 days of treatment with lemborexant as compared with 
placebo.  Subjective measures derived from sleep diary entries yielded results largely 
comparable to PSG-derived results.  Further, there was no evidence of rebound insomnia 
after treatment was completed, as measured either by PSG or Sleep Diary.
At doses up to 10 mg, changes from baseline in next-day sleepiness, as measured by the 
KSS, did not differ from those after placebo.  At the highest doses of 15 and 25 mg, the 
increase in KSS from baseline was statistically significantly different from placebo at some
time points, but the increases in KSS were of small magnitude (ie, less than 1 unit on 
average).  Although there was approximately a two-fold accumulation of lemborexant in 
plasma over the 15-day Treatment Period, next-day sleepiness did not increase from the 
beginning to the end of treatment.
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.
7.2
Study Rationale
The purpose of this study is to provide important information to begin to improve on the 
current treatment paradigm for older patients with sleep maintenance insomnia.  The study 
will help establish the efficacy of lemborexant for the treatment of sleep onset and sleep 
maintenance difficulties, by comparing change from baseline in these parameters to placebo.  
With respect to comparisons to existing therapies, the current market leader, zolpidem has 
been shown to improve sleep onset insomnia. The immediate release (IR) formulation of 
zolpidem is not, however, indicated for sleep-maintenance insomnia.  The extended release 
formulation, zolpidem tartrate extended release 6.25 mg (Ambien CR®; ZOL), was approved 
by the Food and Drug Administration (FDA) for the treatment of sleep maintenance 
symptoms as well as for sleep onset difficulties. However, 2 studies, one using 12.5 mg in 
adults and the other studying 6.25 mg in elderly patients, reported that effects on WASO 
after nights 1 and 2 of treatment were only statistically significantly different from placebo 


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for the first 6 hours (adults) or first 5 hours (elderly) of the 8-hour sleep period.  After 2 
weeks of treatment, WASO was significantly decreased for only the first 5 hours (adults) and 
first 4 hours (elderly) of the 8-hour sleep period.  Given that this is the time of night when 
most sleep maintenance difficulties are experienced, particularly by elderly individuals, there 
is an unmet need that has not been effectively addressed with ZOL.  In brief, while ZOL 
improves sleep maintenance more than the IR formulation, it does not sufficiently decrease 
WASO in the second half of the night (WASO2H). Nonetheless, ZOL was approved based 
on data for the first 6 hours of the sleep period.  It should be noted that the pivotal studies for 
ZOL were based on data from 3-week trials analyzed for Nights 1/2 and 15/16.  A 
comparison of lemborexant with ZOL, especially with respect to sleep maintenance, would 
provide clinically meaningful information for clinicians and patients.  (revised per 
Amendment 03)


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8
STUDY OBJECTIVES
8.1
Primary Objective – US and Non-US (revised per Amendment 03)
Demonstrate using PSG that lemborexant (LEM10 and LEM5) is superior to PBO on 
objective sleep onset as assessed by LPS after the last 2 nights of 1 month of treatment in 
subjects 55 years and older with insomnia disorder.
8.2
Secondary Objectives
8.2.1
Key Secondary Objectives – US ONLY (revised per Amendment 03)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep 
maintenance as assessed by sleep efficiency (SE) after the last 2 nights of treatment

Demonstrate that lemborexant (LEM10) and LEM5) is superior to PBO on sleep 
maintenance as assessed by WASO after the last 2 nights of treatment (revised per 
Amendment 04)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to ZOL on WASO2H 
after the last 2 nights of treatment
8.2.2
Key Secondary Objectives – Non-US ONLY (revised per Amendment 03)

Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep 
maintenance as assessed by SE after the last 2 nights of treatment

Demonstrate that lemborexant (LEM10 and LEM5) are superior to PBO on WASO after 
the last 2 nights of treatment
8.2.3
Additional Secondary Objectives
–
US and Non-US (revised per 
Amendment 03)

Demonstrate that LEM5 or LEM10 or both LEM5 and LEM10 are superior to ZOL on 
postural stability in the morning after the first 2 nights of treatment

Determine whether the efficacy of LEM5 or LEM10, or both LEM5 and LEM10, is 
superior to that of ZOL on selected PSG variables after the first 2 nights and the last 
2 nights of treatment and on selected Sleep Diary variables  over the first 7 nights and last 
7 nights of treatment.  

Confirm the efficacy of LEM5 and LEM10 compared to PBO on sleep as measured by 
PSG after the first 2 and last 2 nights of treatment and as measured by Sleep Diary over 
the first 7 and last 7 nights of treatment 

Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and 
LEM10 and determine whether they are superior to those for ZOL and PBO as defined by 
response on PSG LPS and WASO and Sleep Diary subjective sleep onset latency (sSOL)
and subjective wake after sleep onset (sWASO)

Evaluate the safety and tolerability of lemborexant


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
Determine whether the efficacy of LEM5 or LEM10, or both LEM5 and LEM10, is 
superior to that of ZOL and PBO on daytime functioning as assessed by the Insomnia 
Severity Index (ISI) and Fatigue Severity Scale (FSS) at the end of treatment

Determine whether the safety of LEM5 or LEM10, or both LEM5 and LEM10, is 
superior to that of ZOL and PBO as assessed by cognitive performance in the morning 
after the first 2 nights of treatment
8.3
Exploratory Objectives – US and Non-US (revised per 
Amendment 03)

Explore the effects of LEM5, LEM10, ZOL and PBO on:
o
Subjective quality of sleep
o
Postural stability in the morning after the last 2 nights of treatment
o
Cognitive performance after the last 2 nights of treatment
o
Rebound insomnia in the 2 weeks following 30 days of treatment
o
Subjective ratings of morning sleepiness during and following completion of 
treatment
o
Sleep architecture parameters and other PSG variables
o
Health outcomes on the Patient Global Impression - Insomnia (Patient Global 
Impression [PGI]-Insomnia) and EQ-5D-3L
o
Withdrawal symptoms after completion of treatment

Summarize plasma concentrations of lemborexant and its metabolites M4, M9, and M10

Conduct population PK modeling for lemborexant

Explore PK/PD relationships between lemborexant concentrations and efficacy and 
safety variables


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E2006-G000-304 is a multicenter, randomized, double-blind, placebo-controlled, active 
comparator (ie, ZOL), parallel-group study of 2 dose levels of lemborexant for 30 nights in 
approximately 950 subjects 55 years or older with insomnia disorder.  Subjects will be males
65 years or older or females 55 years or older.  Approximately 60% of the population will be 
age 65 years or older.  (revised per Amendment 03)
The study will have 2 phases, the Prerandomization Phase and the Randomization Phase. The 
Prerandomization Phase will comprise 3 periods that will last up to a maximum of 35 days: a 
Screening Period, a Run-in Period, and a Baseline Period. The Randomization Phase will 
comprise a Treatment Period during which subjects are treated for 30 nights followed by a 
minimum 14-day interval before an End of Study (EOS) Visit.  (revised per Amendment 02)
Throughout the Prerandomization Phase and the Randomization Phase, all subjects will 
undergo routine safety assessments at specified visits, including questioning regarding AEs, 
12-lead electrocardiograms (ECGs), vital signs, weight, height, clinical hematology and 
chemistry analysis and urinalysis, and suicidality.  
Estimates for End of study are as follows: 
o
The study will begin in approximately Apr 2016
o
The end of the study will be the date of the last study visit for the last subject in the 
study.
o
The estimated duration for each subject on study is anticipated to be a maximum of 
81 days / 11.5 weeks (Screening Period plus Run-in Period plus Baseline Period 
maximum of 35 days plus Treatment Period plus Follow-up Period and EOS Visit
maximum of 53 days).  A subject who completes the Treatment Period (assessments 
through discharge from clinic on the morning of Day 31) will be considered to have 
completed the study. (revised per Amendment 02)
The study design is shown in Figure 1.


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Figure 1
Schematic Diagram of E2006-G000-304 Study Design
“D” refers to the study day.
BL = baseline, CDR = Cognitive Drug Research, LEM5 = lemborexant 5 mg, LEM10 = lemborexant 10 mg, PAB = performance assessment battery, PBO = 
placebo, PSG = polysomnography, ZOL = zolpidem tartrate extended release 6.25 mg.
Screening
≥7 days but not >14 days
No treatment
Run-In
≥7 days but not >17 days 
Placebo at bedtime 
each night
BL
(D1)
Randomization
Treatment
≥28 days but not >35 days 
LEM5, LEM 10, ZOL, or PBO at bedtime each night
Follow-Up
≥14 days but not >18 days
No Treatment
Prerandomization
#
# #
#
D1 & D2
PSGsa
D29 & D30 
PSGsa
# #
BL 
PSGsa
#
Screening 
PSGa
In Clinic 
Screening
# = CDR Posture and cognitive PAB assessments in the morning following the PSG assessment.
a:  All PSG visits will require an overnight stay in the clinic.  At least 2 nights must intervene between the second BL PSG and BL 
(D1).


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9.1.1
Prerandomization Phase
9.1.1.1
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At 
the first screening visit (Visit 1), informed consent will be obtained after the study has been 
fully explained to each subject and before the conduct of any screening procedures or 
assessments.  A medical, psychiatric, and sleep history interview will be conducted, and will 
include confirmation that the subject meets diagnostic criteria for insomnia disorder, and 
further that the subject complains of difficulties with sleep maintenance or early morning 
awakening, or both. Screening assessments will include the ISI, as well as the Epworth 
Sleepiness Scale (ESS), the STOPBang, the International Restless Legs Scale (IRLS), and 
the Munich Parasomnia Scale (MUPS), collectively called the Sleep Disorders Screening
Battery (SDSB). Additional eligibility criteria will be assessed and safety assessments will
be conducted as described in Section 9.5.1.5 and summarized in Table 4. (revised per 
Amendment 02)
Subjects will be provided with an electronic device on which they will complete the Sleep 
Diary and will be trained in the use of this device.  Site staff will instruct subjects to 
complete the diary each morning within 1 hour after morning waketime and will emphasize 
the importance of doing so.  The Sleep Diary entries will be reviewed by site staff at least 
weekly throughout the study to ensure subject compliance with completion of the Sleep 
Diary and to ensure that study restrictions are met pertaining to duration of time spent in bed, 
and use of alcohol.  
After subjects have completed the Sleep Diary on at least 7 consecutive mornings, and 
provided that the Sleep Diary entries indicate continued eligibility with regard to sleep 
timing, duration of time spent in bed, and frequency of nights with symptoms of insomnia, 
subjects will undergo the second screening visit.  (Subjects who are not eligible on the basis 
of Sleep Diary entries will return to the clinic for debriefing purposes and to return study 
equipment.) This visit must occur between Day -17 and Day -10.  On this and all nights on 
which PSG is to be recorded, subjects will arrive at the clinic in the evening with sufficient 
time before bedtime to complete check-in procedures, any scheduled assessments, and 
preparations (eg, electrode montage placement) for the PSG recordings.  In addition, at 
check-in before all visits at which PSG is to be recorded, subjects will undergo a urine drug 
test.  (revised per Amendment 02)
After check-in has been completed, study personnel will familiarize subjects with the 
postural stability assessment (CDR posture assessment) and will also conduct a minimum of 
2 training sessions for the cognitive performance assessment battery (PAB).  Subjects will 
then undergo an 8-hour PSG recording, to start at the median habitual bedtime (MHB) as 
calculated from the Sleep Diary entries.  The PSG recording will include channels in the 
electrode montage to screen for symptoms of sleep apnea and periodic limb movement 
disorder.  Within 5 minutes of morning waketime, the CDR posture and PAB assessments 
will be administered under the same conditions (eg, timing of assessments relative to 
waketime, ambient lighting), as will be employed during the testing sessions.  The CDR 


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posture and PAB assessments at this time are for familiarization purposes only.  At 1.5 hours 
after waketime, subjects will rate their morning sleepiness level.  The PSG will be reviewed 
for exclusion criteria related to absence of symptoms of sleep apnea and/or periodic limb 
movement disorder, subjects who continue to meet the eligibility criteria will then be 
dispensed PBO tablets (single-blind) and will enter the Run-in Period.
9.1.1.2
Run-in Period
The Run-in Period will begin when eligible subjects are dispensed PBO tablets and will
continue until the Baseline Period on Day 1.  During the Run-in Period, subjects will take 
PBO each night immediately (ie, within 5 minutes) before bedtime (defined as the time the 
subject intends to try to fall asleep).  They will be reminded that they must remain in bed for 
at least 7 hours each night and maintain a regular bedtime throughout the study according to 
the schedule determined by the study site and the subject. They will also be reminded that 
they must follow study restrictions with regard to timing of meals and use of caffeine and 
alcohol.  
When subjects have completed the Sleep Diary on at least 7 consecutive mornings during the 
Run-In Period, the diary will be reviewed for continued eligibility with regard to whether the 
subject continues to report sWASO ≥60 minutes on at least 3 of the 7 nights, as well as the 
schedule and duration of time spent in bed. Subjects who are still eligible will return to the 
clinic for the first of two consecutive nights on which PSG will be recorded. (Subjects who 
are not eligible on the basis of Sleep Diary entries will return to the clinic for debriefing 
purposes and to return study equipment.)  The first of these 2 nights must be between Day -
10 and Day -4. In the evening before the PSG recording, the ISI, the FSS, and the EQ-5D-3L 
will be assessed.  The ISI score will be reviewed for eligibility and safety assessments will be 
conducted.  Study personnel will administer study drug to subjects within 5 minutes before 
their scheduled bedtime, which will be at the same MHB as used for the second screening 
visit.  Subjects will then undergo an 8-hour PSG.  The next morning, subjects will undergo 
assessments including the CDR posture and PAB assessments and will complete the Sleep 
Diary.  At 1.5 hours after waketime, subjects will rate their morning sleepiness level.  The 
PSG recording will be reviewed for continued eligibility and subjects may then leave the 
clinic only after the investigator determines that is safe for them to do so.  (revised per 
Amendment 02)
Subjects will return to the clinic that evening. Study personnel will administer study drug to
subjects within 5 minutes before the scheduled bedtime.  A PSG will be recorded overnight.  
The following morning subjects will undergo postural stability and PAB assessments and 
will complete the Sleep Diary.  At 1.5 hours after waketime, subjects will rate their morning 
sleepiness level.  The PSG recording will be reviewed for continued eligibility, and both 
PSGs during the Run-in Period will also serve as the baseline for PSG-derived endpoints for 
subjects who are randomized.  Subjects may then leave the clinic only after the investigator 
determines that is safe for them to do so. 
Subjects will continue to take study drug at home within 5 minutes before bedtime and they 
will continue to complete the Sleep Diary each morning within 1 hour after morning 
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each night maintain a regular bedtime throughout the study, and follow study restrictions 
with regard to timing of meals and use of caffeine and alcohol.
9.1.1.3
Baseline Period
After a minimum of 2 nights following the baseline PSGs, the Run-in Period will end and the 
Baseline Period will take place.  On Day 1 subjects will be admitted to the clinic and the ISI, 
FSS, and EQ-5D-3L will be administered.  Blood and urine samples will be collected for 
routine safety assessments, ECG will be performed, and vital signs and weight will be 
assessed.  The electronic Columbia-Suicide Severity Rating Scale (C-SSRS) will be 
administered.  Subjects who complete the Baseline Period and continue to meet the eligibility 
criteria will be randomized and will begin the Treatment Period.  (revised per 
Amendment 02)
9.1.2
Randomization Phase
9.1.2.1
Treatment Period
The Treatment Period will begin on Day 1, and will continue until Day 31.  Subjects will be 
randomized in a double-blind manner, to receive LEM5, LEM10, ZOL, or PBO.  (revised per 
Amendment 02)
Within 5 minutes before the subject’s MHB, study drug will be administered and an 
overnight PSG will be initiated.  At completion of the PSG recording the following morning 
(Day 2), postural stability will be assessed and the PAB will be conducted immediately 
thereafter.  Subjects will complete the Sleep Diary.  At 1.5 hours after waketime, subjects 
will rate their morning sleepiness level.  (revised per Amendment 01)  They may then leave 
the clinic after the investigator determines that is safe for them to do so.
On the evening of Day 2, subjects will return to the clinic.  A PK blood sample will be 
collected predose and study drug will be administered within 5 minutes before the subject’s 
MHB, followed by an overnight PSG.  The next morning (Day 3), the CDR posture and PAB 
assessments will be conducted and a PK blood sample will be obtained.  
Subjects will complete the Sleep Diary.  The electronic Columbia-Suicide Severity Rating 
Scale (eC-SSRS) will be administered. At 1.5 hours after waketime, subjects will rate their 
morning sleepiness level.  Subjects may then leave the clinic after the investigator determines 
that is safe for them to do so.  Study drug will be dispensed, and subjects will be provided 
with instructions to continue to complete the Sleep Diary each morning within 1 hour of 
waketime and to take study drug daily at home according to the same schedule and with the 
same instructions as during the Run-in Period.
On Day 29, subjects will return to the clinic.  Study drug will be administered within 
5 minutes before the subject’s MHB, followed immediately by a PSG.  On the morning of 
Day 30, postural stability will be assessed and the PAB will be conducted.  At 1.5 hours after 
waketime, subjects will rate their morning sleepiness level. Subjects may leave the clinic 
after the investigator determines that is safe for them to do so.  


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On the evening of Day 30, subjects will return to the clinic.  A PK blood sample will be 
collected predose and study drug will be administered within 5 minutes before the subject’s 
MHB, followed by a PSG.  On the morning of Day 31, postural stability and PAB 
assessments will be conducted and a PK sample will be obtained.  Then the ISI, FSS, EQ-
5D-3L and PGI-Insomnia will be administered.  Blood and urine samples will be collected 
for routine safety assessment. An ECG will be performed, and vital signs and weight will be 
assessed.  The eC-SSRS will be administered.  At 1.5 hours after waketime, subjects will rate 
their morning sleepiness level.  Then, after the investigator determines that it is safe for them 
to do so, subjects will be discharged from the clinic.  
9.1.2.2
Follow-up Period
The Follow-up Period will begin when the subjects leave the clinic at the end of the 
Treatment Period.  Subjects will cease to take study drug but will continue to complete the 
Sleep Diary each morning until the EOS Visit.
At least 14 days but no more than 18 days after completion of the Treatment Period, subjects 
will return to the clinic for the EOS Visit.  The Tyrer Benzodiazepine Withdrawal Symptom 
Questionnaire (T-BWSQ) and eC-SSRS will be administered, and routine safety assessments 
will be conducted.
A subject who prematurely discontinues taking study drug should return to the clinic as soon 
as practicable after discontinuing study drug, to complete an Early Termination (ET) Visit.  If 
the subject discontinues from the study due to an AE, the subject must complete an ET Visit 
and the AE must be followed to resolution or for 2 weeks, whichever comes first.  In 
addition, subjects who withdraw due to an AE should undergo a urine drug test.
9.2
Discussion of Study Design, Including Choice of Control Groups
9.2.1
Randomization
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
9.2.2
Run-In 
Insomnia trials are associated with large placebo effects.  This study will include a placebo 
Run-in Period to exclude subjects who show a response to placebo. 
(revised per 
Amendment 03)
The Run-in Period will also help to identify and exclude subjects who are not compliant with 
the Sleep Diary instructions, duration of time spent in bed, or restrictions on alcohol use.  In 
this regard, it is necessary for the subjects to be taking PBO and to obtain Sleep Diary data 
for a minimum of 1 week to adequately evaluate whether there is a PBO response and 


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compliance with the alcohol-related study restrictions.  After this minimum 7 nights of 
treatment, eligible subjects will have PSG recordings on 2 consecutive nights.  These 
recordings will be used to further screen for eligibility, and will serve as baseline values for 
those subjects who continue to randomization.
9.2.3
Efficacy Assessments
The study uses objective (PSG) as well as subjective (Sleep Diary) assessments of efficacy.  
Both assessments have been widely used in registration trials evaluating treatments for 
insomnia disorder.  While PSG indicates that a measurable physiological effect of the study 
drug has occurred, Sleep Diary outcomes indicate the magnitude of the effect for the patient.  
(revised per Amendment 03)
Another focus of this study is on WASO2H, a measure of sleep maintenance in the second 
half of the night.  The rationale for the selection of this endpoint is based on the loss of effect 
of ZOL on sleep maintenance at the end of the sleep period.  However, any benefit on 
WASO2H observed with lemborexant must not be due to a worsening of sleep latency or 
continuity at the beginning of the night.  Therefore, analyses of both LPS and total WASO as 
well as other PSG variables (eg, total sleep time [TST], number and duration of awakenings) 
will be conducted to confirm the efficacy of lemborexant on sleep onset and sleep 
maintenance.  (revised per Amendment 03)
9.2.4
Morning Residual Effects on Postural Stability and Cognitive Performance 
Non-benzodiazepine sleep-inducing agents such as zolpidem have been associated with 
motor and cognitive impairment, and laboratory studies have evaluated these impairments 
both during the middle of the night several hours postdose, and in the morning hours shortly 
after awakening.  Of clinical importance is that the elderly are particularly sensitive to effects 
of zolpidem on postural stability, which is especially problematic given the increased risk of 
falls in the elderly.  
Moderate to large treatment effects versus placebo on measures of postural stability and 
cognitive performance have been reported for both 5 mg and 10 mg doses of the IR 
formulation of zolpidem (Allain, et al., 2003, Mets, et al., 2010, and Boyle, et al., 2009; 
reviewed in Stranks and Crowe, 2014).  Larger impairments are observed near the Cmax of the 
zolpidem IR formulation at approximately 1.5 hours postdose than at later timepoints relative 
to dosing, but there remains a moderate impairing effect of zolpidem even the next morning 
on certain cognitive domains including attention and memory (Stranks and Crowe, 2014).  
With regard to postural stability as measured in this study, zolpidem is assumed to have the 
same effect on body sway as alcohol at 4.5 hours after dosing (Wesnes, et al., 2000).  
Further, there is consistent evidence that the effects on postural stability of hypnotic drugs 
are larger after the first one or two nights of dosing and dissipate thereafter, which has been 
explained as due to behavioral tolerance (Mets, et al., 2010).
For this reason, the key 
secondary objective for the current study is to compare the effects of lemborexant to those of 
zolpidem on postural stability at the beginning of treatment, in the morning shortly after 
waketime on Day 2 and Day 3.  Whether there are differential effects of lemborexant and 


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zolpidem on postural stability at the end of treatment (Day 30 and Day 31) will be explored.  
Effects on cognitive performance in the morning shortly after waketime will be exploratory 
for both the beginning and end of treatment.
9.2.5
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, atypical migraine, loss of 
consciousness, decreased consciousness, myoclonus, syncope, transient global amnesia, 
lipothymia 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 about events of cataplexy or potential cataplexy events, using a questionnaire for 
events potential related to cataplexy and the SAE form for any of the above events 
considered serious. (revised per Amendment 02)
9.2.6
Study Duration
The registration trials for zolpidem were 3 weeks in duration, with analyses of PSG efficacy 
data conducted after the first 2 doses and at the end of 2 weeks of active treatment.  As noted, 
treatment benefit of zolpidem declined over time such that WASO2H, particularly in the last 
2 hours of the night, was not different from placebo on Nights 15/16 in the zolpidem 
registration trials.  In contrast, when lemborexant was studied for 15 nights of treatment in 
Study 201, the treatment benefit was maintained such that there was no significant difference 
in LPS, WASO, or WASO2H between the first 2 and last 2 nights of treatment.  Study 304 
includes 30 days of active treatment.  Based on the results of Study 201, it is expected that 
there will not be a loss of efficacy of lemborexant between 2 weeks and 4 weeks of 
treatment. 
Moreover, as the beneficial effects of zolpidem on WASO2H did not persist for 2 weeks, it is 
not expected that there will be statistically or clinically significant effects of ZOL at the end 
of the 30 days of treatment.
9.2.7
Age Group
While the lower age is not the typical 65 years defining “elderly,” it is physiologically 
meaningful, as insomnia incidence increases at middle age in both men and women, with a 
particularly steep increase in incidence in women at menopause.   In addition, the 
homeostatic and circadian regulation of sleep are disturbed in many older individuals, which 
manifests most frequently as sleep maintenance insomnia in the second half of the night, and 
early morning awakening.  The preponderance of sleep maintenance issues in the second half 
of the sleep period is clear from the literature as well as supported by analyses of data by age 
group from Study 201.  (revised per Amendment 03)


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When Study 201 data were analyzed separately for those aged 55 years and older, the 
apparent treatment effect of lemborexant versus placebo on WASO2H, as well as on WASO, 
was larger than for the full sample (all ages studied), suggesting that older individuals may be 
most likely to benefit from a treatment that reduced difficulties with both sleep onset and 
sleep maintenance.  Table 1 shows the least square (LS) mean treatment difference between 
lemborexant and PBO for various dose groups and dose group combinations from Study 201 
for the full sample and for those aged 55 and older.  Caution must be exercised concerning 
the predictive ability of these data, however, since the observed variability in WASO2H was 
larger in the older subjects.  For this reason, a conservative estimate of the expected 
treatment difference between lemborexant and PBO for WASO2H at the end of treatment 
was used for power analyses and sample size justification.  Enrollment in this study is 
exclusively older subjects, aged 55 years and older.  (revised per Amendment 03)
Table 1
Treatment Effect for Lemborexant versus Placebo (Study 201)
Treatment Effect in Minutes (95% CI)
5 mg
10 mg
5 and 10 mg 
combined
Entire Subject Sample
-7.97
(-19.2, 3.23)
-11.8
(-23.6, -0.05)
-10.0
(-20.6, 0.55)
Aged 55 and Older
-23.9
(-43.8, -3.95)
-14.8
(-36.9, 7.36)
-20.2
(-40.1, -0.35)
CI = confidence interval
9.2.8
Time of Dosing
The time of dosing of study drug will be within 5 minutes before bedtime on nights in the clinic.  
On nights at home, subjects will be instructed to take study drug just before they intend to try to 
fall asleep, but as consistently as possible with respect to the time across the study.  
9.2.9
Interim Analysis
An interim analysis is planned to be conducted after 50% of the subjects (approximately 
475 subjects) have been randomized and have either completed Day 31 assessments or 
discontinued from the study.  The purpose of this analysis is to determine the conditional
probability that a statistically significant difference between LEM10 and ZOL on WASO2H
will emerge at the end of treatment.  This interim analysis will be conducted by an 
independent statistician external to the Sponsor.  The role of the independent statistician and 
procedures undertaken to preclude potential bias will be detailed in the statistical analysis 
plan (SAP) and in the Charter.


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9.3
Selection of Study Population
Approximately 2800 subjects will be screened and approximately 950 subjects will be 
randomized at approximately 105 sites in North America and Europe.  Subjects who do not 
meet all of the inclusion criteria or who meet any of the exclusion criteria will not be eligible 
to receive study drug.  A table providing guidelines on the order in which criteria should be 
assessed and at what visits can be found in Appendix 2. (revised per Amendment 02)
9.3.1
Inclusion Criteria
1. Male age 65 years or older or female, age 55 years or older at the time of informed 
consent
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
criteria for Insomnia Disorder, as follows:
o
Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying 
asleep and/or awakening earlier in the morning than desired despite adequate 
opportunity for sleep (Note that if the complaint is limited to difficulty initiating 
sleep, the subject is not eligible)
o
Frequency of complaint ≥ 3 times per week
o
Duration of complaint ≥ 3 months
o
Associated with complaint of daytime impairment
3. At Screening:  History of subjective WASO (sWASO) typically ≥ 60 minutes on at 
least 3 nights per week in the previous 4 weeks
4. At Screening:  Reports regular time spent in bed, either sleeping or trying to sleep, 
between 7 and 9 hours 
5. At Screening:  Reports habitual bedtime, defined as the time the subject attempts to 
sleep, between 21:00 and 24:00 and habitual waketime between 05:00 and 09:00 
6. At Screening and at check-in before the first PSG during the Run-in Period:  
ISI score ≥13 (revised per Amendment 02)
7. Confirmation of current insomnia symptoms as determined from responses on the 
Sleep Diary on the 7 most recent mornings (minimum 5 of 7 for eligibility) before the 
second screening visit, such that sWASO ≥60 minutes on at least 3 of the 7 nights
8. Confirmation of regular bedtime and waketime as determined from responses on the 
Sleep Diary on the 7 most recent mornings before the second screening visit, such 
that neither bedtime, (defined as the time the subject attempts to try to sleep), nor 
waketime (defined as the time the subject gets out of bed for the day) deviates more 
than 1 hour on more than 2 nights from the calculated MHB or median habitual 
waketime, respectively, from the Screening Sleep Diary entries
9. Confirmation of sufficient duration of time spent in bed, as determined from 
responses on the Sleep Diary on the 7 most recent mornings before the second 


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screening visit, such that there is not more than 2 nights with time spent in bed 
duration < 7 hours or > 10 hours (revised per Amendment 02)
10. During the Run-in Period:  Reconfirmation of insomnia symptoms, as determined 
from responses on the Sleep Diary on the 7 most recent mornings before the first PSG 
during the Run-in Period, such that sWASO ≥60 minutes on at least 3 of the 7 nights 
11. During the Run-in Period:  Reconfirmation of regular bedtimes and waketimes as 
defined in Inclusion Criterion 8
12. During the Run-in Period:  Reconfirmation of sufficient duration of time spent in bed 
as defined in Inclusion Criterion 9 (revised per Amendment 02)
13. During the Run-in Period:  Objective (PSG) evidence of insomnia as follows:  
WASO average ≥ 60 minutes on the 2 consecutive PSGs, with neither 
night < 45 minutes (revised per Amendment 02)
14. Willing and able to comply with all aspects of the protocol, including staying in bed 
for at least 7 hours each night
15. Willing not to start a behavioral or other treatment program for the treatment of 
insomnia during the subject’s participation in the study
9.3.2
Exclusion Criteria
1. A current diagnosis of sleep-related breathing disorder (including obstructive sleep 
apnea with or without continuous positive airway pressure [CPAP] treatment),
periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep 
disorder, or narcolepsy, or an exclusionary score on screening instruments to rule out 
individuals with symptoms of certain sleep disorders other than insomnia as follows:
(revised per Amendment 01)
a.
STOPBang score ≥5  
b.
International Restless Legs Scale score ≥16
c.
Epworth Sleepiness Scale score >15 (Scores of 11-15 require excessive daytime 
sleepiness to be recorded in subject's Medical History) (revised per 
Amendments 01 and 02)
2. Reports symptoms potentially related to narcolepsy that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence 
of narcolepsy  (revised per Amendment 01)
3. On the MUPS, endorsed the item that corresponds to a history of sleep-eating or 
reports a history of sleep-related violent behavior, sleep-driving or symptoms of 
another parasomnia that in the investigator's opinion make the subject unsuitable for 
the study (revised per Amendment 02)
4. Apnea-Hypopnea Index > 15 or Periodic Limb Movement with Arousal Index > 15 as 
measured on the PSG at the second screening visit
5. Beck Depression Inventory – II (BDI-II) score  >19 at Screening


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6. Beck Anxiety Inventory (BAI) score >15 at Screening
7. Habitually naps during the day more than 3 times per week
8. Is a female of childbearing potential
Note: All females will be considered to be of childbearing potential unless they are 
postmenopausal (defined as amenorrheic for at least 12 consecutive months, are in the 
appropriate age group, and are postmenopausal without other known or suspected 
cause), or have been sterilized surgically (ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing).
9. Excessive caffeine use that in the opinion of the investigator contributes to the 
subject’s insomnia, or habitually consumes caffeine-containing beverages after 18:00
and is unwilling to forego caffeine after 18:00 for the duration of his/her participation 
in the study
10. History of drug or alcohol dependency or abuse within approximately the previous 
2 years
11. Reports habitually consuming more than 14 drinks containing alcohol per week 
(females) or more than 21 drinks containing alcohol per week (males), or habitually 
consumes alcohol within the 3 hours before bedtime and unwilling to limit alcohol 
intake to no more than 2 drinks per day or forego having alcohol within the 3 hours 
before bedtime for the duration of his/her participation in the study
12. Known to be positive for human immunodeficiency virus
13. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
14. A prolonged QT/QTcF interval (QTcF > 450 ms) as demonstrated by a repeated ECG 
at Screening (repeated only if initial ECG indicates a QTcF interval >450 ms) 
15. Current evidence of clinically significant disease (eg, cardiac; respiratory including
chronic obstructive pulmonary disease, acute and/or severe respiratory depression; 
gastrointestinal including severe hepatic impairment; renal including severe renal 
impairment;
neurological including
myasthenia gravis; psychiatric disease;
malignancy within the past 5 years other than adequately treated basal cell carcinoma)
or chronic pain that in the opinion of the investigator(s) could affect the subject’s 
safety or interfere with the study assessments, including the ability to perform tasks 
on the cognitive PAB. Subjects for whom a sedating drug would be contraindicated 
for safety reasons because of the subject’s occupation or activities are also excluded.  
(revised per Amendment 01)
16. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom 
during the night
17. Any history of a medical or psychiatric condition that in the opinion of the 
investigator(s) could affect the subject’s safety or interfere with the study 
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18. Any suicidal ideation with intent with or without a plan, at the time of or within 
6 months before the eC-SSRS administration during the Prerandomization Phase (ie, 
answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the eC-SSRS)
19. Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the 
eC-SSRS) (revised per Amendment 02)
20. Scheduled for surgery during the study
21. Used any prohibited prescription or over-the-counter concomitant medications within 
1 week or 5 half-lives, whichever is longer, before the first dose of study medication 
(Run-in Period). (revised per Amendment 01) (A list of prohibited concomitant 
medications is presented in Appendix 3)
22. Used any modality of treatment for insomnia, including cognitive behavioral therapy 
or marijuana within 1 week or 5 half-lives, whichever is longer, before the first dose 
of study medication (Run-in Period) (revised per Amendment 01)
23. Failed treatment with suvorexant (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 in the 2 weeks before Screening, 
or between Screening and Baseline, or plans to travel across more than 3 time zones 
during the study
25. A positive drug test at Screening, Run-In, or Baseline, or unwilling to refrain from 
use of recreational drugs during the study
26. Hypersensitivity to the study drugs (lemborexant or zolpidem) or to their excipients 
27. Currently enrolled in another clinical trial or used any investigational drug or device 
within 30 days or 5× the half-life, whichever is longer preceding informed consent
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.
A subject who discontinues study treatment should return for an ET Visit as soon as possible.  
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected on the Subject Disposition electronic 
case report form (eCRF).  In addition, the date of last dose of study drug(s) will be recorded.  


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9.4
Treatment(s)
9.4.1
Treatment(s) Administered
Test drug
Lemborexant 5 mg, lemborexant 10 mg or lemborexant-matched placebo will be taken orally 
in tablet form at home each night for 30 consecutive nights, immediately before the time the 
subject intends to try to sleep.
Comparator drug
Zolpidem tartrate extended release 6.25 mg (Ambien CR®) or zolpidem-matched placebo 
will be taken orally in tablet form at home each night for 30 consecutive nights, immediately 
before the time the subject intends to try to sleep.  The full Prescribing Information for 
Ambien CR will be provided to sites.  (revised per Amendments 01 and 02)  
Run-in Period
All subjects will receive 1 lemborexant-matched placebo tablet and 1 zolpidem-matched 
placebo tablet in a single-blind manner during the Run-in Period.
Treatment Period
During the Treatment Period, all subjects will receive 2 tablets as described below according 
to the treatment arm to which the subject has been randomized:

LEM5:  1 zolpidem-matched placebo tablet and 1 lemborexant 5 mg tablet

LEM10:  1 zolpidem-matched placebo tablet and 1 lemborexant 10 mg tablet

ZOL:  1 zolpidem 6.25 mg tablet and 1 lemborexant-matched placebo tablet

PBO:  1 zolpidem-matched placebo tablet and 1 lemborexant-matched placebo tablet  
9.4.2
Identity of Investigational Product(s)
The sponsor will provide lemborexant tablets in strengths of 5 mg, 10 mg and lemborexant-
matched placebo, identical in appearance.  The comparator, zolpidem, will be obtained from 
commercial sources as zolpidem tartrate extended release 6.25 mg (Ambien CR 6.25) tablets, 
and the sponsor will provide placebo tablets identical in appearance to the zolpidem tablets.  
Tablets will be packaged in child-resistant blister cards in a double-blind manner. 
Each subject will be dispensed a single card at the beginning of the Run-in Period and on 
Day 3. The subject will take 2 tablets a day; a single lemborexant or lemborexant-matched
placebo tablet and a single zolpidem or zolpidem-matched placebo tablet.  The placebo run-
in card will contain a 17-day supply of lemborexant-matched placebo and zolpidem-matched
placebo tablets per day.  Each card for the Treatment Period will contain a 35-day supply of 


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tablets of either lemborexant or lemborexant-matched placebo and either zolpidem or 
zolpidem-matched placebo depending on the dose, in double-blind, double-dummy fashion.
9.4.2.1
Chemical Name, Structural Formula of E2006/Lemborexant

Test drug code:  E2006

Generic name:  lemborexant

Chemical name:  (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-
(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
9.4.2.2
Comparator Drug
Zolpidem tartrate extended release 6.25 mg (Ambien CR 6.25)
Placebos to match lemborexant or zolpidem tartrate extended release 6.25 mg
9.4.2.3
Labeling for Study Drug
Lemborexant and zolpidem will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.
The following information has to be provided:

For clinical trial 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 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.


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9.4.3
Method of Assigning Subjects to Treatment Groups
At Baseline, subjects will be randomized, in a double-blind manner, to receive LEM5, 
LEM10, ZOL, or PBO in a 5:5:5:4 ratio. Randomization will be stratified by country and by 
age group (55 to 64 years; 65 years or older).  Randomization to study treatments will be 
based on a computer-generated randomization scheme that will be reviewed and approved by 
an independent statistician.  The randomization scheme and identification for each subject 
will be included in the final clinical study report for this study.
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized blister card 
identification numbers.  At enrollment (and after successful completion of study procedures 
the morning of Day 1), the investigator or designee will call the IxRS to register the subject 
information.  At Randomization (morning of Day 1), the IxRS will assign each subject a 
unique 6-digit randomization number.
9.4.4
Selection of Doses in the Study
In Study 201, all doses studied met the first primary objective of balancing significant efficacy 
as measured by change from baseline in SE with sufficient safety measured by subjective 
sleepiness reported on the KSS.  The second primary objective was also achieved, as there 
were no significant increases in the KSS at 1 hour after waketime at the end of treatment.  
However, there were dose-related increases in the KSS at both the beginning and end of 
treatment, and the rate of AEs of somnolence also increased with increasing dose level.  
In Study 201, lemborexant 5 mg and 10 mg showed significant efficacy measured by SE, as 
well as decreases in sleep onset latency.  These effects were maintained across the 15-day 
Treatment Period.  For sleep maintenance, lemborexant 10 mg showed significant decreases, 
and while the magnitude of decreases in WASO was less for 5 mg, there was a significant 
proportion of subjects whose WASO decreased substantially, providing evidence for clinical 
benefit of 5 mg on sleep maintenance as well.  
Because of the observed dose-related increases in subjective sleepiness and AEs of somnolence 
in Study 201, Study 107 was conducted to obtain additional information about the risk of 
clinically meaningful morning residual sleepiness.  The study assessed average sleep onset 
latency on the M-MSLT after a single dose of LEM5 or LEM10 versus PBO.  The results 
indicated that the pre-specified threshold for a clinically meaningful decrease in average sleep 
onset latency was not met by either the 5 mg or 10 mg dose level of lemborexant, supporting 
their use in the Phase 3 clinical trials.  Taken together with the efficacy and safety results for 
lemborexant 5 mg and 10 mg in the Phase 2 study, these dose levels were selected for the 
current study.
Regarding ZOL, the FDA-approved doses of Ambien CR are 6.25 mg (recommended dose 
for women and elderly patients) and 12.5 mg (highest recommended dose for non-elderly 
patients). In the present study, only the 6.25 mg dose of ZOL will be administered.  Of note 
is that a maximum of 40% of the study sample will be in the age range of 55 to 64 years old, 
and stratification by age will be implemented to ensure that approximately 60% will be


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65 years or older.  All of the subjects in the 55 to 64 years age group will be females. (revised 
per Amendment 03)
9.4.5
Selection and Timing of Dose for Each Subject
Throughout the Run-in Period and the Treatment Period, study drug will be taken 
immediately before the subject intends to sleep.  When the subject is to sleep in the clinic for 
PSG, study personnel will administer study drug.  On other nights, the subject will take study 
drug at home on as consistently a time schedule as possible. Subjects should not eat a meal 
within 3 hours before taking the study drug. 
9.4.6
Blinding
During the Run-in Period of the Prerandomization Phase, single blinding will be in effect 
such that the subject will be blinded to study treatment but study personnel will not be 
blinded.  During the Randomization Phase, subjects and all personnel involved with the 
conduct and interpretation of the study, including investigators, site personnel, and sponsor 
staff will be blinded to the treatment codes.  Randomization data will be kept strictly 
confidential, filed securely by an appropriate group with the sponsor or CRO and accessible 
only to authorized persons (eg, Eisai Global Safety) until the time of unblinding, per standard 
operating procedure.
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.
Disclosure of information from the interim analysis (Section 9.7.3) will be limited as detailed 
in the Interim Analysis charter. No individuals involved with the conduct of the study will 
have access to this information. 
9.4.7
Prior and Concomitant Therapy
9.4.7.1
Drug-Drug Interactions
Not applicable
9.4.7.2
Prohibited Concomitant Therapies and Drugs
Caffeine will be permitted in limited quantities during the study.  Subjects will be advised to 
limit caffeine consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg caffeine 
per day.  They will be instructed to avoid caffeine after 13:00 on days when they are 
scheduled for a PSG recording and after 18:00 on all other days during the study.  


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Alcohol will be permitted in limited quantities during the study.  Subjects may consume a 
maximum of 2 alcoholic drinks on any day during the study, and will be advised not to 
consume any alcohol within 3 hours before bedtime. They must not consume alcohol on any 
days when they are scheduled for a PSG recording.  Compliance with these restrictions will 
be monitored via questions on the Sleep Diary.  If subjects cannot comply after an infraction 
and counseling, they may be discharged from the study.
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A 
inducers.  Prohibited therapies also include any treatment for insomnia disorder, including 
any drugs or non-pharmacological treatment such as cognitive behavioral therapy; 
medications that are used for the purpose of inducing sleep (hypnotics) or inducing 
wakefulness (stimulants; except caffeine; see above) and medications that have known 
sedating effects or alerting effects. This prohibition applies even if the entire class to which 
that medication belongs is not prohibited (eg, anticonvulsants).  
A subject must discontinue any prohibited medication (Appendix 3) at least 1 week (or at 
least 5 half-lives, whichever is longer) before starting the Sleep Diary, ie, at least 2 weeks 
before the start of the Run-In Period.  
Prohibited therapies include treatments for insomnia disorder (drugs or non-pharmacological 
treatment such as cognitive behavioral therapy) and any medication which, in the opinion of 
the investigator, causes or exacerbates the subject’s insomnia.  (revised per Amendment 01)
If a medication is not on the list of prohibited medications but in the opinion of the 
investigator causes or exacerbates the subject’s insomnia, it must not be used throughout the 
study.  If a medication is not specified as prohibited but is in the same class as a medication 
that is listed in Appendix 3, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that strong CYP3A inhibitors will not be permitted at any 
time for any duration of use during the study.  (revised per Amendment 01)
Any medication (including over-the-counter medications) or therapy administered to the 
subject within the last 3 months before Screening (ie, Prior Medications) or during the study,
starting on the date of informed consent, will be recorded on the Prior and Concomitant 
Medication eCRF or Non-Pharmacological Procedures eCRF.  The investigator will record 
on the Adverse Event eCRF any AE for which the concomitant medication/therapy was 
administered.  If the concomitant medication/therapy is being administered for a medical 
condition present at the time of entry into the study, the investigator will record the medical 
condition on the Medical History and Current Medical Conditions eCRF.
9.4.8
Treatment Compliance
Compliance will be assessed for each study drug by examination of blister packs returned to 
the investigator at the end of the Run-in and Treatment Periods.  


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All subjects 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 
to be effective. Compliance will be monitored closely and determined at specific visits by 
tablet count. Tablets will be counted separately for tablets that are matched to lemborexant 
and tablets that are matched to zolpidem. 
When subjects arrive for the first screening/baseline PSG during the Run-in Period, and the 
treatment compliance check indicates that a subject has missed any doses, the subject will be 
counseled by site personnel. If the subject has missed more than 1 dose, and given that the 
subject continues to meet eligibility criteria, the investigator must consult with the sponsor 
prior to the subject being randomized and come to a collaborative decision on whether the 
subject should continue in the study.  When subjects arrive for Baseline, and the treatment 
compliance check indicates that a subject has missed any doses, the investigator must use 
clinical judgment to decide if the subject should continue in the study.
Records of treatment compliance for each subject will be kept during the study. Clinical 
research associates 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 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 Form FDA 1572

Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572

A signed and dated curriculum vita of the PI including a copy of the PI’s current medical 
license or medical registration number on the curriculum vitae

A signed and dated clinical studies agreement

A copy of the regulatory authority approval for the country in which the study is being 
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The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.
The site must maintain an accurate and timely record of the following receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs/ that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor.  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, Sleep Diary 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 (where allowed). In applicable 
countries, to protect personal data, only the year of birth will be collected, and the month and 


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date of each subject’s date of birth will be masked where necessary as January 1.  (revised 
per Amendment 01)
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Sleep, medical, and psychiatric history and current medical conditions will be recorded at the 
Screening Visit.  All sleep, medical, and psychiatric history within 5 years must be noted in 
the Medical History and Current Medical Conditions eCRF.  If a subject has a score of 11-15 
on the ESS at Screening, then the presence of excessive daytime sleepiness must be recorded 
in the subject's Medical History.  Note that the presence of excessive daytime sleepiness in a 
subject's Medical History, combined with the definition of Adverse Event as specified in 
Section 9.5.1.5.3 means that only a worsening in daytime sleepiness during the study should
be reported as an Adverse Event.  (revised per Amendment 02)
Physical examinations (full or brief) will be performed as described in Section 9.5.1.5.7.
9.5.1.2.2
SLEEP DISORDERS HISTORY AND SCREENING BATTERY 
The SDSB will be administered only at the Screening Visit, and will include the:

StopBANG:  a list of eight questions to be answered Yes or No, which screens potential 
subjects for obstructive sleep apnea  (Chung et al., 2008)

IRLS:  a subjective scale comprising ten questions, which measures disease of symptoms 
of restless legs syndrome (Abetz et al., 2006)

ESS:  a questionnaire that asks subjects to rate their probability of falling asleep, on a 
scale of increasing probability from 0 to 3 for eight different situations that most people 
engage in during their daily lives, which assesses the severity of daytime sleepiness
(Johns, 1992)

MUPS:  a scale comprising 21 questions asking whether the subject has experienced 
phenomena related to International Classification of Sleep Disorders Version 2 classified 
parasomnias (eg, enuresis, sleepwalking, sleep paralysis) along with a time frame for 
occurrences of these experiences ranging from within past month to lifetime and 
frequency within the time frame ranging from occasionally to almost every night (Fulda 
et al., 2008).  An adapted version will be used.  (revised per Amendment 01)
9.5.1.2.3
BECK DEPRESSION INVENTORY - II
The BDI-II is a 21-question multiple-choice self-report questionnaire that subjects will use to 
rate the presence, frequency, and severity of symptoms of depression using a 4-point Likert 
scale (Beck, et al., 1961).  Scores on the BDI-II may range from 0 to 63, with higher scores 
indicating higher levels of depressive symptoms.  Subjects with BDI-II scores greater than 19 
will be excluded from participation.


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9.5.1.2.4
BECK ANXIETY INVENTORY
The BAI is a 21-question multiple-choice self-report inventory that subjects will use to rate 
the presence, frequency, and severity of symptoms of anxiety using a 4-point Likert scale
(Beck, et al., 1988).  Scores on the BAI may range from 0 to 63, with higher scores 
indicating higher levels of anxiety symptoms.  Subjects with scores on the BAI greater than 
15 will be excluded from participation. 
9.5.1.3
Efficacy Assessments
9.5.1.3.1
POLYSOMNOGRAPHY
Each PSG recording will include an electrode montage with electroencephalography (EEG), 
electromyography (EMG), electrooculography, and ECG channels, for scoring of sleep 
parameters and sleep architecture via standard sleep scoring criteria.  In addition, the 
screening PSG will include channels for assessment of symptoms of sleep apnea and periodic 
limb movement disorder.
Trained PSG scorers will score PSG records in 30-second epochs according to standard 
criteria.  The PSG at the second screening visit will be used only to calculate the Apnea-
Hypopnea Index and the Periodic Limb Movements with Arousal Index for evaluation of 
eligibility criteria; sleep parameters and sleep architecture will not be evaluated from this 
PSG.  The 2 PSGs obtained during the Run-in Period will be used to a) determine eligibility 
and b) derive baseline PSG parameters for those subjects who are randomized.
All PSG parameters will be obtained separately for each PSG recording and averaged across 
the pairs of consecutive PSG nights.
The following parameters will be derived from all PSGs:

LPS:  minutes from lights off to the first epoch of 20 consecutive epochs of non-
wakefulness

SE:  proportion of time spent asleep per TIB, calculated as TST/interval from “lights off” 
until “lights on”

WASO:  minutes of wake from the onset of persistent sleep until lights on 

WASO2H:  minutes of wake during the interval from 240 minutes after lights off until 
lights on

TST:  minutes of sleep from sleep onset until terminal awakening 

Mean duration of long awakenings (DurLongAw):  average duration of all long 
awakenings (with long awakening defined as 10 or more consecutive epochs [ie, 
5 minutes or longer] scored as wake or N1, initiated with at least 1 epoch of wake, after 
onset of persistent sleep, and including any terminal awakening
Additional sleep architecture parameters will also be calculated from each PSG, including:


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
Sleep onset latency: minutes from lights off to the first epoch of any stage of sleep (N1, 
N2, N3, REM)  (revised per Amendment 01)

Number of awakenings after persistent sleep, with an awakening defined as at least 
2 consecutive epochs of wakefulness; an awakening cannot be interrupted by stage N1, 
but must be interrupted by stage N2, N3, or REM

Number of long awakenings

WASO1H (wake after sleep onset in the first half of the night): minutes of wake during 
the interval from onset of persistent sleep until 240 minutes after lights off (revised per 
Amendment 03)

Percentage of sleep stages per TIB: wake, non-REM (NREM) sleep (stages N1, N2, N3 
separately and combined), REM sleep 

Minutes of sleep stages per TIB: wake, NREM sleep (stages N1, N2, N3), REM sleep 

Percentage of sleep stages per TST: wake, NREM sleep (stages N1, N2, N3 separately 
and combined), REM sleep 

Minutes of sleep stages per TST: wake, NREM sleep (stages N1, N2, N3), REM sleep

REM episode frequency and duration

Mean REM/NREM cycle duration

REM latency: minutes from first epoch of sleep (N1, N2, or N3) to first epoch of REM  
(revised per Amendment 01)
Each of these PSG-derived variables, with the exceptions of SE, REM episode frequency and 
duration, mean REM/NREM cycle duration, and REM latency, will also be calculated by 
hour and by half of the 8-hour time interval in bed.  
9.5.1.3.2
ELECTRONIC SLEEP DIARY
The Sleep Diary will be completed within an hour of morning waketime on each morning of 
the study from Screening through the end of the Follow-Up Period.  Sleep Diary entries may 
be maintained in paper format as a backup to the electronic Sleep Diary, if necessary.  This 
diary will yield several self-reported measures of sleep that will be used to determine 
eligibility, as well as to assess efficacy and safety.  (revised per Amendment 02)
Subjects must comply with requirements for completion of the Sleep Diary.  Failure to 
comply will require discussion with the Medical Monitor and may result in discontinuation 
of the subject from the study.
Sleep Parameters

Subjective Sleep Onset Latency (sSOL): estimated minutes from the time that the subject 
attempts attempting to sleep until sleep onset 

Subjective Wake After Sleep Onset (sWASO):  sum of estimated minutes of wake during 
the night after initial sleep onset until the time the subject stops trying to sleep for the 
night


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
Subjective Total Sleep Time (sTST): derived minutes of sleep from sleep onset until the 
time the subject stops trying to sleep for the night

Subjective Sleep Efficiency (sSE):  proportion of sTST per subjective time spent in bed, 
calculated as the interval from the time that subject reports attempting to sleep until the 
time the subject stops trying to sleep for the night, and time spent asleep derived from 
subjective time spent in bed minus sWASO
Quality of Sleep
The Sleep Diary will also include items assessing sleep quality and morning 
sleepiness/alertness.
The Sleep Diary will also be used to assess the subject’s perception of the quality of sleep on 
the previous night with the following question:  “How would you rate the quality of your 
sleep last night?” Subjects will rate the quality of their sleep on a scale from 1 to 9, with 1 
being extremely poor and 9 being extremely good.
Morning Sleepiness
The Sleep Diary will also be used to assess subjective ratings of morning sleepiness with the 
following question: “How alert/sleepy do you feel this morning?” Subjects will rate their 
sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely sleepy and 9 being 
extremely alert.  (revised per Amendment 03)
The morning sleepiness question that is part of the electronic Sleep Diary will also be asked 
verbatim, using a paper-and-pencil format, at 1.5 hours after waketime each morning the 
subjects is in the clinic following a PSG recording.  The rating on this question will be taken 
into consideration by the investigator when making the determination about whether it is safe 
for the subject to be discharged from the clinic.
Alcohol Consumption
The Sleep Diary will include questions that ask whether or not the subject consumed alcohol 
the previous day within 3 hours before bedtime or exceeded the daily maximum of 2 
alcoholic drinks.  (revised per Amendment 01)
9.5.1.3.3
INSOMNIA SEVERITY INDEX
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of 
insomnia (Bastien et al., 2001). The dimensions evaluated are: severity of sleep onset, sleep 
maintenance, early morning awakening problems; sleep dissatisfaction; interference of sleep 
difficulties with daytime functioning, noticeability of the sleep problems by others; and 
distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each item (from 
0 = no problem to 4 = very severe problem) yielding a total score from 0 to 28. Subscores 
can be used to determine the functional impact of symptoms of insomnia disorder.


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9.5.1.3.4
FATIGUE SEVERITY SCALE
The FSS is a self-report scale on which subjects are instructed to choose a number from 1 to 
7 that indicates their degree of agreement with each of 9 statements about their fatigue where 
“1” indicates strongly disagree and “7”, strongly agree. The FSS score is the sum of all 
responses to the 9 questions (Schwartz et al., 1993).  Higher scores indicate greater fatigue. 
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
At predefined visits, a single, 4-mL blood sample per timepoint to determine plasma 
concentrations of lemborexant and its metabolites (M4, M9, and M10) or zolpidem will be 
taken and will be processed according to instructions in a laboratory manual to be provided 
to the study sites.  Plasma concentrations will be using validated liquid chromatography-
tandem mass spectrometry assay methods.  Concentrations of zolpidem will be determined 
only on an as needed basis as determined by the Study Director or Medical Monitor.  The 
time and date of the 2 most recent doses preceding the samples obtained on Day 2 and Day 
30 will be documented.  (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Postural Stability using the CDR Posture Assessment
Postural stability will be assessed using an apparatus similar to the Wright ataxiameter, and 
referred to as the CDR posture device.  This device measures directional trunk movements 
(ie, body sway) through a cord placed around the subject’s waist and connected to the 
ataxiameter.  On the evening of the Screening PSG visit, subjects will be introduced to the 
CDR posture assessment.  Subjects will stand on a firm surface with feet comfortably apart, 
either barefoot or wearing socks.  The standing position (inside heel-to-inside heel distance)
and barefoot/socks conditions will be documented to ensure they remain the same for a given 
subject at each postural stability assessment timepoint.  They will be instructed to stand as 
still as possible with eyes closed for 1 minute.  (revised per Amendment 01)  On the morning 
after the Screening PSG, subjects will complete a CDR posture assessment session for 
familiarization purposes only; no data from this session will be used for analyses.  This 
session must be conducted under the same conditions (eg, starting within 5 minutes of 
morning waketime, at bedside) as during the testing sessions at subsequent visits.
Body sway is detected through the cable around the subject’s waist by the ataxiameter and 
these data are transmitted to a laptop. Body sway is measured in units of 1/3° of the angle of 
arc. For ease in reporting these will be called arbitrary units, with a higher number indicating 
more body sway (less postural stability). 


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Cognitive Performance Assessment Battery
A computerized PAB will be administered on a laptop computer after the postural stability 
test.    (revised per Amendment 01)  While completing the PAB, subjects will be in bed and 
ambient lighting will be maintained at a level of 80 to 100 lux at the subject’s eye level.  On 
the evening of the Screening PSG visit, before bedtime, subjects will be introduced to the 
PAB tasks and will undergo a minimum of 2 training sessions. If subjects cannot adequately 
perform the tasks during the training sessions, they will be excluded from further 
participation.  On the morning after the Screening PSG, subjects will complete a session of 
the cognitive PAB for familiarization purposes only; no data from this session will be used 
for analyses.  This session must be conducted under the same conditions (eg, lighting, subject 
in bed) as during the testing sessions at subsequent visits.
The PAB comprises 9 tasks, including Simple Reaction Time, Choice Reaction Time, Digit 
Vigilance, Immediate Word Recall, Delayed Word Recall, Word Recognition, Picture 
Recognition, Numeric Working Memory, and Spatial Working Memory.  The full PAB will 
take approximately 18 to 30 minutes to complete.  Four composite domain factor scores are 
calculated by combining outcome variables from the various tests, as described below:

Power of Attention
o
A composite score from the speed scores of 3 tests of attention
o
Reflects the ability to focus attention and process information

Continuity of Attention
o
A composite score created by combining the accuracy scores from the tests of 
attention 
o
Reflects the ability to sustain attention (vigilance)

Quality of Memory
o
A composite score created by combining the accuracy measures from the two tests of 
working memory and the four tests of episodic memory 
o
Reflects the ability to store information in memory and subsequently retrieve it

Speed of Memory Retrieval
o
A composite score created by combining the reaction time scores from the two 
working memory tests and the two episodic recognition tests
o
Reflects time taken to retrieve information held in both working and episodic memory
9.5.1.4.3
PHARMACOGENOMIC ASSESSMENTS
Not applicable
9.5.1.4.4
OTHER BIOMARKER ASSESSMENTS
Not applicable.


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9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; regular laboratory 
evaluation for hematology, blood chemistry, and urine values; periodic measurement of vital 
signs, weight and ECGs; and the performance of physical examinations.  Safety will be 
assessed at every clinic visit throughout the study, and at the EOS Visit.
9.5.1.5.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Suicidality will be assessed using a self-rated 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.
9.5.1.5.2
TYRER BENZODIAZEPINE WITHDRAWAL SYMPTOM QUESTIONNAIRE 
An assessment of withdrawal symptoms will be made using the T-BWSQ (Tyrer et al., 1990) 
to be completed at the EOS Visit. Subjects will be asked about the presence/absence and 
severity of the symptoms listed in the questionnaire.  For each listed symptom, the subject is 
to respond “No” (Score = 0), “Yes – moderate” (Score = 1) or “Yes – severe” (Score = 2).  
The sum of responses will be the subject’s score. (revised per Amendment 02)
9.5.1.5.3
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product. For this study, the study drug is lemborexant. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding of 
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All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit.  Serious adverse events (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.
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 28 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
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.5.4) for the definition of an SAE).


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ASSESSING RELATIONSHIP TO STUDY TREATMENT
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
CLASSIFICATION OF CAUSALITY
The relationship of each AE to the study drug will be recorded on the eCRF in response to 
the following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.4
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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)
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 


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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 (EASS) 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 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
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.
9.5.1.5.5
LABORATORY MEASUREMENTS
Clinical laboratory tests are to be performed according to the schedule in Table 2.  Blood and 
urine samples will be collected for the clinical laboratory tests as listed in Table 3.  Subjects 
should be in a seated or supine position during blood collection.  
Viral testing for hepatitis B and C will be conducted from a blood sample obtained at 
Screening. The specific test for hepatitis B is the surface antigen panel (HBsAg) with 
confirmation as needed.  The specific tests for hepatitis C are the hepatitis C virus (HCV) 
antibody immunoglobulin G (IgG), with confirmation as needed using the HCV score.  
(revised per Amendment 01)
A 30-mL urine sample for assessment of drugs of abuse will be collected at designated time 
points as specified in the Schedule of Procedures/Assessments (Table 4).  These samples will 
be tested for common drugs of use/abuse:  eg, cocaine, cannabinoids, phencyclidine, opioids 
(as a group), benzodiazepines, barbiturates, and amphetamines.  (revised per Amendment 01)


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Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function 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 3
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments
Volume per Sample 
Collection
(mL)
Collection 
Time Points
Window Around Time 
Point
Volume 
Collected 
(mL)
Clinical laboratory 
tests
12a
Screening
Baseline
Day 31
EOS/ET
n/a
48
Viral tests
6a
Screening
n/a
6
PK sampling
4
Day 2 pm
Day 3 am
Day 30 pm
Day 31 am
pm: within 2 hours 
predose
am: 
after PAB and within 1 
hour after morning 
waketime
16
Total Volume Collected
70
EOS = end of study, ET = early termination, n/a = not applicable, PK = pharmacokinetic
a.
Estimated volume.
Clinical laboratory tests during the study will be performed by a central laboratory.
All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  In cases of a safety concern, blood samples will be 
split (or 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 9.5.1.5.3) 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).
9.5.1.5.6
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], and body temperature [in centigrade]) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 4) 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; once only) and weight (kg) will 
also be measured.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.7
PHYSICAL EXAMINATIONS
Physical examinations (full or brief) will be performed as designated in the Schedule of 
Procedures/Assessments Table 4).  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 4, a brief 
physical examination will be conducted to assess health status by brief evaluation of the 
head, eyes, ears, nose, throat, heart, lungs, abdomen, and extremities, and other physical 
conditions of note.  Documentation of the physical examinations, including the brief 
neurological examinations, will be included in the source documentation at the site.  Only 
changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the AE eCRF.
9.5.1.5.8
ELECTROCARDIOGRAMS
Electrocardiograms 
will 
be 
obtained 
as 
designated 
in 
the 
Schedule 
of 
Procedures/Assessments (Table 4). 


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An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.3).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events eCRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.4), 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]).
9.5.1.5.9
OTHER ASSESSMENTS
EQ-5D-3L
The EQ-5D-3L 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 (Brooks 
et al., 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”).
PATIENT GLOBAL IMPRESSION – INSOMNIA 
The PGI-Insomnia questionnaire is a self-report assessment asking about a subject’s 
perception of the effects of the study medication on their sleep relative to their sleep before 
entering in the study.  As such, the PGI-Insomnia does not have a baseline and the outcome 
is not change from baseline, but rather the global impression of the study medication’s 
effects at the end of treatment. The PGI-Insomnia has 3 items related to study medication 
effects (a:  helped/worsened sleep, b: decreased/increased time to fall asleep, and c: 
increased/decreased TST) and 1 item related to perceived appropriateness of study 
medication strength.  The first 3 items are answered on a 3-point scale (1=positive 
medication effect, 2=neutral medication effect, 3=negative medication effect) and the last 
item on a different 3-point scale (medication:  1=too strong, 2=just right, 3=too weak).  Each 
item will be reported separately.  This scale was used in studies of zolpidem (Roth et al., 
2006; Walsh et al., 2008).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for this study.


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Table 4
Schedule of Procedures/Assessments in Study E2006-G000-304
Phase
Prerandomization
Randomization
Period
Screening
Run-in
BL
Treatment
Follow-Up
ETe
UN
Visit
1
2a
2b
3a
3b
4aa
4b
5a
5b
5c
6ab
6b
7a
7b
8ac
8b
EOSd
Target Study Day
-21
-14
-13
-7
-6
-6
-5
1
1
2
2
3
29
30
30
31
44
Window
-14/+4
-3/+4
-3/+3
-3/+3
n/a
n/a
-2/+5
-2/+5
Possible Study 
Day(s) Given 
Window
-35
to
-17
-17
to
-10
-16
to
-9
-10
to
-4
-9 
am 
to   
-3
am
-9 
pm 
to   
-3
pm
-8
to
-2
1
1
pm
2
am
2
pm
3
am
29
pm
30
am
30
pm
31
am
31
to 
44
44
Procedures/   
Assessments
Demographics
X
Informed consent
X
Inclusion/exclusion 
criteriaf
Height
X
Weight
X
X
X
X
X
Clinical laboratory 
tests
X
X
X
X
X
X
Viral screeningg
X
Vital signs
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Sleep, medical, and 
psychiatric history
X
ISI 
X
X
X
X
SDSBh
X
Physical exami
X
X
X
X
X
Prior / concomitant 


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Table 4
Schedule of Procedures/Assessments in Study E2006-G000-304
Phase
Prerandomization
Randomization
Period
Screening
Run-in
BL
Treatment
Follow-Up
ETe
UN
Visit
1
2a
2b
3a
3b
4aa
4b
5a
5b
5c
6ab
6b
7a
7b
8ac
8b
EOSd
Target Study Day
-21
-14
-13
-7
-6
-6
-5
1
1
2
2
3
29
30
30
31
44
Window
-14/+4
-3/+4
-3/+3
-3/+3
n/a
n/a
-2/+5
-2/+5
Possible Study 
Day(s) Given 
Window
-35
to
-17
-17
to
-10
-16
to
-9
-10
to
-4
-9 
am 
to   
-3
am
-9 
pm 
to   
-3
pm
-8
to
-2
1
1
pm
2
am
2
pm
3
am
29
pm
30
am
30
pm
31
am
31
to 
44
44
Procedures/   
Assessments
medications
Beck Depression 
Inventory II 
X
Beck Anxiety 
Inventory
X
Urine drug test
X
X
X
X
X
X
X
X
X
Postural stability
Xj
Xk
X
X
X
X
X
X
Cognitive PAB
Xj
Xk
X
X
X
X
X
X
FSS
X
X
X
X
Morning Sleepiness
X
X
X
X
X
X
X
Sleep Diaryl
EQ-5D-3L
X
X
X
X
PK blood samplingm
X
X
X
X
X
eC-SSRS
X
X
X
X
X
X
X
Polysomnographyn
X
X
X
X
X
X
X


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Table 4
Schedule of Procedures/Assessments in Study E2006-G000-304
Phase
Prerandomization
Randomization
Period
Screening
Run-in
BL
Treatment
Follow-Up
ETe
UN
Visit
1
2a
2b
3a
3b
4aa
4b
5a
5b
5c
6ab
6b
7a
7b
8ac
8b
EOSd
Target Study Day
-21
-14
-13
-7
-6
-6
-5
1
1
2
2
3
29
30
30
31
44
Window
-14/+4
-3/+4
-3/+3
-3/+3
n/a
n/a
-2/+5
-2/+5
Possible Study 
Day(s) Given 
Window
-35
to
-17
-17
to
-10
-16
to
-9
-10
to
-4
-9 
am 
to   
-3
am
-9 
pm 
to   
-3
pm
-8
to
-2
1
1
pm
2
am
2
pm
3
am
29
pm
30
am
30
pm
31
am
31
to 
44
44
Procedures/   
Assessments
Randomization
X
PGI-Insomnia
X
T-BWSQ
X
X
Dispense study drug
X
X
Study drug at 
bedtimeo
Retrieve unused 
study drug
X
X
Check study drug 
compliancep
X
X
X
Admission to clinic
X
X
X
X
X
X
X
Discharge from 
clinic
X
X
X
X
X
X
X
Discharge from 
study
X
X
Adverse eventsq


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(revised per Amendment 01)
Table 4
Schedule of Procedures/Assessments in Study E2006-G000-304
BL = baseline, eC-SSRS = electronic Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, EMG = electromyography, EOS = end of study; 
ET = early termination, FSS = Fatigue Severity Scale, ISI = Insomnia Severity Index, PAB = performance assessment battery, PGI = Patient Global 
Impression, PK = pharmacokinetic, PSG = polysomnography, SDSB = Sleep Disorders Screening Battery, T-BWSQ = Tyrer Benzodiazepine Withdrawal 
Symptom Questionnaire; UN = unscheduled visit.
a:
Must be consecutive with Visit 3a.
b:
Must be consecutive with Visit 5b.
c:
Must be consecutive with Visit 7a. 
d:
Must occur 14 – 18 days after Visit 8.
e:
Subjects who discontinue the study early for any reason after Randomization at Visit 5 should complete this visit.
f:
Inclusion and exclusion criteria to be evaluated at visits other than or in addition to Visit 1 are listed in Appendix 2.
g:
Viral screening for hepatitis B (HBsAg) and hepatitis C (HCV antibody IgG) will be conducted.  (revised per Amendment 01)
h:
The Sleep Disorders Screening Battery includes: STOPBang, International Restless Legs Scale, Epworth Sleepiness Scale, and Munich Parasomnia Scale.
i:
Full physical examination (including a brief neurological exam) will be carried out at Screening and EOS and ET (if applicable). Brief physical 
examinations will be carried out at other visits.
j:
For training purposes only.  Introduction to the CDR posture assessment and at least 2 training sessions of cognitive PAB to be completed before the end 
of Visit 2a. (revised per Amendment 02)
k:
For familiarization purposes only.  The CDR posture and cognitive PAB assessments are to be completed at Visit 2b under the same conditions as for 
testing at subsequent visits.
l:
Should be completed, within 1 hour of morning waketime, on every day of the study from Screening until the end of the study, and reviewed for eligibility 
before initiating any study assessments at Visit 2 and Visit 3.
m:
One PK blood sample (approximately 4 mL) will be obtained at the following timepoints: within 2 hours predose Day 2 and Day 30; within 1 hour after 
morning waketime on Day 3 and Day 31.
n:
PSG recordings will include a standard montage on all PSG nights.  Diagnostic channels (respiratory effort, airflow, leg EMG) will be added to the 
standard montage on the PSG at Visit 2.  All PSG visits will require an overnight stay in the clinic.  At least 2 nights must intervene between the second 
BL PGG (Visit 4b) and BL (Visit 5a).  (revised per Amendment 02)
o:
First dose of study drug is taken by the subject on the first night at home after Visit 2b.  On the days that subjects are admitted to the clinic, study drug will 
be administered to the subject by clinical staff.  The first dose of active study drug will be administered at Visit 5.  On days that the subjects are not 
admitted to the clinic subjects will self-administer study drug.  All study drug administration must be within 5 minutes of bedtime (defined as the time the 
subject attempts to sleep). (revised per Amendment 02)
p:
Subjects will be questioned about study drug compliance upon check-in at Visits 3a, 5a, and 7a.  Tablet counts for study drug compliance will be done 
after end of Run-in Period and end of Treatment Period.
q:
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 9.2.5 Adjudication Committee.


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9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 4.
9.5.3
Appropriateness of Measurements
Most of the clinical assessments are standard measurements commonly used in studies of 
drugs for the treatment of subjects with insomnia disorder.
Completion of sleep diaries by subjects is considered to be an appropriate method to measure 
changes in subjective sleep parameters, thereby allowing assessments of secondary efficacy 
in this study.  The advantages of the electronic Sleep Diary to be used in this study include 
that the questions and instructional text have been adapted from sleep diaries that have were 
developed by clinicians and researchers with expertise in insomnia disorder, and have 
undergone linguistic validation and cognitive debriefing to optimize their use in this study. 
The Sleep Diary will include questions to assess the subject’s rating of sleep quality each 
night and sleepiness/alertness level in the morning.  The ISI has been widely used to evaluate 
the subjective impact of insomnia severity on psychosocial functioning, which is one type of 
daytime functioning impairment experienced by those with insomnia disorder.  The FSS 
measures fatigue, which is another type of daytime impairment that is often a consequence of 
insomnia.  This scale has been employed primarily in clinical trials of cognitive and 
behavioral treatments for insomnia disorder. Because the objectives of this study include 
assessing the response to lemborexant of both nighttime sleep and daytime impairment 
complaints, the ISI and the FSS will be evaluated for changes from baseline.  The PGI-
Insomnia and EuroQoL assessment (version EQ-5D-3L) will also be employed.  Both 
measures have been used in studies evaluating the impact of treatment for insomnia on the 
patients’ global perceptions of sleep quality and quality of life. Together these measures will 
provide a broad evaluation of the effects of lemborexant on each patient’s sleep, daytime 
functioning, and quality of life.
The CDR posture and cognitive PAB will assess whether there are residual effects of study 
drug on morning postural stability and cognition.  There are documented effects of hypnotic 
drugs, including zolpidem, on postural stability and certain cognitive domains in the morning 
hours.  These effects are associated with an increased risk of falling and other negative 
effects on functioning in the morning hours.  The measures to be employed to evaluate the 
effects on postural stability and cognition have been widely used in clinical trials of drugs in 
older individuals, including clinical trials of treatments for insomnia disorder. 
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 time the investigator becomes aware of the event.  (revised 
per Amendment 01)


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Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution 
or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be 
related to the study treatment or any protocol-required procedure should be reported to the 
sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues 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.  (revised per Amendment 01) If the follow-up information changes the investigator’s 
assessment of causality, this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
or the responsible CRO, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Although the female subject population will be postmenopausal, in the event that a 
pregnancy does occur, investigators will capture and report such events.
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours after the time the investigator becomes 


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aware of the pregnancy.  (revised per Amendment 01)  The contact information for the 
reporting of pregnancies and exposure to study drug through breastfeeding is provided in the 
Investigator Study File.  The Pregnancy Report Form must be used for reporting.  All 
pregnancies must be followed to outcome.  The outcome of the pregnancy must be reported 
as soon as possible but no later than 24 hours after the time the investigator becomes aware 
of the outcome.  (revised per Amendment 01)
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  
Investigators should report whether one or both study drugs had been taken incorrectly. 
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.
9.5.4.4
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.


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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.
9.5.5
Completion/Discontinuation of Subjects
For purposes of entering subject disposition in the eCRF, a subject will be considered to have 
completed the study per protocol after the End of Study visit has been completed. (revised 
per Amendment 01) For analysis purposes, a subject will be considered to have completed 
the study once the assessments on the morning after the last dose of study drug have been 
completed.  All subjects will be required to return to the clinic at least 14, but not more than 
18 days later for an End of Study (EOS) visit. 
The investigator or subject may elect to discontinue the subject’s participation in the study at 
any time for any reason.  Subjects who discontinue study drug prematurely at any time after 
randomization at Visit 5 (Baseline) will be encouraged to return to the site as soon as 
possible (preferably within 7 days) to undergo an early termination (ET) Visit, as described 
in the Schedule of Procedures/Assessments (Table 4). 
If the investigator or sponsor discontinues the study prematurely, the investigator will 
promptly explain to the subject involved that the study will be discontinued for that subject 
and will provide appropriate referral for medical treatment and other necessary measures for 
the subject.  A subject who has ceased to return for visits will be followed up by mail, phone, 
or other means to gather information such as the reason for failure to return, the status of 
treatment compliance, the presence or absence of AEs, and clinical courses of signs and 
symptoms.  This information will be recorded in the eCRF.
Subjects who discontinue early from the study will be discontinued for one of these primary 
reasons:  AE(s), lost to follow-up, subject choice, lack of therapeutic effect, or 
administrative/other.  Discontinuations due to non-compliance with study drug, time spent in 


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bed, or alcohol restrictions will be assigned to “administrative/other.” In addition to the 
primary reason, the subject may indicate one or more of secondary reasons for 
discontinuation.  Study disposition information will be collected on the Subject Disposition 
eCRF.
A subject removed from the study for any reason will not be replaced.  
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 9.5.1.5.4. Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  
9.6.1
Data Collection
Data required by the protocol will be collected on the 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 CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.


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9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (eg, laboratory data), will be entered into a clinical system.
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 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 SAP.
All statistical tests will be based on the 5% level of significance (2-sided).  If statistical 
comparisons are not defined, all pairwise comparisons will be tested.
9.7.1.1
Study Endpoints
Unless otherwise stated, the time points for Sleep Diary endpoints refer to the mean of the 
final 7 nights before the visit.
9.7.1.1.1
PRIMARY ENDPOINT(S)
The primary endpoint is:

Change from baseline of mean LPS on Days 29 and 30 of LEM10 and LEM5 compared 
to PBO (revised per Amendment 03)
9.7.1.1.2
SECONDARY ENDPOINT(S)
Key Secondary Endpoints – US ONLY (revised per Amendment 03)

Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to 
PBO

Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5
compared to PBO (revised per Amendment 04)

Change from baseline of mean WASO2H on Days 29 and 30 of LEM10 and LEM5
compared to ZOL
Key Secondary Endpoints – Non-US ONLY (revised per Amendment 03)

Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to 
PBO


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
Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5
compared to PBO
Additional Secondary Endpoints – US and Non-US (revised per Amendment 03)

Change from baseline on the postural stability test of mean units of body sway on Days 2 
and 3 of LEM5 and LEM10 compared to ZOL 

Change from baseline of mean LPS, WASO, and TST on Days 1 and 2 and Days 29 and 
30 of  LEM5 and LEM10 compared to ZOL 

Change from baseline of mean subjective Sleep Diary variables including  sSOL, 
sWASO, sSE and sTST over the first 7 and last 7 nights of the Treatment Period of 
LEM5 and LEM10 compared to ZOL

Change from baseline of mean LPS, SE, WASO, WASO2H, and TST on Days 1 and 2 of 
LEM5 and LEM10 compared to PBO

Change from baseline of mean WASO2H and TST on Days 29 and 30 of LEM5 and 
LEM10 compared to PBO

Change from baseline mean of subjective Sleep Diary variables including sSOL, 
sWASO, sSE and sTST over the first 7 and last 7 nights of the Treatment Period of 
LEM5 and LEM10 compared to PBO 

Proportion of responders on Days 1 and 2 and Days 29 and 30 (PSG), and over the first 7 
nights and last 7 nights of treatment (Sleep Diary), to LEM5 and LEM10 compared to 
ZOL and PBO, such that 
o
Objective sleep onset response is defined as LPS ≤20 minutes (provided mean 
baseline LPS was > 30 minutes)
o
Subjective sleep onset response is defined as sSOL ≤ 20 minutes (provided mean
baseline sSOL was > 30 minutes)
o
Objective sleep maintenance response is defined as WASO ≤ 60 minutes (provided 
mean baseline WASO was > 60 minutes and is reduced by > 10 minutes compared to 
baseline)
o
Subjective sleep maintenance response is defined as sWASO ≤ 60 minutes  (provided 
mean WASO was > 60 minutes and is reduced by > 10 minutes compared to baseline)

Safety and tolerability of LEM

Change from baseline of the score from items 4-7 on the ISI at Day 31 of LEM5 and 
LEM10 compared to ZOL and PBO

Change from baseline on the FSS score at Day 31 of LEM5 and LEM10 compared to 
ZOL and PBO

Change from baseline of mean power of attention, mean continuity of attention, mean 
quality of memory, and mean speed of memory retrieval on Days 2 and 3


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9.7.1.1.3
EXPLORATORY ENDPOINT(S) – US AND NON-US (REVISED PER AMENDMENT 03)
The change from baseline of WASO2H for LEM5 and LEM10 compared to ZOL will be 
considered as exploratory for non-US.  The following endpoints will be also explored for 
LEM5 and LEM10.  Except for PK endpoints, comparisons to ZOL and PBO will be made. 
(revised per Amendment 03)

Change from baseline of the mean rating on the Quality of Sleep question from the Sleep 
Diary of the first 7 days and last 7 days of the Treatment Period 

Change from baseline of mean power of attention, mean continuity of attention, mean 
quality of memory, and mean speed of memory retrieval on Days 30 and 31 

From the postural stability test, change from baseline of mean units of body sway after 
the first 2 nights of the Treatment Period compared to PBO and the last 2 nights of the 
Treatment Period compared to ZOL and PBO

Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up 
Period
o
Change from baseline of sSOL at the following timepoints during the Follow-up 
Period: each of the first 3 nights, mean of the first 3 nights, mean of the first 7 
nights,mean sSOL of the second 7 nights (revised per Amendment 03)
o
Change from baseline of sWASO at the following timepoints during the Follow-up 
Period: each of the first 3 nights, mean of the first 3 nights, mean of the first 7, mean 
of the second 7 nights (revised per Amendment 03)
o
Proportion of subjects whose sSOL at the following timepoints during the Follow-up 
Period: each of the first 3 nights, mean of the first 3 nights, mean for first 7 nights,
mean of the second 7 nights (revised per Amendments 02 and 03)
o
Proportion of subjects whose sWASO is higher at Screening at the following 
timepoints during the Follow-up Period: each of the first 3 nights, mean of the first 3 
nights, mean for the first 7 nights, for thesecond 7 nights(revised per Amendments 02
and 03)

Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings 
and last 7 mornings of the Treatment Period 

Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings 
and second 7 mornings of the Follow-up Period 

Change from baseline of mean morning sleepiness ratings assessed at 1.5 hours after 
waketime when subjects are in clinic on Days 1 and 2, and Days 29 and 30  (revised per 
Amendment 01)

Change from baseline of mean minutes and mean percentage (a) per TIB and (b) per 
TST of sleep stage N1, N2, N3 (separately and combined) and REM on Days 1 and 2 and 
Days 29 and 30 

Change from baseline of mean REM latency, mean number of awakenings, and mean 
number of long awakenings at Days 1 and 2 and Days 29 and 30 (revised per Amendment 
03)


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
Number and percentage of subjects with a rating of a positive medication effect on each 
PGI-Insomnia item at Day 31

Change from baseline on the EQ-5D-3L at Day 31

Mean score on the T-BWSQ of LEM5 and LEM10 compared to ZOL and PBO at end of 
study

Proportion of subjects who score ≥ 3 on the T-BWSQ of LEM5 and LEM10 compared to 
ZOL and PBO at end of study

PK of lemborexant and its metabolites M4, M9, and M10

Relationships between lemborexant PK, efficacy, and/or safety variables using PK/PD 
modeling 
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 primary efficacy measurement.
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with 
the protocol.  Details of the evaluability criteria will be determined before database lock and 
treatment unblinding and will be specified in the SAP.
The PK Analysis Set is the group of subjects who have at least one quantifiable plasma 
concentration of lemborexant or its metabolites, or zolpidem, 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 one 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.


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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, weight, and BMI; categorical variables include 
sex, age group (55 <65 years; 65 – <75 years; and 75 years or older), BMI group (less than 
18.5, 18.5 to less than 25, 25 to 30, above 30), race and ethnicity.  (revised per Amendments
03 and 04)
Characteristics of insomnia at Study Baseline will be summarized using Sleep Diary
variables including sSOL, sWASO, sSE and sTST; PSG variables including LPS, WASO, 
SE, WASO2H and TST; ISI score and its individual question score, and FSS. The BDI-II and 
BAI scores will also be summarized at Study Baseline.
The above tables will be produced for the FAS if it differs from the Safety Analysis Set. 
If sufficient numbers of subjects with a particular medical history (major depression, anxiety 
disorder, chronic pain, etc) are enrolled, demographic and other baseline characteristics will 
be summarized for each medical history group using descriptive statistics.
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 during the Run-In Period.
Concomitant medications are defined as medications that (1) started before the first dose of 
randomized 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 randomized study drug to the last dose day plus 
14 days. All medications will be presented in subject data listings. (revised per 
Amendment 02)
9.7.1.6
Efficacy Analyses
Where Sleep Diary endpoints are described, the first 7 nights of treatment refer to diary data 
entered on the first 7 mornings following the start of treatment; the last 7 nights of treatment 
refer to diary data entered on the last 7 mornings (up to and including the morning following 
the last PSG). Details of the handling of missing data for the various assessments will be 
addressed in the SAP.


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Where PSG endpoints are described, Days 1 and 2 refer to the first two PSG recordings after 
start of treatment (scheduled on Visits 5 and 6), and Days 29 and 30 refer to the last two PSG 
recordings of the Treatment Period (scheduled on Visits 7 and 8). 
Definition of Baseline
Baseline is defined as the means from the 2 PSGs during the Run-in period for PSG-derived 
variables; and the mean of the last 7 mornings before the first Baseline PSG during the Run-
In Period for Sleep Diary variables. For other endpoints, baseline data are captured during 
the Run-in Period and Baseline Period.  Details will be specified in the SAP.
Control of Type I Error (revised per Amendment 03)
A sequential gate-keeping procedure will be used for the primary and the key secondary 
endpoint comparisons to control for the overall type I error at the 0.05 significance level 
(Figure 2).  The first endpoint comparison will be tested at the 0.05 significance level.  If the 
testing is found to be statistically significant, then proceed to the next endpoint testing at 
significance level of 0.05, otherwise stop testing.  
The primary endpoints will be tested in the following order:

Change from baseline of the mean LPS of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean LPS of Days 29 and 30 of LEM5 compared to PBO
The key secondary endpoints will only be tested if both primary analyses are statistically 
significant at the 0.05 level.  The key secondary endpoints will be tested in the following 
order:
US Only

Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO

Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to 
PBO (revised per Amendment 04)

Change from baseline of the mean WASO2H of Days 29 and 30 of LEM10 compared to 
ZOL 

Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to 
PBO (revised per Amendment 04)

Change from baseline of the mean WASO2H on Days 29 and 30 of LEM5 compared to 
ZOL
Non-US Only

Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO

Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO


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
Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to 
PBO 

Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to 
PBO
No multiplicity adjustment will be done on other efficacy analyses.
Figure 2
Flow Chart of Gate Keeping Testing Procedure – Study E2006-
G000-304 (revised per Amendment 04)
LEM5 = lemborexant 5 mg, LEM10 = lemborexant 10 mg, LPS = latency to persistent sleep, PBO = placebo, SE = sleep 
efficiency, US = Unites States, WASO = wake after sleep onset, WASO2H = wake after sleep onset in the second half of the 
night, ZOL = zolpidem tartrate extended release 6.25 mg.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Null Hypothesis:  No difference exists in the mean change from baseline of the mean LPS of 
Days 29 and 30 for treatment with LEM10 (or LEM5) as compared with PBO.  (revised per 
Amendment 03)
Alternative Hypothesis:  A difference exists in the mean change from baseline of the mean 
LPS of Days 29 and 30 for LEM10 (or LEM5) compared to PBO.  (revised per 
Amendment 03)


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The LPS change from baseline (the mean of Days 1 and 2, and the mean of Days 29 and 30) 
will be analyzed using the mixed effect model repeated measurement analysis (MMRM) on 
the FAS. The model will include all data and will be adjusted for the corresponding baseline 
value (the means from the 2 PSG recordings during the Run-in Period), region, age group 
(55 <65 years; 65 years or older), treatment, time (Days 1/2, and Days 29/30), and the 
interaction of treatment by time.  Since LPS is known to be non-normally distributed, a log-
transformation will be used in the analysis An unstructured covariance matrix will be used, 
and if the model fails to converge, then an autoregressive matrix will be used.  The missing 
values will be imputed using a pattern mixture model utilizing multiple imputations (MI) 
assuming the missing values are missing not at random (MNAR) utilizing the complete case 
missing value pattern (CCMV - subjects who completed primary efficacy assessments 
without missing values).  The missing values for a given visit will be imputed using all 
available values including the retrieved measurement from the post-discontinuation data. The 
treatment comparison will be performed using contrasts. The p-value, least square (LS) 
means and the 95% confidence interval (CI) for the treatment difference will also be 
provided.  (revised per Amendments 03 and 04)
Subgroup analyses and additional sensitivity analysis will be performed as appropriate.  
The following analyses will be considered as sensitivity analyses: 

PP analysis: The same primary efficacy analyses described above will be repeated based 
on PP analysis set. 

Completer analysis: The same primary efficacy analyses described above will be repeated 
on subjects who completed all efficacy assessments and have no missing values.

As-treated analysis: The same primary efficacy analyses described in Section 5.4.1 
(MMRM analysis with MI for missing value imputation) will be repeated based on the 
actual treatment the subject received regardless of randomization.

MMRM analysis assuming missing at random (MAR): The same primary endpoint 
analysis described above will be analyzed using MMRM assuming the missing values are 
MAR.  (revised per Amendment 03)

MI Imputation assuming MNAR utilizing CCMV-4: The same MMRM method used in 
the primary analysis will be applied utilizing CCMV-4 (ie, up to 4 monotone missing 
patterns will be used for missing value imputation as follows):
(revised per 
Amendment 04)
Study days where results are available
1
2
29
30
Pattern 1
x
x
x
x
Pattern 2
x
x
x
.
Pattern 3
x
x
.
.
Pattern 4
x
.
.
.
x = result present; . = result missing


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
Tipping point analysis: A range of shifts will be used in the multiple imputation of 
missing data assuming MNAR to identify the specific shift and treatment effect that will 
tip the results from statistically significant to non-significant.
(revised per 
Amendment 04)
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
Key Secondary Efficacy Analysis (revised per Amendments 03 and 04)
Changes from baseline of mean SE, WASO2H, and WASO of Days 1 and 2 and the mean of 
Days 29 and 30 will be analyzed using a pattern mixture model utilizing MI assuming 
MNAR.  The treatment comparison will be performed using contrasts.  The p-value, LS 
means and the 95% CI of the treatment differences will also be provided.  The comparison of 
LEM10 and LEM5 to ZOL on WASO2H will be considered as exploratory for all non-US 
submissions. (revised per Amendment 03)
Other Secondary Efficacy Analysis (revised per Amendment 03)
The other secondary efficacy endpoints (change from baseline of the mean of the following 
endpoints:  LPS, SE, WASO2H, and WASO of the mean of Days 1 and 2; TST of the mean 
of Days 1 and 2 and of the mean of Days 29 and 30; sSOL, sWASO, sSE, and sTST for the 
mean of the first 7 and last 7 days of the Treatment Period) will be analyzed using MMRM 
assuming MAR. (revised per Amendment 03)
The proportion of responders will be analyzed using the Cochran-Mantel-Haenszel test, 
controlled for region and age group, for each dose of lemborexant compared to PBO and 
ZOL. The analysis will be similarly repeated for responder analysis based on Sleep Diary 
variables (sSOL and sWASO) over the first 7 and last 7 nights of treatment. (revised per 
Amendment 03)
The change from baseline of the ISI total of four items on daytime functioning at Day 31 and 
the FSS score at Day 31 will be analyzed using analysis of covariance (ANCOVA), adjusted 
for the corresponding baseline value, age group, region, and treatment.  (revised per 
Amendment 03)
Changes from baseline in mean power of attention, mean continuity of attention, mean 
quality of memory, and mean speed of memory retrieval for the PAB tasks will be analyzed
using MMRM assuming MAR. (revised per Amendments 01 and 03)
Secondary endpoints may also presented graphically or analyzed by modeling methods if 
warranted.
No multiplicity adjustment or missing value imputation is planned for other secondary 
analyses.  (revised per Amendment 03)


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9.7.1.6.3
EXPLORATORY EFFICACY AND PHARMACODYNAMIC ANALYSES
The change from baseline mean score of the quality of sleep item on the Sleep Diary for the 
means of the first 7 days and last 7 days of the Treatment Period will be analyzed using
MMRM assuming MAR.  (revised per Amendment 03)
Rebound insomnia is defined as worsened sleep relative to Screening after study drug 
treatment is completed.  Sleep Diary data from the Follow-up Period will be compared to 
Sleep Diary data from the Screening Period to assess whether subjects experience rebound 
insomnia.  Specifically, a higher value for sSOL or sWASO during the Follow-up Period 
compared to the mean sSOL or sWASO value during the Screening Period will be considered 
worsened sleep. (revised per Amendments 01 and 02)
To assess rebound insomnia, both categorical analysis at the subject level and continuous 
analysis at the group mean level will be performed.  For each of the first 3 nights, the mean 
of the first 3 nights, and the mean of each of the 2 weeks of the Follow-up Period the 
proportion of subjects whose corresponding value for sSOL or sWASO exceeds the 
corresponding Screening Period value by 5 minutes will be summarized by treatment group 
and compared to placebo. The percentage of ‘rebounders’ between each treatment and 
placebo group will be analyzed using a CMH test.  (revised per Amendments 01, 02, and 03)
To assess statistical significance using the continuous data at the group mean level, the data 
will be analyzed using ANCOVA, adjusted for region, age group and treatment.  The LS 
mean of each of the first 3 nights and each week of the Follow-up Period will be compared to 
the Screening Period between each treatment group and placebo.  If the lower bound of the 
95% CI of sSOL or sWASO for each of the first 3 nights and the mean of each week of the 
Follow-Up Period exceeds the upper bound of a 95% CI for the values during the Screening 
Period in the given treatment group, it will be considered strong evidence for rebound 
insomnia. If the LS means for sSOL and sWASO for the Follow-up Period are all lower than 
for the Screening Period, then no rebound insomnia is suggested.  (revised per Amendments
01 and 03)
To evaluate morning residual sleepiness during study treatment and following completion of 
treatment, the change from baseline of the mean of morning sleepiness item on the Sleep 
Diary for the first 7 mornings of the Treatment Period, the last 7 mornings of the Treatment 
Period, as well as the means of the first 7 days and second 7 days of the Follow-up Period 
will be analyzed using MMRM assuming MAR. Change from baseline of the mean morning 
sleepiness ratings assessed at 1.5 hours after waketime when subjects are in clinic on days 1 
and 2 and days 29 and 30 will be similarly analyzed using MMRM assuming MAR.  (revised 
per Amendments 01 and 03)
The change from baseline of the mean of Days 1 and 2 and of the mean of Days 29 and 30 
for the sleep architecture and other PSG endpoints (WASO1H, minutes and percentage [a] 
per TIB and [b] per TST of sleep stage N1, N2, N3, total NREM and REM; REM latency, 
DurLongAW, number of awakenings, number of long awakenings, REM episode frequency 


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and duration, and mean REM/NREM cycle duration) will be summarized.  (revised per 
Amendment 03)
Each item on the PGI-Insomnia at Day 31 will be analyzed separately by calculating the 
number and percentages of subjects for each response category (eg, negative [3], neutral [2], 
positive [1] medication effect).  The percentage of positive responses will be compared 
between treatment groups using the chi-square test, and repeated for age subgroups.
The change from baseline in the EQ-5D-3L score at Day 31 will be analyzed using 
ANCOVA, adjusted for region, age group and treatment.  (revised per Amendment 03)
No multiplicity adjustment or missing value imputation is planned for exploratory and 
pharmocodynamic analyses.  (revised per Amendment 03)
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, 
and M10, as well as zolpidem (where quantified) plasma concentration listings. The PK 
Analysis Set will be used for summaries of lemborexant and its metabolites M4, M9, and 
M10, as well as zolpidem (where quantified) plasma concentrations by dose, time and day.
A population PK approach will be used to characterize the PK of lemborexant. For this 
approach, PK analysis data from this study will be pooled with relevant data from Phase 1 
and 2 studies, and other Phase 3 studies if available. To explore sources of variability in 
lemborexant PK, the effect of covariates (eg, demographics) on the PK of lemborexant will 
be evaluated. The PK model will be parameterized for clearance (CL) and volumes of 
distribution. 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 
and dosing history. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic Analyses
These analyses are described in the Secondary Efficacy Analyses, and Exploratory and
Pharmacodynamic Analyses sections (above).
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship between exposure to lemborexant and efficacy variables including 
but not limited to LPS and WASO, and safety variables including but not limited to morning 
sleepiness and frequently occurring treatment-emergent adverse events (TEAEs), will be 
explored graphically.  Any emergent PK/PD relationships will be evaluated by population 
PK/PD modeling. The population PK/PD analysis plan will be described and results will be 
reported in a separate document. 


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Population PK and PK/PD analyses will be performed using NONMEM version 7.2 or later.
Pharmacogenomic Analyses
Not applicable
Other Biomarker Analyses
Not applicable.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the relevant 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 each study drug.
Compliance for each study drug will be calculated on the basis of number of tablets 
dispensed, lost and returned, separately for each type 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 (including the Run-In Period), 
having been absent at pretreatment (before the PBO Run-In Period) or 

Reemerges during treatment, having been present at pretreatment (before the Run-In 
Period) but stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that 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.
Adverse events will be summarized by descriptive statistics, using the Safety Analysis Set.  
The TEAEs will be summarized by treatment group at the start of the TEAE.  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 


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experienced more than 1 TEAE within a specific SOC and PT.  The number (percentage) of 
subjects with TEAEs during the Run-In Period will be summarized separately. The number 
(percentage) of subjects with TEAEs during the Treatment Period will be summarized 
separately. 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 or other events that are 
characterized according to the customized MedDRA query PT as potential cataplexy-related 
events, as well as somnolence and related events, and drug abuse liability will be summarized 
separately.  (revised per Amendment 01)
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 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 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, HEIGHT, AND WEIGHT
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiration rate, temperature) and weight, and changes from Study Baseline will be presented 
by visit and treatment group.  Height will be measured once at Visit 1.
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 5).  Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital 
sign ranges will also be presented for change from Study Baseline, by treatment group and by 
time point.  
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, 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 Study Baseline will be presented 
by treatment group.  Shift tables will present changes from Study Baseline in ECG 
interpretation (categorized as normal
or abnormal) by time point. 
(revised per 
Amendment 02)
For each subject, the maximum observed corrected QT interval calculated using Fridericia’s 
formula (QTcF), the corrected QT interval calculated using Bazett’s formula (QTcB), 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 Study 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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9.7.1.8.6
OTHER SAFETY ANALYSES
To evaluate morning residual sleepiness during study treatment and following completion of 
treatment, the change from baseline of the mean of morning residual sleepiness item on the 
Sleep Diary for the first 7 mornings of the Treatment Period, the last 7 mornings of the 
Treatment Period, as well as the means of each of the 2 weeks after treatment discontinuation 
will be analyzed using MMRM assuming MAR.  (revised per Amendment 03)
The results of eC-SSRS assessments will be listed for each subject.  The incidence of suicidal 
ideation or suicidal behavior will be summarized by treatment group using descriptive 
statistics as appropriate.  
Withdrawal symptoms will be assessed using the T-BWSQ.  The mean score will be 
summarized by treatment group, and number (percentage) of subjects with a score ≥3 will be 
summarized.
Urine drug test results will also be listed.
9.7.1.9
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed 
by modeling methods if warranted.  
Although zolpidem is included in the study as an active comparator, comparison of ZOL to 
PBO, and comparison between LEM5 and LEM10 may be made to facilitate evaluation of 
study results. 
9.7.2
Determination of Sample Size
The sample size was estimated for the each comparison of LEM10 vs. PBO, and LEM5 vs
PBO with respect to the mean change from baseline of LPS at Month 1, on the basis of a 
2-sided t-test at the 0.05 α-level for each treatment comparison.  (revised per Amendment 03)
On the basis of the dose finding study E2006-G000-201 (Study 201), across various 
lemborexant doses (1 to 25 mg) at Days 14 and 15, the standard deviation (SD) of change 
from baseline for log-transformed LPS is assumed to be 0.9. The LS mean treatment 
difference at Days 14/15 from Study 201 for log-transformed LPS of LEM10 and LEM5 
compared with PBO was 0.75 and -1.15, respectively.  Therefore, a sample size of 250 
subjects for LEM5, 250 subjects for LEM10, and 200 subjects for PBO has at least 95%
power for each treatment comparison, LEM10 with PBO, and LEM5 with PBO, based on 
2-sided, 2-sample t-test at 5% significance level.  (revised per Amendment 03)
Power is also estimated for the key secondary objectives, the comparison of LEM10 and
LEM5 to PBO on change from baseline of SE and WASO, and LEM10 and LEM5 to ZOL 
on WASO2H.  A sample size of 250 subjects each for LEM5, LEM10, and ZOL, and 200 
subjects for PBO has at least a 95% power for detecting a statistically significant difference 
between LEM and PBO for change from baseline in SE, at least 80% power for detecting a 


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statistically significant difference between LEM10 and ZOL/PBO for change from baseline 
in WASO/WASO2H based on 2-sided 2-sample t-test at 5% significance level. (revised per 
Amendments 03 and 04).
Table 6:
Power and Sample Size Calculation for Change from Baseline 
of LPS, SE, WASO2H, and WASO
Endpoint (Test)
Estimated Treatment Difference
Estimated SD
Power
Log(LPS) (LEM5 vs PBO)
-0.75
0.9
>95%
Log(LPS) (LEM10 vs PBO)
-1.15
0.9
>95%
SE (LEM5 vs PBO)
5%
14%
>95%
SE (LEM10 vs PBO)
7%
14%
>95%
WASO (LEM5 vs PBO)
-10 min
55 min
48%
WASO (LEM10 vs PBO)
-15 min
55 min
81%
WASO2H (LEM5 vs ZOL)
-8 min
38 min
65%
WASO2H (LEM10 vs ZOL)
-11 min
38 min
89%
NOTE:  Estimated treatment difference and SD are based on Study 201.
9.7.3
Interim Analysis
An interim analysis is planned to be conducted after approximately 50% of subjects 
(approximately n=475 subjects) have been randomized and either completed Day 31 
assessments or discontinued from the study.  This interim analysis will be conducted for 
administrative reasons as detailed in the separate Interim Analysis charter.  When the 
specified number of subjects has completed the Day 31 assessments, an independent 
statistician external to the Sponsor will be provided with the relevant PSG dataset and will be 
unblinded to the primary endpoint, ie, change from baseline in WASO2H for the mean of 
Days 29 and 30.  A conditional power will be calculated to predict the probability that the 
trial will achieve a significant treatment effect for WASO2H in the LEM10 versus ZOL arms 
at the end of the study, given what is observed at the time of interim analysis. The interim 
analysis will be limited to the comparison of LEM10 versus ZOL on the change from 
baseline in WASO2H for the mean of Days 29 and 30.  No other endpoints, dose groups, or 
timepoints will be analyzed at the interim analysis. The study will not be terminated for 
either futility or efficacy.  Therefore no impact to the type I error rate is expected.  
The method of calculating the conditional power will be detailed in the Interim Analysis 
charter, along with operational procedures, unblinding procedures, procedures for 
communicating the results of the conditional power calculation and recipients of this 
information.  To preclude potential influence on the conduct of the remainder of the study, 
disclosure of the conditional power will be limited to a prespecified set of executive-level 
individuals at the sponsor and sponsor's co-development partner. No individuals involved 
with the conduct of the study will have access to the interim data or the results of the interim 


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analysis (i.e., the conditional power of LEM10 versus ZOL on the change from baseline in 
WASO2H for the mean of Days 29 and 30).
Enrollment of subjects will not be stopped during the interval during which the interim 
analysis is conducted.  The interim analysis may be waived or otherwise not conducted, for 
reasons including but not limited to a higher than anticipated enrollment rate which would 
make the interim analysis unnecessary as the majority of subjects would have been enrolled 
by the time the interim analysis is concluded. 
9.7.4
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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10 REFERENCE LIST
Abetz L, Arbuckle R, Allen RP, Garcia-Borreguero D, Hening W, Walters AS, et al.  The 
reliability, validity and responsiveness of the International Restless Legs Syndrome Study 
Group rating scale and subscales in a clinical-trial setting.  Sleep Med. 2006;7:340–9.
Allain H, Bentué-Ferrer D, Tarral A, Gandon JM.  Effects on postural oscillation and 
memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 
mg in elderly healthy subjects. A randomized, cross-over, double- blind study versus placebo.  
Eur J Clin Pharmacol. 2003;59(3):179-88.
Bastien CH, Vallières A, Morin CM.  Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research.  Sleep Med. 2001;2(4):297-307.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J.
An inventory for measuring 
depression. Arch. Gen. Psychiatry. 1961;4(6):561–71.
Beck AT, Epstein N, Brown G, Steer RA.  An inventory for measuring clinical anxiety: 
Psychometric properties  J Consult Clinical Psychol. 1988;56: 893–7.
Boyle J, Wolford D, Gargano C, McCrea J, Cummings C, Cerchio K, et al.  Next-day 
residual effects of gaboxadol and flurazepam administered at bedtime:  a randomized double-
blind study in healthy elderly subjects. Hum Psychophamacol Clin Exp. 2009;24:61-71.
Brooks R. EuroQol: the current state of play. Health Policy 1996;37(1):53-72.
Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, et al.  STOP 
Questionnaire A Tool to Screen Patients for Obstructive Sleep Apnea. Anesthesiology 
2008;108:812–21.
Fulda S, Hornyak M, Müller K, Cerny L, Beitinger PA, Wetter TC.  Development and 
validation of the Munich Parasomnia Screening (MUPS). A questionnaire for parasomnias 
and nocturnal behaviors.  Somnologie 2008;12:56–65.
Johns MW.  Reliability and factor analysis of the Epworth Sleepiness Scale.  Sleep 
1992;15(4):376-81.
Jongen S, Vuurman E, Ramaekers J, Vermeeren A.  Alcohol calibration of tests measuring 
skills related to car driving. Psychopharmacology (Berl). 2014;231(12):2435 47.
Mets MA, Volkerts ER, Olivier B, Verster JC. Effect of hypnotic drugs on body 
balance and standing steadiness. Sleep Med Rev. 2010;14(4):259-67.
Posner K, Brown G.K, 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;168:1266-77


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Roth T, Soubrane C, Titeux L, et al. Efficacy and safety of zolpidem-MR: A double-blind, 
placebo-controlled study in adults with primary insomnia. Sleep Med. 2006;7:397–406.
Schwartz JE, Jandorf L, Krupp LB. The measurement of fatigue: a new instrument. J 
Psychosom Res. 1993 37(7):753-62.
Stranks EK, Crowe SF. The acute cognitive effects of zopiclone, zolpidem, zaleplon, and 
eszopiclone: a systematic review and meta analysis. J Clin Exp Neuropsych. 2014;36(7):691-
700.
The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy. 1990;16(3):199-208. 
Tyrer P, Murphy S, Riley P.  The benzodiazepine withdrawal symptom questionnaire.          
J Affect Disord. 1990;19(1):53-61.
Walsh JK, Soubrane C, Roth T.  Efficacy and safety of zolpidem extended release in elderly 
primary insomnia patients.  Am J Geriatr Psychiatry. 2008 Jan;16(1):44-57.
Wesnes KA, Garatt C, Wickens M, Gudgoen A, Oliver S. Effects of sibutramine alone and 
with alcohol on cognitive function in healthy volunteers. 
Br J Clin Pharmacol.
2000;49:110-7.
eC-SSRS Reference: http://www.cssrs.columbia.edu/ecssrs.html


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to 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 sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits,  Monitoring visits to each site and remote 
monitoring will be conducted between onsite monitoring visits by the assigned CRA as 
described in the monitoring plan.  The investigator (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 eCRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review.
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, x-rays, and other imaging 
reports (eg,, ECGs, rhythm strips, EEGs, polysomnographs) regardless of how these 
images are stored, including microfiche and photographic negatives  (revised per 
Amendment 01)

Quality of life or medical history questionnaires completed by subjects  (revised per 
Amendment 01)

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 dipsticks) (revised per 
Amendment 01)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

eCRF components (eg, questionnaires) that are completed directly by subjects and serve 
as their own source
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents. 
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 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 ICFs, and IRB/IEC correspondence).  In addition, the 


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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 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the PI (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, when approval is given by the sponsor, will destroy supplies and 
containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 


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


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


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Appendix 2 Inclusion/Exclusion Criteria Schedule
Inclusion/exclusion criteria (Section 9.3.1 and Section 9.3.2) will be obtained at study visits 
as shown below.
Schedule of Inclusion/Exclusion Criteria Assessments (revised per Amendment 02)
Visit Name
V1
V2
V3
V4
V5
Screening
Screening 2
During Run-In 
Period
During Run-
In Period
Baseline Period 
(just prior to 
Randomization)
Inclusion 
Criterion 
Number
I1, I2, I3, I4, I5, 
I6, I14, I15
I7, I8, I9
I6, I10, I11, 
I12, I13
I13
N/A
Exclusion 
Criterion 
Number
E1, E2, E3, E5, 
E6, E7, E8, E9, 
E10, E11, E12, 
E13, E14, E15, 
E16, E17, E18, 
E19, E20, E21, 
E23, E24, E25, 
E26, E27, E28
E4, E21 ,E22, 
E24, E25
E24, E25
E25
E24, E25
N/A = not applicable, V = visit.


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Appendix 3 List of Prohibited Concomitant Medications
If a medication is not presented in the list below, but does fit into a class of medications 
noted in the list, the Medical Monitor must be consulted to determine whether it is permitted. 
Category
Medication
Anticholinergics (centrally-acting)
-
Anticonvulsants with known sedating effects
o
Barbiturates 
o
Benzodiazepines 
o
GABA analogues 
o
Hydantoins 
o
Phenyltriazines
Antihistamines (centrally-acting H1, including over-the-
counter)
o
Diphenhydramine HCl
o
Carbinoxamine 
o
Doxylamine 
o
Dimenhyrinate 
o
Triprolidine 
o
Bromopheniramine 
o
Chlorphenamine 
o
Hydroxazine
(revised per Amendment 02)
Antihistamines with known sedating effects
o
Non-sedating, eg, Claritin™ is not 
prohibited
Anxiolytics with known sedating effects
o
Lorazepam 
o
Alprazolam 
o
Buspirone
Strong CYP3A inhibitors
o
Amiodarone 
o
Bocepravir
o
Clarithomycin 
o
Cobicistat
o
Conivaptan
o
Diltiazem
o
Danoprevir
o
Eltegravir
o
Fluvoxamine 
o
Grapefruit juice
o
Idelalisib
o
Indinavir
o
Itraconazole 
o
Ketoconazole 
o
Lopinavir
o
Mibefradil 
o
Nefazodone 
o
Nelfinavir
o
Posaconazole
o
Ritonavir
o
Saquinavir
o
Telapravir
o
Telethromycin
o
Tipranavi
o
Troleandomycin 
o
Voriconazole
(revised per Amendment 02)


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Category
Medication
Moderate CYP3A inhibitors
o
Amprenavir
o
Aprepitant
o
Atazanavir
o
Casopitant
o
Cimetidine
o
Ciprofloxacin
o
Clotrimazole
o
Crizotinib
o
Cyclosporin
o
Darunavir
o
Dronadarone
o
Erythromycin
o
Faldaprevir
o
Fluconazole
o
Fluvoxamine
o
Imatinib
o
Netupitant
o
Tofisopam
o
Verapamil
(revised per Amendment 02)
CYP3A inducers
o
Avasimibe
o
Bosentan
o
Carbamazepine 
o
Efavirenz
o
Enzaluteamide
o
Etravirine
o
Lersivirine
o
Modafinil
o
Mitotane
o
Nafcillin
o
Phenobarbital 
o
Phenytoin
o
Rifabutin 
o
Rifampin
o
St. John’s Wort
o
Troglitazone 
o
Talviraline
o
Thiroiridazine
(revised per Amendment 02)
Hypnotics
o
Melatonin 
o
Prescribed or OTC
Herbal preparations with sedating effects
-
MAOIs
-
Opioid Analgesics
-
Muscle relaxants (centrally-acting) with known sedating 
effects
o
GABA analogues 
o
Hydantoins 
o
Phenyltriazines
Stimulants
o
Amphetamines 
o
Modafinil 
o
Armodafinil
o
Methylfenidate


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Category
Medication
Other
o
Warfarin, heparin, ticlopidine
o
Non-stimulant diet pills
o
Systemic isoretinoin
o
Systemic glucocorticoids
o
Tryptophan
(revised per Amendment 01)


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-G000-304
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Active Comparator, Parallel-Group Study of the Efficacy and Safety 
of Lemborexant in Subjects 55 Years and Older with Insomnia 
Disorder
Investigational Product
Name:
E2006/lemborexant
IND Number:
111,871
EudraCT Number:
2015-004347-39
SIGNATURES
Authors:  (revised per Amendments 01, 02, and 03)
Neuroscience Business Group
Eisai Inc.
Date
 
Neuroscience Business Group
Eisai Ltd.
Date
Neuroscience Business Group
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-G000-304
Study Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Active Comparator, Parallel-Group Study of the Efficacy and Safety 
of Lemborexant in Subjects 55 Years and Older with Insomnia 
Disorder
Investigational Product
Name:
E2006/lemborexant
IND Number:
111,871
EudraCT Number:
2015-004347-39
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on 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

SAP_001.pdf: 
Statistical Analysis Plan 
E2006-G000-304 
 
 
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Final V3.0:  05Feb2018 
Confidential 
Page 1 of 50 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2006-G000-304 
Study Protocol 
Title: 
A Multicenter, Randomized, Double-Blind, Placebo Controlled, 
Active Comparator, Parallel-Group Study of the Efficacy and Safety 
of Lemborexant in Subjects 55 Years and Older with Insomnia 
Disorder 
 
Date: 
05Feb2018 
 
Version: 
Final Version 3.0  
 
 
 
 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 2 of 50 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................5 
1 
INTRODUCTION .............................................................................................................7 
1.1 
Study Objectives ......................................................................................................7 
1.1.1 
Primary Objective - US and Non-US .............................................................7 
1.1.2 
Secondary Objectives.....................................................................................7 
1.1.3 
Exploratory Objectives - US and Non-US .....................................................8 
1.2 
Overall Study Design and Plan ................................................................................9 
2 
DETERMINATION OF SAMPLE SIZE ........................................................................10 
3 
STATISTICAL METHODS ............................................................................................11 
3.1 
Study Endpoints .....................................................................................................11 
3.1.1 
Primary Endpoint(s) .....................................................................................11 
3.1.2 
Secondary Endpoint(s) .................................................................................11 
3.1.3 
Exploratory Endpoint(s) - US and Non-US .................................................12 
3.1.4 
Other Endpoints ...........................................................................................14 
3.2 
Study Subjects ........................................................................................................14 
3.2.1 
Definitions of Analysis Sets.........................................................................14 
3.2.2 
Subject Disposition ......................................................................................15 
3.2.3 
Protocol Deviations ......................................................................................15 
3.2.4 
Demographic and Other Baseline Characteristics .......................................15 
3.2.4.1 
Medical History .................................................................................16 
3.2.5 
Prior and Concomitant Therapy ...................................................................16 
3.2.6 
Treatment Compliance .................................................................................16 
3.3 
Data Analysis General Considerations ..................................................................17 
3.3.1 
Pooling of Centers........................................................................................17 
3.3.2 
Adjustments for Covariates..........................................................................17 
3.3.3 
Multiple Comparisons/Multiplicity .............................................................17 
3.3.4 
Examination of Subgroups ...........................................................................19 
3.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................19 
3.3.6 
Other Considerations ...................................................................................20 
3.4 
Efficacy/Pharmacodynamic Analyses ...................................................................22 
3.4.1 
Primary Analyses .........................................................................................22 
3.4.1.1 
Primary Analysis ................................................................................22 
3.4.1.2 
Subgroup Analyses ............................................................................23 
3.4.1.3 
Sensitivity Analyses ...........................................................................23 
3.4.2 
Secondary Analyses .....................................................................................24 
3.4.2.1 
Key Secondary Analyses ...................................................................24 
3.4.2.2 
Other Secondary Analyses .................................................................26 


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3.4.3 
Other Efficacy/Pharmacodynamic Analyses ...............................................28 
3.5 
Pharmacokinetic, Pharmacogenomic, and Other Biomarker Analyses .................30 
3.5.1 
Pharmacokinetic Analyses ...........................................................................30 
3.5.2 
Pharmacokinetic/Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses .....................................................................................30 
3.6 
Safety Analyses ......................................................................................................30 
3.6.1 
Extent of Exposure .......................................................................................30 
3.6.2 
Adverse Events ............................................................................................31 
3.6.2.1 
Selected Adverse Events ....................................................................32 
3.6.3 
Laboratory Values ........................................................................................32 
3.6.4 
Vital Signs ....................................................................................................33 
3.6.5 
Electrocardiograms ......................................................................................33 
3.6.6 
Other Safety Analyses..................................................................................34 
3.6.6.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..........................34 
3.6.6.2 
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (T-
BWSQ) ...............................................................................................34 
3.7 
Other Analyses .......................................................................................................34 
3.7.1 
Health Outcome Economics Analyses .........................................................34 
3.7.1.1 
EQ-5D-3L ..........................................................................................34 
3.7.1.2 
Patient Global Impression (PGI) - Insomnia .....................................35 
3.8 
Exploratory Analyses .............................................................................................35 
4 
INTERIM ANALYSES ...................................................................................................35 
5 
CHANGES IN THE PLANNED ANALYSES ...............................................................36 
6 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................37 
6.1 
Visit Window .........................................................................................................37 
6.2 
Baseline Assessment ..............................................................................................37 
6.3 
Missing Data Handling ..........................................................................................38 
6.3.1 
Polysomnography, Cognitive Performance Assessment, Posture 
Stability, and Morning Sleepiness Questionnaire ........................................38 
6.3.2 
Sleep Diary...................................................................................................38 
7 
PROGRAMMING SPECIFICATIONS ..........................................................................38 
8 
STATISTICAL SOFTWARE ..........................................................................................41 
9 
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................41 
10 REFERENCES ................................................................................................................41 
SIGNATURE PAGE ...............................................................................................................50 
 


Statistical Analysis Plan 
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Final V3.0:  05Feb2018 
Confidential 
Page 4 of 50 
 
LIST OF IN-TEXT TABLES 
Table 1 
Power and Sample Size Calculation for Change from Baseline of LPS, 
SE, WASO2H, and WASO ..........................................................................................10 
Table 2 
Vital Sign Criteria ......................................................................................33 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ................................................................................................9 
Figure 2 
Flow Chart of Gate-Keeping Testing Procedure .......................................19 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results 
42 
Appendix 2 
Derivations of Efficacy Endpoints from Electronic Sleep Diary...............44 
Appendix 3 
List of Abuse Liability Events ...................................................................45 
 
 
 


Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AR 
autoregressive covariance matrix 
ATC 
anatomical therapeutic class 
BAI 
Beck Anxiety Inventory 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
CCMV 
complete case missing value 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
clinical study report 
eC-SSRS 
electronic version of Columbia-Suicide Severity Rating Scale 
EOS 
end of study  
EQ VAS 
visual analogue score from EQ-5D-3L questionnaire 
FAS 
full analysis set 
FSS 
Fatigue Severity Scale 
LEM5 
lemborexant 5 mg 
LEM10 
lemborexant 10mg 
ISI 
Insomnia Severity Index 
LPS 
latency to persistent sleep 
LS 
least squares 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation  
MNAR 
missing not at random 
PAB 
Performance Assessment Battery 
PBO 
placebo 


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Abbreviation 
Term 
PD 
pharmacodynamic 
PGI-Insomnia 
Patient Global Impression - Insomnia 
PK 
pharmacokinetic 
PSG 
polysomnography 
QTcB 
corrected QT interval by Bazett’s formula  
QTcF 
corrected QT interval by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard deviation 
SE 
sleep efficiency 
SI 
Système International 
SMQ 
Standardized MedDRA Queries  
SOC 
System Organ Class 
sSE 
subjective sleep efficiency 
sSOL 
subjective sleep onset latency 
sTST 
subjective total sleep time 
sWASO 
subjective wake after sleep onset 
T-BWSQ 
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TIB 
time in bed 
TST 
total sleep time 
UN 
unstructured covariance matrix 
WASO 
wake after sleep onset 
WASO1H 
wake after sleep onset in the first half of the night 
WASO2H 
wake after sleep onset in the second half of the night 
WHO DD 
World Health Organization Drug Dictionary 
ZOL 
zolpidem tartrate extended release 6.25 mg (Ambien CR®) 
 


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1 
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-
G000-304.   
This document is prepared based on the final study protocol amendment 4 (dated 05Feb2018).  
Reader is referred to the study protocol, the case report form (CRF), general CRF completion 
guidelines for details of study design, conduct and data collection. 
1.1 
Study Objectives 
1.1.1 
Primary Objective - US and Non-US 
Demonstrate using polysomnography (PSG) that lemborexant (LEM10 and LEM5) is 
superior to placebo (PBO) on sleep onset as assessed by latency to persistent to sleep (LPS) 
after the last 2 nights of 1 month of treatment in subjects 55 years and older with insomnia 
disorder. 
1.1.2 
Secondary Objectives 
Key Secondary Objectives - US Only 
• Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep 
maintenance as assessed by sleep efficiency (SE) after the last 2 nights of treatment 
• Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep 
maintenance as assessed by WASO after the last 2 nights of treatment 
• Demonstrate that lemborexant (LEM10 and LEM5) is superior to zolpidem tartrate 
extended release 6.25 mg (Ambien CR®; ZOL) on wake after sleep onset in the second 
half of the night (WASO2H)  after the last 2 nights of treatment  
 
Key Secondary Objectives - Non-US Only 
• Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on sleep 
maintenance as assessed by SE after the last 2 nights of treatment 
• Demonstrate that lemborexant (LEM10 and LEM5) is superior to PBO on wake after 
sleep onset (WASO) after the last 2 nights of treatment 
 
Additional Secondary Objectives - US and Non-US  
• Demonstrate that LEM5 or LEM10 or both LEM5 and LEM10 are superior to ZOL on 
postural stability in the morning after the first 2 nights of treatment  
• Determine whether the efficacy of LEM5 or LEM10 or both LEM5 and LEM10 is 
superior to that of ZOL on selected PSG variables after the first 2 nights and the last 


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2 nights of treatment and on selected Sleep Diary variables over the first 7 nights and the 
last 7 nights of treatment.   
• Confirm the efficacy of LEM5 and LEM10 compared to PBO on sleep as measured by 
PSG after the first 2 and last 2 nights of treatment and as measured by Sleep Diary over 
the first 7 and last 7 nights of treatment  
• Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and 
LEM10 and determine whether they are superior to that of ZOL and PBO as defined by 
response on PSG LPS and WASO and Sleep Diary subjective sleep onset latency (sSOL) 
and subjective wake after sleep onset (sWASO) 
• Evaluate the safety and tolerability of lemborexant 
• Determine whether the efficacy of LEM5 or LEM10 or both LEM5 and LEM10 is 
superior to that of ZOL and PBO on daytime functioning as assessed by the Insomnia 
Severity Index (ISI) and Fatigue Severity Scale (FSS) at the end of treatment 
• Determine whether the safety of LEM5 or LEM10 or both LEM5 and LEM10 is superior 
to that of ZOL and PBO as assessed by cognitive performance in the morning after the 
first 2 nights of treatment 
 
1.1.3 
Exploratory Objectives - US and Non-US  
• Explore the effects of LEM5, LEM10, ZOL and PBO on: 
◦ 
Subjective quality of sleep 
◦ 
Postural stability in the morning after the last 2 nights of treatment 
◦ 
Cognitive performance after the last 2 nights of treatment 
◦ 
Rebound insomnia in the 2 weeks following 30 days of treatment 
◦ 
Subjective ratings of morning sleepiness during and following completion of 
treatment 
◦ 
Sleep architecture parameters and other PSG variables 
◦ 
Health outcomes on the Patient Global Impression - Insomnia (PGI-Insomnia) and 
EQ-5D-3L 
◦ 
Withdrawal symptoms after completion of treatment 
• Summarize plasma concentrations of lemborexant and its metabolites M4, M9, and M10 
• Conduct population pharmacokinetic (PK) modeling for lemborexant 
• Explore PK/pharmacodynamic (PK/PD) relationships between lemborexant 
concentrations and selected efficacy and safety variables 
 
 


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1.2 
Overall Study Design and Plan 
E2006-G000-304 is a multicenter, randomized, double-blind, placebo-controlled, active 
comparator (ZOL), parallel-group study of 2 dose levels of lemborexant for 30 nights in 
approximately 950 subjects 55 years or older with insomnia disorder.  Subjects will be males 
65 years or older or females 55 years or older.  Approximately 60% of the subjects will be 
age 65 years or older. 
The study will have 2 phases: The Prerandomization Phase and the Randomization Phase. 
The Prerandomization Phase will comprise 3 periods that will last up to a maximum of 28 
days: a Screening Period, a Run-in Period, and a Baseline Period. The Randomization Phase 
will comprise a Treatment Period during which subjects are treated for 30 nights, and a 
minimum 14-day Follow-up Period before an End of Study (EOS) Visit. 
An interim analysis is planned to be conducted after approximately 50% of subjects 
(approximately 475 subjects) have been randomized and either completed Day 31 
assessments or discontinued from the study.  This interim analysis will be conducted for 
administrative reasons as detailed in the separate Interim Analysis Charter.  
The study design is illustrated in Figure 1. 
 
Figure 1 
Study Design 
“D” refers to the study day.  
BL = baseline, EOS = End of Study, LEM5 = lemborexant 5 mg, LEM10 = lemborexant 10 mg, PAB = performance assessment 
battery, PBO = placebo, PSG = polysomnography, ZOL = zolpidem tartrate extended release 6.25 mg. 
 
 
 


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2 
DETERMINATION OF SAMPLE SIZE 
The sample size was estimated for each comparison of LEM10 vs. PBO and LEM5 vs. PBO 
with respect to the mean change from baseline of LPS at Month 1, on the basis of a two-sided 
t-test at the 0.05 α-level for each treatment comparison.   
On the basis of the dose finding study E2006-G000-201 (Study 201), across various 
lemborexant doses (1 to 25 mg) at Days 14 and 15, the standard deviation (SD) of change 
from baseline for log-transformed LPS is assumed to be 0.9.  The LS mean treatment 
difference at Days 14/15 from Study 201 for log-transformed LPS of LEM5 and LEM10 
compared with PBO was -0.75 and -1.15, respectively.  Therefore, a sample size of 250 
subjects for LEM5, 250 subjects for LEM10, and 200 subjects for PBO has at least 95% 
power for each treatment comparison, LEM10 with PBO, and LEM5 with PBO, based on 2-
sided 2-sample t-test at 5% significance level (Table 1). 
Power is also estimated for the key secondary objectives, the comparison of LEM5 and 
LEM10 to PBO on change from baseline of SE and WASO, and LEM5 and LEM10 to ZOL 
on change from baseline of WASO2H (Table 1).  A sample size of 250 subjects each for 
LEM5, LEM10, and ZOL, and 200 subjects for PBO has at least 95% power for detecting a 
statistically significant difference between LEM and PBO for change from baseline in SE, at 
least 80% power for detecting a statistically significant difference between LEM10 and 
ZOL/PBO for change from baseline in WASO/WASO2H based on 2-sided 2-sample t-test at 
5% significance level.  
Table 1 
Power and Sample Size Calculation for Change from Baseline of 
LPS, SE, WASO2H, and WASO 
Endpoint (Test) 
Estimated Treatment 
Difference 
Estimated SD 
Power 
Log(LPS) (LEM5 vs PBO) 
-0.75 
0.9 
>95% 
Log(LPS) (LEM10 vs PBO) 
-1.15 
0.9 
>95% 
SE (LEM5 vs PBO) 
5% 
14% 
>95% 
SE (LEM10 vs PBO) 
7% 
14% 
>95% 
WASO (LEM5 vs PBO) 
-10 min 
55 min 
48% 
WASO (LEM10 vs PBO) 
-15 min 
55 min 
81% 
WASO2H (LEM5 vs ZOL) 
-8 min 
38 min 
65% 
WASO2H (LEM10 vs ZOL) 
-11 min 
38 min 
89% 
Estimated treatment difference and SD are based on Study 201. 
 
 


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3 
STATISTICAL METHODS 
All final statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.   
All descriptive statistics for continuous variables will be reported using number of 
observations (n), mean (arithmetic unless otherwise specified), standard deviation (SD), 
median, minimum and maximum.  Categorical variables will be summarized as number and 
percentage of subjects.  In summaries for safety the denominator for all percentages will be 
the number of subjects in a given treatment. 
All statistical tests will be based on the 5% level of significance (two-sided).   
3.1 
Study Endpoints 
3.1.1 
Primary Endpoint(s) 
The primary endpoint is: 
• Change from baseline of mean LPS on Days 29 and 30 of LEM10 and LEM5 compared 
to PBO 
 
3.1.2 
Secondary Endpoint(s) 
Key Secondary Endpoints - US Only 
• Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to 
PBO  
• Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5 
compared to PBO 
• Change from baseline of mean WASO2H on Days 29 and 30 of LEM10 and LEM5 
compared to ZOL  
 
Key Secondary Endpoints - Non-US Only 
• Change from baseline of mean SE on Days 29 and 30 of LEM10 and LEM5 compared to 
PBO  
• Change from baseline of mean WASO on Days 29 and 30 of LEM10 and LEM5 
compared to PBO 
 
Additional Secondary Endpoints - US and Non-US 
• Change from baseline on the postural stability test of mean units of body sway on Days 2 
and 3 of LEM5 and LEM10 compared to ZOL  


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• Change from baseline of mean LPS, WASO, and total sleep time (TST) on Days 1 and 2 
and Days 29 and 30 of  LEM5 and LEM10 compared to ZOL  
• Change from baseline of mean subjective Sleep Diary variables including  sSOL, 
sWASO, subject sleep efficiency (sSE) and subjective total sleep time (sTST) over the 
first 7 and last 7 nights of the Treatment Period of LEM5 and LEM10 compared to ZOL  
• Change from baseline of mean LPS, SE, WASO, WASO2H, and TST on Days 1 and 2 of 
LEM5 and LEM10 compared to PBO 
• Change from baseline of mean WASO2H and TST on Days 29 and 30 of LEM5 and 
LEM10 compared to PBO  
• Change from baseline mean of subjective Sleep Diary variables including sSOL, 
sWASO, sSE and sTST over the first 7 and last 7 nights of the Treatment Period of 
LEM5 and LEM10 compared to PBO  
• Proportion of responders on Days 1 and 2 and Days 29 and 30 (PSG), and over the first 7 
nights and last 7 nights of treatment (Sleep Diary), to LEM5 and LEM10 compared to 
ZOL and PBO, such that  
◦ 
Objective sleep onset response is defined as LPS ≤20 minutes (provided mean 
baseline LPS was >30 minutes) 
◦ 
Subjective sleep onset response is defined as sSOL ≤20 minutes (provided mean 
baseline sSOL was >30 minutes) 
◦ 
Objective sleep maintenance response is defined as WASO ≤60 minutes 
(provided mean baseline WASO was >60 minutes and is reduced by >10 minutes 
compared to baseline) 
◦ 
Subjective sleep maintenance response is defined as sWASO ≤60 minutes  
(provided mean WASO was >60 minutes and is reduced by >10 minutes 
compared to baseline) 
• Change from baseline of the score from items 4-7 on the ISI at Day 31 of LEM5 and 
LEM10 compared to ZOL and PBO 
• Change from baseline on the FSS score at Day 31 of LEM5 and LEM10 compared to 
ZOL and PBO 
• Change from baseline of mean power of attention, mean continuity of attention, mean 
quality of memory, and mean speed of memory retrieval on Days 2 and 3 
 
3.1.3 
Exploratory Endpoint(s) - US and Non-US 
The change from baseline of WASO2H for LEM10 and LEM5 compared to ZOL is 
considered exploratory for non-US.  The following endpoints will also be explored for LEM5 
and LEM10.  Except for PK endpoints, comparisons to both ZOL and PBO will be made.  
• Change from baseline of the mean rating on the Quality of Sleep question from the Sleep 
Diary of the first 7 days and last 7 days of the Treatment Period  


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• Change from baseline of mean power of attention, mean continuity of attention, mean 
quality of memory, and mean speed of memory retrieval on Days 30 and 31  
• From the postural stability test, change from baseline of mean units of body sway after 
the first 2 nights of the Treatment Period compared to PBO and the last 2 nights of the 
Treatment Period compared to ZOL and PBO 
• Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up 
Period 
◦ 
Change from baseline of sSOL on each of the first 3 nights, mean sSOL of the 
first 3 nights, mean sSOL of the first 7 nights, and mean sSOL of the second 7 
nights of the Follow-up Period 
◦ 
Change from baseline of sWASO on each of the first 3 nights, mean sWASO of 
the first 3 nights, mean sWASO of the first 7 and mean sWASO of the second 7 
nights of the Follow-up Period 
◦ 
Proportion of subjects whose sSOL is longer than at Screening at the following 
time points during Follow-up Period: each of the first 3 nights, mean of  the first 3 
nights, mean of the first 7 nights, mean of the second 7 nights  
◦ 
Proportion of subjects whose sWASO is higher than at Screening at the following 
time points during Follow-up Period: each of the first 3 nights, mean of the first 3 
nights, mean of the first 7 nights,  mean of the second 7 nights  
• Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings 
and last 7 mornings of the Treatment Period  
• Mean rating on the morning sleepiness item of the Sleep Diary on the first 7 mornings 
and second 7 mornings of the Follow-up Period  
• Change from baseline of mean morning sleepiness ratings assessed at 1.5 hours after 
wake time when subjects are in clinic on Days 1 and 2, and Days 29 and 30 
• Change from baseline of mean minutes and mean percentage (a) per time in bed (TIB) 
and (b) per total sleep time (TST) of sleep stage N1, N2, N3 (separately and combined) 
and REM on Days 1 and 2 and Days 29 and 30  
• Change from baseline of mean REM latency, mean number of awakenings, and mean 
number of long awakenings at Days 1 and 2 and Days 29 and 30 
• Number and percentage of subjects with a rating of a positive medication effect on each 
PGI-Insomnia item at Day 31 
• Change from baseline on the EQ-5D-3L at Day 31 
• Mean score on the T-BWSQ of LEM5 and LEM10 compared to ZOL and PBO at end of 
study 
• Proportion of subjects who score ≥3 on the T-BWSQ of LEM5 and LEM10 compared to 
ZOL and PBO at end of study 
• PK of lemborexant and its metabolites M4, M9, and M10 


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• Relationships between lemborexant PK, efficacy, and/or safety variables using PK/PD 
modeling  
 
3.1.4 
Other Endpoints  
The following PSG endpoints will be explored on an exploratory basis: 
• Wake after sleep onset in the first half of the night (WASO1H) 
• Duration of awakenings after persistent sleep 
• Duration of long awakenings after persistent sleep 
• Minutes and percentage of sleep stages per TIB: wake, non-REM (N1, N2, N3 separately 
and combined), REM 
• Minutes and percentage of sleep stages per TST: non-REM (N1, N2, N3 separately and 
combined), REM 
• WASO by quarter of the night 
 
3.2 
Study Subjects 
3.2.1 
Definitions of Analysis Sets 
Safety Analysis Set:  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. 
Full Analysis Set (FAS):  The FAS is the group of randomized subjects who received at least 
1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. 
PK Analysis Set:  The PK analysis set is the group of subjects who have at least 1 
quantifiable plasma concentration of lemborexant or its metabolites, or zolpidem, with 
adequately documented dosing history. 
Per Protocol Analysis Set (PP):  The PP is the group of all randomized subjects who received 
protocol-assigned study drug and do not meet any of the following criteria: 
• Violated inclusion/exclusion criteria 
• Duplicate randomization 
• Missing primary efficacy assessment 
• Primary efficacy assessment out of window 
• Prohibited concomitant medication 
• Study drug not administered 


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• Incorrect study drug kit dispensed 
 
Subjects who met any of the criteria listed above will be excluded from the PP due to 
possible introduction of bias. 
The number and percentage of subjects in each analysis set will be summarized by treatment 
groups using descriptive statistics.  The summaries for FAS and PP will be based on subjects 
“as randomized”.  The summary for Safety Analysis Set will be based on subjects “as 
treated”. 
3.2.2 
Subject Disposition 
Subject disposition will be summarized by treatment group for all randomized subjects.  The 
number and percentage of subjects who completed or discontinued prematurely from the 
study and their reason for discontinuation will be summarized by treatment group.       
In addition, the number of subjects screened the number and percentage of screen failures 
and their primary reason for screen failures will be summarized.  The number and percentage 
of randomized subjects will be summarized by region, country and sites by treatment group 
for all randomized subjects.  The number and percentage of subjects in each of the analysis 
sets will also be summarized.  
3.2.3 
Protocol Deviations 
Protocol deviations will be identified, reviewed and documented by the clinical team prior to 
database lock/treatment unblinding.  All protocol deviations will be categorized according to 
major/minor and standard classifications including but not limited to the following: 
• Violations of inclusion/exclusion criteria 
• Noncompliance with or incorrect implementation of protocol procedures 
• Noncompliance of study drug/dosage intervention 
• Use of prohibited concomitant medication 
Major protocol deviations will be summarized by category and treatment group.   
3.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for FAS and Safety Analysis Set will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, weight, and BMI; categorical variables include 
sex, age group (55 to <65, 65 to <75, ≥75 years), BMI group (<18.5, 18.5 to <25, 25 to 30, 
>30), race and ethnicity.   
The selected baseline assessments of Sleep Diary variables including sSOL, sWASO, sSE 
and sTST; PSG variables including LPS, WASO, SE, WASO2H and TST; ISI score and its 


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individual question score, and FSS will be summarized by treatment group.  The BDI-II and 
BAI scores will also be summarized at study baseline. 
3.2.4.1 
Medical History 
All medical histories as documented by the Medical History and Current Medical Conditions 
CRF will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The number and percent of subjects with medical history will be summarized by System 
Organ Class (SOC), preferred term for each treatment group based on Safety Analysis Set.   
3.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD; Mar 2017 or latest 
version).   
Prior medications are defined as medications that stopped before the first dose of study drug, 
including placebo during the Run-In Period.  Concomitant medications are defined as 
medications that (1) started before the first dose of study drug (including the Run-In Period) 
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 (including the Run-In Period) to the last dose day plus 14 days.  
The number and percentage of subjects who take prior and concomitant medications will be 
summarized using the Safety Analysis Set by treatment group, Anatomical Therapeutic 
Chemical class (ATC), and WHO DD preferred term (PT).  If a subject takes the same 
medications for the same class level or drug name, the subject will be counted only once for 
that class level or drug name.  Separate summary will be provided for subjects who take 
concomitant medication during Run-in Period and Treatment Period. 
3.2.6 
Treatment Compliance 
Treatment compliance (in %) is defined as follows:   
100 x (total number of tablets dispensed - total number of tablets returned or lost)    
number of tablets expected to be taken  
Treatment compliance during the Run-in and Treatment Period will be summarized 
separately using descriptive statistics based on Safety analysis set.  Treatment compliance 
will also be summarized by treatment group using the categories <80%, ≥80% to ≤100%, 
>100% to ≤120%, and >120%. In addition to overall treatment compliance, separate 
summaries will also be provided for tablets that are matched to LEM and tablets that are 
matched to ZOL. 


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3.3 
Data Analysis General Considerations 
The FAS will be used as the primary population for all efficacy analyses.  The Per Protocol 
analysis set will be used for sensitivity analyses to corroborate the primary efficacy 
endpoints.   
3.3.1 
Pooling of Centers  
This study was a multicenter, international study with an estimated 105 centers participating 
in the study.  Due to small expected number of subjects in each center, sites will be pooled 
within specific regions for primary and secondary efficacy analyses.  Other analyses will be 
performed with all centers pooled across the study unless stated otherwise.  Consistency of 
results across regions (North America and Europe) will be examined as specified in the 
respective sections in this document.  
3.3.2 
Adjustments for Covariates 
Baseline assessment and age groups (55 to 64, and ≥ 65 years old) are used as covariates in 
the primary and secondary analyses.  
3.3.3 
Multiple Comparisons/Multiplicity 
A sequential gate-keeping procedure will be used for the primary and the key secondary 
endpoint comparisons to control for the overall type I error at the 0.05 significance level 
(Figure 2).  The first endpoint comparison will be tested at the 0.05 significance level.  If the 
testing is found to be statistical significant, then proceed to the next endpoint testing at 
significance level of 0.05, otherwise stop testing.   
The primary endpoints will be tested in the following order: 
• Change from baseline of the mean LPS of Days 29 and 30 of LEM10 compared to PBO 
• Change from baseline of the mean LPS of Days 29 and 30 of LEM5 compared to PBO 
 
The key secondary endpoints will only be tested if both primary analyses are statistically 
significant at the 0.05 level.  The key secondary endpoints will be tested in the following 
order: 
US Only 
• Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO 
• Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO 
• Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to 
PBO 


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• Change from baseline of the mean WASO2H of Days 29 and 30 of LEM10 compared to 
ZOL  
• Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to 
PBO 
• Change from baseline of the mean WASO2H on Days 29 and 30 of LEM5 compared to 
ZOL  
 
Non-US Only 
• Change from baseline of the mean SE of Days 29 and 30 of LEM10 compared to PBO 
• Change from baseline of the mean SE of Days 29 and 30 of LEM5 compared to PBO 
• Change from baseline of the mean WASO of Days 29 and 30 of LEM10 compared to 
PBO  
• Change from baseline of the mean WASO on Days 29 and 30 of LEM5 compared to 
PBO 
 
No multiplicity adjustment will be done on other efficacy analyses.   
The gate-keeping testing procedure of the primary and secondary endpoints is illustrated in 
Figure 2:  
 
 


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Figure 2 
Flow Chart of Gate-Keeping Testing Procedure 
LEM5 = lemborexant 5 mg, LEM10 = lemborexant 10 mg, LPS = latency to persistent sleep, PBO = placebo, SE = sleep efficiency, WASO 
= wake after sleep onset, WASO2H = wake after sleep onset in the second half of the night, ZOL = zolpidem tartrate extended release 6.25 
mg. 
3.3.4 
 Examination of Subgroups 
Subgroup analysis of primary and key-secondary efficacy endpoints will be performed using 
age group (55 to <65, 65 to <75, ≥75 years old), alternative age group (55 to <65, ≥65 years 
old), sex (male and female), race (white, black, Asian, and other), region (North America and 
Europe), and BMI group (<18.5, 18.5 to <25, 25 to 30, >30) as detailed in Section 3.4.   
3.3.5 
Handling of Missing Data, Dropouts, and Outliers 
Based on data on file and published clinical trials of similar mechanism (suvorexant, orexin 
receptor antagonist), the percentage of missing values related to efficacy is expected to be 
minimal and unlikely to affect the result of the primary and secondary efficacy analyses.  
Based primarily on data from the 1-month Phase 2 study of lemborexant (Study 201), the 
percentage of discontinued subjects from the lemborexant treatment group is expected to be 
approximately 5%.  In suvorexant’s Phase 3 program, the reported discontinuation rate due to 
any reason within 3 month of treatment was 8%, including less than 2% who discontinued 
due to lack of efficacy 
The primary and key secondary efficacy endpoints will be analyzed using mixed effect 
model repeated measurement analysis (MMRM), the missing values will be imputed using 


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pattern-mixture multiple imputation (MI) assuming the missing data is missing not at random 
(MNAR) utilizing the complete case missing value pattern (CCMV).  Additional sensitivity 
analyses will also be performed on primary and key secondary efficacy endpoints as follows:  
MI Methods 
Details 
Analysis 
Type 
Complete Case 
Missing Value 
(CCMV) 
Subjects with missing data at any day are assumed to have a similar 
distribution as the completers within the respective treatment group  
(Pattern 1, below), where completers are defined as having no missing 
assessments for any post-baseline visits 
Primary 
Complete Case-4 
CCMV(k=4) 
This MI method will use all available monotone missing patterns to 
impute missing data assuming MNAR.  This will relax the assumption 
of using only the complete cases as in the primary analysis. 
 
Study days where 
results are available                1        2       29      30 
----------------------------------------------------------------  
 Pattern 1                                 x       x        x        x 
 Pattern 2                                 x       x        x        . 
 Pattern 3                                 x       x        .         .    
 Pattern 4                                 x       .         .         . 
 
Sensitivity 
Tipping Point 
Imputation towards the null hypotheses: A range of shifts will be used 
in the multiple imputation of missing data assuming MNAR to 
identify the specific shift and treatment effect that will tip the results 
from statistically significant to non-significant.  
Sensitivity 
 
Unless stated otherwise, missing values will be considered as non-responders in responder 
analyses and the continuous variables will be analyzed using MMRM assuming MAR.  
Details can be found in Section 3.4. 
All safety analyses will be performed based on the observed data only. 
3.3.6 
Other Considerations 
The following estimands are evaluated for the primary and key secondary efficacy endpoints 
in this study (Mallinckrodt, et al., 2012, and ICH E9(R1) Final Concept Paper, 2014).  The 
details of the analysis method are discussed in Section 3.4. 
Estimand 
Description 
Population Intervention Effect of Interest 
Analysis 
Type 
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 imputed using MI assuming MNAR 
utilizing CCMV missing value pattern (complete 
cases) 
(Assumes the probability of missing observations for 
any subject depends on the unobserved events.  For 
the missing pattern, complete cases will be used in the 
imputation.  Thus this method assumes dropouts or 
subjects with missing values have similar treatment 
effect as the completers within the respective 
treatment group.) 
primary  


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Estimand 
Description 
Population Intervention Effect of Interest 
Analysis 
Type 
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.) 
 Sensitivity 
(MMRM 
analysis 
assuming 
MAR) 
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 imputed using MI assuming MNAR 
utilizing CCMV-4 missing value pattern (all available 
up to 4 monotone missing patterns) 
 
(Assumes the probability of missing observations for 
any subject depends on the unobserved events.  For 
the missing pattern, complete cases up to 4 monotone 
missing patterns will be used in the imputation – see 
Section 3.4.1.3 for details.  Thus this method relaxes 
the assumption of the primary analysis of using only 
completers to impute the missing data. 
Sensitivity 
(CCMV-4) 
Difference in outcome 
improvement for all 
randomized subjects 
- all randomized subjects 
regardless of what 
treatment subjects 
actually received  
- include data after 
dropout 
 FAS 
a range of shifts will be used in the multiple 
imputation of missing data assuming MNAR to 
identify the specific shift and treatment effect that will 
tip the results from statistically significant to non-
significant 
Sensitivity 
(tipping 
point) 
Difference in outcome 
improvement for all 
randomized subjects 
- all randomized subjects 
regardless of what 
treatment subjects 
actually received  
- subjects who complete 
the study without 
missing efficacy 
assessments 
 FAS 
subjects who completed all primary and secondary 
efficacy assessments without missing visits  
Sensitivity 
(completer 
analysis) 
Difference in outcome 
improvement for those 
who adhere to 
treatment 
- subjects without major 
protocol violations that 
would impact efficacy 
assessments  
- include data after 
dropout 
PP 
missing values imputed using MI assuming MNAR 
utilizing CCMV missing value pattern (complete 
cases) 
(Assumes the probability of missing observations for 
any subject depends on the unobserved events.  For 
the missing pattern, complete cases will be used in the 
imputation.  Thus this method assumes dropouts or 
subjects with missing values have similar treatment 
effect as the completers within the respective 
treatment group.) 
sensitivity 
(PP analysis) 
Difference in outcome 
improvement for those 
who adhere to 
treatment 
- all randomized 
subjects; subject will be 
analyzed based on the 
actual treatment received 
- include data after 
dropout 
FAS 
missing values imputed using MI assuming MNAR 
utilizing CCMV missing value pattern (complete 
cases) 
(Assumes the probability of missing observations for 
any subject depends on the unobserved events.  For 
the missing pattern, complete cases will be used in the 
imputation.  Thus this method assumes dropouts or 
subjects with missing values have similar treatment 
effect as the completers within the respective 
treatment group.) 
sensitivity 
(as-treated 
analysis) 
CCMV = complete case missing value; FAS = full analysis set; MI = multiple imputation; MAR = missing at random; MMRM = mixed 
effect model with repeated measurement; MNAR = missing not at random; PP = per-protocol analysis set; WASO2H = wake after sleep 
onset in the second half of the night 


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3.4 
Efficacy/Pharmacodynamic Analyses 
Unless specified otherwise, all efficacy endpoints will be summarized and analyzed using 
FAS.  Baseline values for each efficacy parameter are defined in Section 6.2.   
Unless specified otherwise, all efficacy/pharmacodynamic endpoints will be derived by 
calculating the averages of pairs of values [eg, average of LPS on Day 1 and Day 2 (denoted 
as Days 1/2 hereafter), average of LPS on Day 29 and Day 30 (denoted as Days 29/30 
hereafter), …, etc.]   
The primary and key secondary endpoints comparisons are tested following the gate-keeping 
testing procedure described in Section 3.3.3, Multiple Comparison/Multiplicity, to control for 
the overall type I error at the 0.05 significance level.  The first primary efficacy endpoint 
comparison will be performed at the 0.05 significance level.  The subsequent testing will 
only proceed if the previous test is statistically significant at the 0.05 level. 
3.4.1 
Primary Analyses 
3.4.1.1 
Primary Analysis 
The primary efficacy endpoint is the change from baseline of LPS on Days 29/30 of LEM10 
and LEM5 compared to PBO. 
The null hypothesis of primary objective is that no difference exists in the mean change from 
baseline of LPS of Days 29/30 for treatment with LEM10 (or LEM5) as compared with PBO, 
and the corresponding alternative hypothesis is that a difference exists in the mean change 
from baseline of LPS of Days 29/30 for LEM10 (or LEM5) compared to PBO.  The change 
from baseline of LPS on Days 1/2 and Days 29/30, will be analyzed using the mixed effect 
model repeated measurement analysis (MMRM) with factors of age group (55 to 64, and ≥ 
65 years old), region (North America and Europe), treatment, visit (Days 1/2 and Days 
29/30), and treatment-by-visit interaction as fixed effect, and baseline LPS as a covariate 
based on FAS.  Since LPS is known to be non-normally distributed, a log-transformation will 
be used in the analysis.  The unstructured covariance matrix (UN) will be used in the 
analysis.  In the case of non-convergence of UN, the autoregressive [AR(1)] covariance 
matrix will be used in the model.  Before the implementation of the MMRM model, the 
missing values will be imputed using pattern-mixture model multiple imputation (MI) 
assuming the missing values are missing not at random (MNAR) utilizing the complete case 
missing value pattern (CCMV - subjects who completed primary efficacy assessments 
without missing values).  The missing values for a given visit will be imputed using all 
available values including the retrieved measurement from the post-discontinuation data.    
The treatment comparison will be performed using contrasts. The p-value, least square (LS) 
means and the 95% confidence interval (CI) for the treatment difference will also be 
provided. 


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MULTIPLE IMPUTATION 
Step 1 (imputing missing data): Thirty multiple imputed complete datasets were to be 
constructed using the imputation regression model of age, sex, race (white, black, and other), 
and region (North America, and Europe), baseline BMI, baseline log(LPS), baseline ISI, 
baseline sSOL, and individual log(LPS) assessments on Days 1, 2 , 29, and 30, with a 
predefined arbitrary seed number (seed=2359).  SAS PROC MI will be used to implement 
the imputation procedure using all available values.  The dataset will be converted into 
monotone missing pattern by imputing arbitrary missing data as the first step.  The monotone 
data will then be imputed with monotone regression method and MNAR.  The sample SAS 
statement can be found in Section 7. 
Step 2 (performing MMRM using each imputed dataset): The MMRM model with factors of 
age group (55 to 64, and ≥ 65 years old), region (North America, and Europe), treatment, 
visit (Days 1/2, and Days 29/30), and treatment-by-visit interaction as fixed effect, and the 
baseline log(LPS) as a covariate will be applied to each imputed dataset.  SAS PROC 
MIXED will be used for the MMRM analysis.  The sample SAS statement can be found in 
Section 7. 
Step 3 (combine results): Resulting treatment effect parameter estimators and standard errors 
from each of 30 multiple imputed datasets from Step 2 will be combined using SAS PROC 
MIANALYZE to obtain the pooled treatment effect and variance parameter estimators 
according to Rubin’s rules (Rubin DB, 1987).  The sample SAS statement can be found in 
Section 7. 
3.4.1.2 
Subgroup Analyses 
The primary endpoint described in Section 3.4.1 will be summarized using descriptive 
statistics by each subgroup listed below.  The MMRM model assuming MAR will be applied 
to provide the LS means and 95% CI for the treatment difference.  No hypothesis testing (p-
value) will be performed in the subgroup analyses.  
In addition, forest plot, and median and median change over time of LPS will also be 
provided for each subgroup listed below. 
• Age group (55 to 64, 65 to 74, ≥75 years old) 
• Sex (male and female) 
• Race (white, black, Asian and other) 
• Region (North America and Europe) 
• BMI group (<18.5, 18.5 to <25, 25 to 30, >30) 
 
3.4.1.3 
Sensitivity Analyses 
The following analyses will be considered as sensitivity analyses: 


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• PP analysis: The same primary efficacy analyses described in Section 3.4.1 (MMRM 
analysis with MI for missing value imputation) will be repeated based on PP analysis set. 
• Completer analysis: The same primary efficacy analyses described in Section 3.4.1 
(MMRM analysis without missing value imputation) will be repeated on subjects who 
completed all primary efficacy assessments and have no missing visits.  
• As-treated analysis: The same primary efficacy analyses described in Section 3.4.1 
(MMRM analysis with MI for missing value imputation) will be repeated based on the 
actual treatment the subject received regardless of randomization. 
• MMRM analysis assuming MAR: The same primary endpoint analysis described above 
will be analyzed using MMRM assuming the missing values are missing at random 
(MAR; MMRM analysis without missing value imputation). 
• MI Imputation assuming MNAR utilizing CCMV-4: The same MMRM method used in 
the primary analysis will be applied utilizing CCMV-4 (ie, up to 4 monotone missing 
patterns will be used for missing value imputation as follows): 
Study days where results are available 
1 
2 
29 
30 
Pattern 1 
x 
x 
x 
x 
Pattern 2 
x 
x 
x 
. 
Pattern 3 
x 
x 
. 
. 
Pattern 4 
x 
. 
. 
. 
x = result present; . = result missing 
• Tipping point analysis: A range of shifts will be used in the multiple imputation of 
missing data assuming MNAR to identify the specific shift and treatment effect that will 
tip the results from statistically significant to non-significant. 
3.4.2 
Secondary Analyses 
3.4.2.1 
Key Secondary Analyses 
CHANGE FROM BASELINE OF SE ON DAYS 29/30  
The change from baseline of SE on Days 1/2 and on Days 29/30 will be analyzed using the 
same MMRM model as the primary efficacy endpoint with factors of age group (55 to 64, 
and ≥65 year old), region (North America, and Europe), treatment, visit (Days 1/2, and Days 
29/30), and treatment-by-visit interaction as fixed effect, and baseline SE as covariates based 
on FAS.  The unstructured covariance matrix will be used in the analysis.  In case of non-
convergence, the AR(1) will be used in the model.  The missing values will be imputed using 
a pattern mixture model utilizing MI assuming MNAR.   Before the implementation of the 
MMRM model, the missing values for a given visit will be imputed using all available values 
including the retrieved measurement from the post-discontinuation data.  
The treatment comparison will be performed using contrasts.  The p-value, least square (LS) 
means and the 95% confidence interval (CI) of the treatment differences will also be 
provided. 


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Multiple Imputation 
The same 3 steps (imputing missing data, performing MMRM using each imputed dataset, 
and combine results) will be implemented as described in Section 3.4.1.  The complete  data 
sets will be constructed using regression model of age, sex, race (white, black, and other), 
region, baseline BMI, baseline SE, baseline ISI, baseline sSE, and individual SE assessments 
on Days 1, 2 , 29, and 30. 
CHANGE FROM BASELINE OF WASO2H ON DAYS 29/30 
The change from baseline of WASO2H on Days 1/2 and on Days 29/30 will be analyzed 
using the same MMRM model as the primary efficacy endpoint with factors of age group (55 
to 64 years, and ≥ 65 year old), region (North America, and Europe), treatment, visit (Days 
1/2, and Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline 
WASO2H as covariates based on FAS.  The unstructured covariance matrix will be used in 
the analysis.  In case of non-convergence, the AR(1) covariance matrix will be used in the 
model.  The missing values will be imputed using a pattern mixture model utilizing MI 
assuming MNAR.   Before the implementation of the MMRM model, the missing values for 
a given visit will be imputed using all available values including the retrieved measurement 
from the post-discontinuation data. 
The treatment comparison will be performed using contrasts.  The p-value, least square (LS) 
means and the 95% confidence interval (CI) of the treatment differences will also be 
provided. 
Multiple Imputation 
The same 3 steps (imputing missing data, performing MMRM using each imputed dataset, 
and combine results) will be implemented as described in Section 3.4.1.  The complete  data 
sets will be constructed using regression model of age, sex, race (white, black, and other), 
region, baseline BMI, baseline WASO2H, baseline ISI, baseline sWASO, and individual 
WASO2H assessments on Days 1, 2 , 29, and 30. 
CHANGE FROM BASELINE OF WASO ON DAYS 29/30 
The change from baseline of WASO on Days 1/2 and on Days 29/30 will be analyzed using 
the same MMRM model as the primary efficacy endpoint with factors of age group (55 to 64, 
and ≥65 year old), region (North America, and Europe), treatment, visit (Days 1/2, and Days 
29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO as 
covariates based on FAS.  The unstructured covariance matrix will be used in the analysis.  
In case of non-convergence, the AR(1) covariance matrix will be used in the model.  The 
missing values will be imputed using a pattern mixture model utilizing MI assuming MNAR.   
Before the implementation of the MMRM model, the missing values for a given visit will be 
imputed using all available values including the retrieved measurement from the post-
discontinuation data. 


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The treatment comparison will be performed using contrasts.  The p-value, least square (LS) 
means and the 95% confidence interval (CI) of the treatment differences will also be 
provided. 
Multiple Imputation 
The same 3 steps (imputing missing data, performing MMRM using each imputed dataset, 
and combine results) will be implemented as described in Section 3.4.1, Primary Analyses.  
The complete  data sets will be constructed using regression model of age, sex, race (white, 
black, and other), region, baseline BMI, baseline WASO, baseline ISI, baseline WASO, and 
individual WASO assessments on Days 1, 2 , 29, and 30. 
The subgroup analyses including plots (forest plot, and mean and mean change from baseline 
over time) described in Section 3.4.1.2 and the sensitivity analyses described in Section 
3.4.1.3 will be repeated for all key secondary endpoints.  
3.4.2.2 
Other Secondary Analyses 
Unless it is covered from the same model from the primary and secondary efficacy endpoints, 
or specified otherwise, for all other secondary endpoints, the change from baseline 
assessments will be analyzed using MMRM assuming MAR (no missing value imputation) 
and the portion of responders will be analyzed using the Cochran Mantel Haenszel (CMH) 
test adjusted for age group.  Missing values will be considered as non-responders in all 
responder analyses.  No multiplicity adjustment will be made for all analyses.  
POLYSOMNOGRAPHY 
The following endpoints will be analyzed from PSG:  
• Change from baseline of LPS, SE, WASO on Days 1/2 of LEM5 and LEM10 compared 
to PBO  
• Change from baseline of LPS, SE, WASO on Days 1/2 and Days 29/30 of LEM5 and 
LEM10 compared to ZOL 
• Change from baseline of WASO2H on Days 1/2 of LEM5 and LEM10 compared to ZOL 
• Change from baseline of WASO2H on Days 1/2 and Days 29/30 of LEM5 and LEM10 
compared to PBO 
• Change from baseline of WASO on Days 1/2 of LEM5 and LEM10 compared to PBO 
• Change from baseline of WASO on Days 1/2 and Days 29/30 of LEM5 and LEM10 
compared to ZOL 
• Change from baseline of TST on Days 1/2 and Days 29/30 of LEM5 and LEM10 
compared to ZOL and PBO 
• Proportion of responders on Days 1/2 and Days 29/30 of LEM5 and LEM10 compared to 
ZOL and PBO in which the responder is defined as follows:  


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◦ 
Objective sleep onset responder: defined as LPS ≤20 minutes provided baseline 
LPS >30 minutes 
◦ 
Objective sleep maintenance responder: defined as WASO ≤60 minutes, a 
reduction from baseline by >10 minutes  provided baseline WASO >60 minutes  
 
ELECTRONIC SLEEP DIARY 
The following endpoints will be analyzed from the Sleep Diary:  
• Change from baseline of mean sSOL, sWASO, sTST, and sSE over the first 7 and last 7 
nights of the treatment period of LEM 5 and LEM 10 compared to ZOL and PBO.  The 
derivation of sSOL, sWASO, sTST and sSE is detailed in Appendix 2. 
• Proportion of responders over the first 7 and last 7 nights of the treatment period of 
LEM5 and LEM10 compared to ZOL and PBO in which the responder is defined as 
follows:  
◦ 
Subjective sleep onset responder: defined as sSOL ≤20 minutes and baseline 
sSOL >30 minutes 
◦ 
Subjective sleep maintenance responder: defined as sWASO ≤60 minutes,  
reduction from baseline by > 10 minutes, and  baseline sWASO >60 minutes  
POSTURAL STABILITY USING THE CDR POSTURE ASSESSMENT 
• Change from baseline of units of body sway on Days 2/3 of the Treatment Period 
compared to ZOL  
INSOMNIA SEVERITY INDEX AND FATIGUE SEVERITY SCALE 
The following endpoints will be analyzed from the ISI and FSS: 
• Change from baseline of the total score from items 1-7 as well as items 4-7 on the ISI at 
Day 31 of LEM5 and LEM10 compared to ZOL and PBO 
• Change from baseline on the FSS score at Day 31 of LEM5 and LEM10 compared to 
ZOL and PBO 
COGNITIVE PERFORMANCE ASSESSMENT BATTERY 
The following endpoints will be analyzed from computerized performance assessment 
battery (PAB)  
• Change from baseline of the 4 composite domain factor scores of PAB (power of 
attention, mean continuity of attention, mean quality of memory, and mean speed of 
memory retrieval ) on Days 2/3 


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3.4.3 
Other Efficacy/Pharmacodynamic Analyses 
The following endpoints are considered exploratory.  Comparison of LEM10 and LEM5 will 
be made with ZOL and PBO. 
Unless specified otherwise, for all other efficacy analyses endpoints, the change from 
baseline assessment will be analyzed using MMRM assuming MAR and the portion of 
responders will be analyzed using the Cochran Mantel Haenszel test adjusted for age group.  
Missing values will be considered as non-responders in all responder analyses. No 
multiplicity adjustment will be made for all analyses. 
POLYSOMNOGRAPHY 
• Change from baseline of total duration (in minutes) of sleep stage of non-REM (N1, N2, 
N3 separately and combined) and REM on Days 1/2 and Days 29/30 
• Percentage of the change from baseline of total duration of sleep stage of non-REM (N1, 
N2, N3 separately and combined) and REM  
◦ 
per time in bed (TIB) on Days 1/2 and Days 29/30 
◦ 
per TST on Days 1/2 and Days 29/30 
• Change from baseline of REM latency (defined as the first sleep epoch to first REM sleep 
epoch) on Days 1/2 and Days 29/30 
• The change from baseline of mean REM latency will be analyzed separately for Days 1/2 
and for Days 29/30 using Wilcoxon rank sum test.  The treatment difference will be 
estimated using Hodges-Lehmann estimation, and the asymptotic (Moses) 95% CI for the 
difference will be provided. 
• Change from baseline in number of awakenings on Days 1/2 and Days 29/30 
• Change from baseline in number of long awakenings (defined as awakenings of 5 
minutes or longer) on Days 1/2 and Days 29/30 
ELECTRONIC SLEEP DIARY  
• Change from baseline of the mean rating on the Quality of Sleep question from the Sleep 
Diary of the first 7 days and last 7 days of the Treatment Period  
• Rebound insomnia endpoints during the Follow-up Period.  Rebound insomnia is defined 
as worsened sleep (ie, higher value of sSOL or sWASO) relative to Screening after study 
drug treatment is completed.   
◦ 
Change from baseline of sSOL on each of the first 3 nights, mean of the first 3 
nights, mean sSOL of the first 7 nights, and mean sSOL of the second 7 nights of 
the Follow-up Period 
◦ 
Change from baseline of sWASO on each of the first 3 nights, mean of the first 3 
nights, mean sWASO of the first 7 and mean sWASO of the second 7 nights of 
the Follow-up Period 


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◦ 
Proportion of subjects whose sSOL is longer than at Screening at the following 
time points of the Follow-up Period by at least 5 minutes: each of the first 3 
nights, mean of the first 3 night, mean of the first 7 nights, and mean of the 
second 7 nights  
◦ 
Proportion of subjects whose sWASO is higher than at Screening at the following 
time points of the Follow-up Period by at least 5 minutes: each of  the first 3 
nights, mean of the first 3 nights, mean of the first 7 nights, and mean of the 
second 7  
The actual value of sSOL and sWASO will be analyzed separately using analysis of 
covariance model (ANCOVA) with factors of age group (55 to <65, and ≥65 years older), 
region (North America, and Europe), and treatment for each time point (baseline, each of 
the first 3 night, mean of the first 3 nights, mean of the first 7 days, and mean of the last 7 
days).  The 95% CI of the treatment difference will be constructed for each time point.  It 
will be considered as having strong evidence of rebound insomnia if the lower bound of 
the 95% CI of sSOL or sWASO for each of the 3 night, the mean of the first 3 nights, 
mean of the first 7 days, and mean of the second 7 nights of the Follow-up Period 
exceeds the upper bound of a 95% CI for the values during the Screening Period in the 
given treatment group.  If the LS means for sSOL and sWASO for the Follow-up Period 
are all lower than for the Screening Period, then no rebound insomnia is suggested.   
• Mean rating on morning sleepiness over the first 7 mornings and last 7 mornings of the 
Treatment Period and over the first 7 mornings and last 7 mornings of the Follow-up 
Period. 
MORNING SLEEPINESS QUESTIONNAIRE 
• Change from baseline of morning sleepiness ratings on Days2/3, and Days 30/31 
POSTURAL STABILITY USING THE CDR POSTURE ASSESSMENT 
• Change from baseline of units of body sway on Days 2/3 of the Treatment Period 
compared to PBO and on Days 30/31 of the Treatment Period compared to ZOL and 
PBO 
COGNITIVE PERFORMANCE ASSESSMENT BATTERY 
• Change from baseline of power of attention, continuity of attention, quality of memory, 
and speed of memory retrieval on Days 30/31 
OTHER POLYSOMONGRAPHY ASSESSMENTS 
The following endpoints from PSG will also be summarized using frequency count or 
descriptive statistics by treatment groups for exploratory purpose.  No hypothesis testing will 
be performed on these endpoints. 
Unless specified otherwise, the following endpoints will be summarized for Days 1/2 and 
Days 29/30: 
• WASO1H 


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• Number of awakenings after persistent sleep 
• Number and duration of long awakenings after persistent sleep 
• Minutes of sleep stages: WASO, non-REM (N1,N2, N3 separately and combined), REM 
• Percentage of minutes for each sleep stages per TIB: total wake time, non-REM (N1, N2, 
N3 separately and combined), REM 
• Percentage of minutes for each sleep stages per TST: non-REM (N1, N2, N3 separately 
and combined), REM 
• REM latency (defined as the first sleep epoch to first REM sleep epoch) 
• Number of subjects with REM latency within 15 minutes of sleep onset 
• WASO by quarter (every 2 hours) of the night 
3.5 
Pharmacokinetic, Pharmacogenomic, and Other Biomarker 
Analyses 
3.5.1 
Pharmacokinetic Analyses 
The plasma concentrations of lemborexant and its metabolites M4, M9, and M10, as well as 
zolpidem (where quantified) will be summarized using descriptive statistics by dose, time 
and day based on Safety Analysis Set. 
A separate analysis plan for the population PK analyses will be developed and finalized 
before the database lock. 
3.5.2 
Pharmacokinetic/Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
A separate analysis plan for the PK/PD analyses will be developed and finalized before the 
database lock. 
3.6 
Safety Analyses  
All safety analyses will be performed based on observed data using the Safety Analysis Set.  
Safety data will be summarized on an “as treated” basis using descriptive statistics or 
frequency count only.  No hypothesis testing will be performed for safety analyses. 
3.6.1 
Extent of Exposure 
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study 
drug will be summarized using descriptive statistics by treatment group.  Duration of 
exposure of study drug will be defined as the number of days between the date the subject 
received the first dose of study drug during Treatment Period and the date the subject 
received the last dose of study drug during Treatment Period, inclusive.    


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3.6.2 
Adverse Events 
The adverse event (AE) verbatim descriptions (investigator terms from the CRF) will be 
classified into standardized medical terminology using the MedDRA.  Adverse events will be 
coded to the MedDRA (Version 20.1 or higher) lower level term closest to the verbatim term.  
The linked MedDRA PT and primary system organ class (SOC) are also captured in the 
database. 
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment 
(including the Run-In Period up to 14 days after the last dose of study drug from the 
Treatment Period), having been absent at pretreatment (before the Run-In Period) or  
• Reemerges during treatment (including the Run-In Period up to 14 days after the last dose 
of study drug from the Treatment Period), having been present at pretreatment (before the 
Run-In Period) but stopped before the last dose of study drug plus 14 days, or  
• Worsens in severity during treatment (including the Run-In Period up to 14 days after the 
last dose of study drug from the Treatment Period) relative to the pretreatment state, 
when the AE is continuous. 
For TEAEs occurred during the Run-in Period, the incidence of TEAEs will be summarized 
by SOC and PT. 
An overview table of TEAE occurred during Treatment Period, including number of subjects 
with TEAEs, treatment-emergent serious adverse events (SAEs), deaths, severe TEAEs, 
study drug related TEAEs, TEAEs leading to study drug withdrawal during the Treatment 
Period will be provided.  In addition, the following summaries will be produced for the 
TEAEs occurred during the Treatment Period: 
• Incidence of TEAEs by PT in descending order  
• Incidence of TEAEs by SOC and PT  
• Incidence of treatment-related TEAEs by SOC and PT 
• Incidence of TEAEs by SOC, PT, and severity 
• Incidence of treatment-related TEAEs by SOC, PT, and severity 
• Incidence of TEAEs by SOC, PT, and relationship to treatment 
• Incidence of non-serious TEAEs (>5%) by SOC and PT 
If a subject experiences more than one TEAE within a preferred term, the subject will be 
counted only once in the calculation of incidence of TEAE within that preferred term.  
Similarly, if a subject experiences more than one TEAE within a SOC, the subject will be 
counted only once in the calculation of incidence of TEAE within that SOC.  If a subject 
experiences more than one TEAE within a preferred term (or SOC), the occurrence with the 
highest severity will be used in the calculation of the incidence of TEAE within that preferred 
term (SOC) by severity.  If a subject experiences more than one TEAE within a preferred 
term (or SOC), the occurrence considered most closely related to study drug will be used in 


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the calculation of the incidence of TEAE with that preferred term (SOC) by relationship 
(given by investigator). 
The following summaries will also be presented for the treatment-emergent SAEs occurred 
during the Treatment Period: 
• Incidence of treatment-emergent SAEs by SOC and PT  
• Incidence of treatment-emergent SAEs by SOC, PT, and relationship to treatment. 
In addition, number and percentage of subjects with TEAEs and treatment-related TEAEs 
leading to discontinuation from study treatment during the Treatment Period will also be 
summarized by MedDRA SOC, PT for each treatment group. 
3.6.2.1 
Selected Adverse Events 
The following significant AEs will be summarized by SOC and PT: 
• Cataplexy 
• Falls 
• Seizures 
• Abuse liability events 
Cataplexy includes the TEAEs with MedDRA PT of cataplexy, and drop attack. 
Falls includes the TEAEs with MedDRA PT of “fall” only. 
Seizure includes TEAEs with MedDRA PTs belonging to MedDRA Standardized MedDRA 
Query (SMQ) of “Convulsions” (Narrow Terms). 
Abuse liability events includes TEAEs with MedDRA PT listed in Appendix 3. 
3.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
With the exception of urinalysis, all quantitative parameters listed in protocol Section 
9.5.1.5.5 Laboratory Measurements, the actual value and the change from baseline will be 
summarized at each visit using descriptive statistics by treatment group.  For urinalysis, the 
actual and the change from baseline of pH and specific gravity will be summarized at each 
visit by treatment group.  Analysis of changes from baseline will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.  
Laboratory test results will be assigned a low- normal-high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Shifts from baseline (LNH) to the Day 31, End of Treatment and the EOS 
visit will be provided by treatment groups for each laboratory parameter.   


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The Sponsor’s Grading for Laboratory Values (Appendix 1) presents the criteria that will be 
used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject will be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable. 
3.6.4 
Vital Signs 
For each vital signs parameters (ie, diastolic and systolic BP, pulse, respiration rate, 
temperature) and weight, the actual value and changes from Study Baseline will be 
summarized by treatment group at each visit using descriptive statistics.  Analysis of changes 
from baseline will be based on the number of subjects with both nonmissing baseline and 
relevant postbaseline results. 
In addition, clinically notable vital sign values will be identified using the criteria in Table 2.  
The clinically notable vital sign values will be summarized using frequency count at each 
visit by treatment group.   
Table 2 
Vital Sign Criteria 
 
Criterion valuea 
Change relative to 
baselinea 
Clinically notable range 
Heart rate 
>120 bpm 
Increase of  15 bpm 
H 
 
<50 bpm 
Decrease of  ≥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 
Weight 
-- 
Increase of ≥7%  
H 
 
-- 
Decrease of ≥7% 
L 
Respiratory Rate 
>20 bpm 
-- 
H 
 
< 10 bpm 
-- 
L 
BP = blood pressure, H = high, L = low. 
a. 
Clinically notable means that a value must meet the criterion value and must attain the specified magnitude 
of change relative to baseline. 
3.6.5 
Electrocardiograms 
For each ECG parameters (including PR interval, RR interval, QRS interval, QT interval, 
QTcB interval, QTcF interval and heart rate) and actual value and changes from baseline will 
be summarized by treatment group at each visit using descriptive statistics.  Shift tables from 


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baseline to the Day 31, End of Treatment and the EOS visits will be presented by treatment 
group for ECG interpretation (categorized as normal and abnormal).  
In addition, maximum postbaseline measurement will also be tabulated by treatment group as 
follows: 
• Number and percentage of subjects with QTcF of >450 msec, and >500 msec during the 
treatment 
• Number and percentage of subjects with a QTcF increment of >30 msec, and >60 msec 
from the baseline visit. 
• Number and percentage of subjects with PR of >220 msec 
• Number and percentage of subjects with QRS of >120 msec 
 
3.6.6 
Other Safety Analyses 
3.6.6.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be assessed using a self-rated electronic version of the C-SSRS (eC-SSRS).  
The eC-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  The incidence of suicidal ideation, suicidal behavior, and self-
injurious non-suicidal behavior at each visit will be summarized by treatment group using 
frequency count.  A subject will be counted once in a category if at least one question is 
answered positive in the category.   
3.6.6.2 
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (T-BWSQ) 
Withdrawal symptoms will be assessed using the T-BWSQ at the EOS visit.  Subjects will be 
asked about the presence/absence and severity of the symptoms listed in the questionnaire. 
For each listed symptom, the subject is to respond “No” (Score = 0), “Yes – moderate” 
(Score = 1) or “Yes – severe” (Score = 2).  The sum of responses will be the subject’s total 
score.  The total score will be summarized by treatment group using descriptive statistics.  In 
addition, the number and percentage of subjects with a total score of ≥3 will be summarized 
using frequency count. 
3.7 
Other Analyses 
3.7.1 
Health Outcome Economics Analyses 
3.7.1.1 
EQ-5D-3L 
The EQ-5D-3L instrument comprises questions on 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression) and a visual analogue score (EQ VAS).  
Each dimension has 3 levels: no problem, some problems, extreme problems and the EQ 
VAS is ranged from 0 (“Worst imaginable health state”) to 100 (“Best imaginable health 


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state”).  Each dimension score will be summarized separately at Baseline and Day 31 using 
frequency count on observed data only with no imputation.  The change from baseline of EQ 
VAS will be analyzed using ANCOVA with factors of age group (55 to 64, and ≥65 years   
old), region (North America, and Europe), treatment based on FAS and baseline VAS as a 
covariate.  
3.7.1.2 
 Patient Global Impression (PGI) - Insomnia 
The PGI-Insomnia questionnaire captures the global impression of the study medication’s 
effect at the end of treatment and is collected on Day 31 visit only.  The PGI-Insomnia has 3 
items related to study medication effect (helped/worsened sleep, decreased/increased time to 
fall asleep, and increased/decreased TST) on a 3-point scale (1=positive medication effect, 
2=neutral medication effect, and 3=negative medication effect) and 1 item related to 
perceived appropriateness of study mediation strength also on a 3-point scale (medication: 
1=too strong, 2=just right, and 3=too weak).  Each item will be analyzed summarized 
separately (“positive medication effect” versus others for the first 3 item; “just right” versus 
others for the last item) using chi-square test on observed data only based on FAS with no 
imputation for missing values, and repeated for age subgroups. 
3.8 
Exploratory Analyses 
None   
4 
INTERIM ANALYSES 
An interim analysis is planned to be conducted after approximately 50% of subjects 
(approximately n=475 subjects) have been randomized and either completed Day 31 
assessments or discontinued from the study.  This interim analysis will be conducted for 
administrative reasons as detailed in the separate Interim Analysis Charter.  When the 
specified number of subjects has completed the Day 31 assessments, an independent 
statistician external to the Sponsor will be provided with the relevant PSG dataset and will be 
unblinded to the primary endpoint, ie, change from baseline in WASO2H for the mean of 
Days 29 and 30.  A conditional power will be calculated to predict the probability that the 
trial will achieve a significant treatment effect for WASO2H in the LEM10 versus ZOL arms 
at the end of the study, given what is observed at the time of interim analysis. The interim 
analysis will be limited to the comparison of LEM10 versus ZOL on the change from 
baseline in WASO2H for the mean of Days 29 and 30.  No other endpoints, dose groups, or 
timepoints will be analyzed at the interim analysis. The study will not be terminated for 
either futility or efficacy.  Therefore no impact to the type I error rate is expected.   
The method of calculating the conditional power will be detailed in the Interim Analysis 
Charter, along with operational procedures, unblinding procedures, procedures for 
communicating the results of the conditional power calculation and recipients of this 
information.  To preclude potential influence on the conduct of the remainder of the study, 
disclosure of the interim results will be limited to a prespecified set of executive-level 
individuals at the sponsor and sponsor's co-development partner.  No individuals involved 


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with the conduct of the study will have access to the interim data or the results of the interim 
analysis (i.e., the conditional power of LEM10 versus ZOL on the change from baseline in 
WASO2H for the mean of Days 29 and 30). 
Enrollment of subjects will not be stopped during the interval during which the interim 
analysis is conducted.  The interim analysis may be waived or otherwise not conducted, for 
reasons including but not limited to a higher than anticipated enrollment rate which would 
make the interim analysis unnecessary as the majority of subjects would have been enrolled 
by the time the interim analysis is concluded.  
5 
CHANGES IN THE PLANNED ANALYSES 
The following changes were made in version 2.0 of the SAP from version 1.0: 
• Section 3.3.5 “Handling of Missing Data, Dropouts, and Outlier”, Section 3.3.6 “Other 
Considerations”, Section 3.4 “Efficacy/Pharmacodynamic Analyses”: Sensitivity 
analyses are added to evaluate different missing value patterns.  Sensitivity and subgroup 
analyses are added to key secondary efficacy endpoints for completeness.   
• Section 3.6.2.1 “Selected Adverse Events” and Appendix 13.3 “List of Abuse Liability 
Events”: The definition of “Abuse Lability Events” is updated to utilize MedDRA SMQs.  
Appendix 13.3 from version 1.0 is removed from this section. 
• Section 6.1 “Visit Window”: Visit window description is added for diary efficacy 
endpoints. 
• Throughout the document: Editorial comments are made to correct typos or for 
clarification purposes. 
The following changes were made in version 3.0 of the SAP from version 2.0: 
 Section 3.1.2“Secondary Endpoints”, Section 3.3.3 “Multiple 
Comparisons/Multiplicity”:  The order of the objectives and endpoints is updated to 
incorporate feedback from regulatory authorities. 
 Section 3.2.1 “Definitions of Analysis Sets”: List of exclusion reasons from the PP 
population is updated. 
 Section 3.6.2.1 “Selected Adverse Events” and Appendix 3 “List of Abuse Liability 
Events”: The definition of “Abuse Lability Events” is updated to revert back to the 
approach from version 1.0.   
 Section 7 “Programming Specifications”: The description of a planned tipping point 
analysis has been included. 
 Throughout the document: Editorial comments are made to correct typos or for 
clarification purposes. 


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6 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
6.1 
Visit Window 
Study Day 1 is defined as the date of the first dose of study drug during the Treatment Period.  
The nominal visit (ie, study visit captured on the CRF) will be used as the analysis visits in 
all by-visit summaries except for sleep diary efficacy endpoints.  The Early Term visit will be 
considered as unscheduled visit and will not be included in the by-visit summary.  Where 
applicable, the Early Term visit will be used along with the Day 31 visit for completers as the 
End of Treatment visit for the safety analyses. 
For diary efficacy endpoints, the following visit window will be applied: 
Timepoint  
Visit Window (in study days) 
First 7 days of Treatment 
2-8 
Last 7 days of Treatment 
22-36a 
a: Last seven days within this window while on treatment 
6.2 
Baseline Assessment  
Unless otherwise specified, baseline measurement is the last observed measurement, 
including unscheduled assessments, prior to the first dose of study medication of treatment 
period for a given assessment.  For the following endpoints, baseline measurement is defined 
as follows:  
• PSG parameters : average of the two PSG recordings during the Run-in Period  
• Sleep diary parameters:  
◦ 
For rebound insomnia: the mean of diary data entered on the last 7 mornings 
before the Screening PSG during the Screening Period 
◦ 
Other Sleep Diary-derived endpoints: the mean of diary data entered on the last 7 
mornings before the first Baseline PSG during the Run-In Period 
• Morning sleepiness questionnaire at 1.5 hours after wake time on mornings after PSG 
recordings: Average of the 2 morning sleepiness ratings during the Run-in Period 
• ISI: Last available ISI measurement on or prior to Visit 3  
• Postural Stability parameters: Average of non-missing measurements from Visit 3 Visit 4  
• Cognitive PAB parameters: Average of non-missing measurements from Visit 3 and Visit 
4 
• FSS: Last available FSS measurement on or prior to Visit 5  
• EQ-5D-3L: Last available EQ-5D-3L measurement on or prior to Visit 5 
• C-SSRS: Visit 5 (“since last visit” form) 
 


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6.3 
Missing Data Handling 
Unless stated otherwise, missing values will be considered as non-responders in responder 
analyses and the continuous variables will be analyzed using MMRM to handle the missing 
values assuming MAR in all other efficacy analyses.  Details can be found in Section 3.4 
All safety analyses will be performed based on the observed data only. 
6.3.1 
Polysomnography, Cognitive Performance Assessment, Posture Stability, 
and Morning Sleepiness Questionnaire 
Each PSG, PAB, posture stability, and morning sleepiness questionnaire parameters will be 
derived by calculating the averages of pairs of values, i.e., the average of the two PSG 
recordings during the Run-in Period, Day 1 and Day 2, and Day 29 and Day 30.  If one of 
each pair of values is missing, the other available value will be taken as the average of the 
pair; if both values are missing, then the parameter will be missing for the corresponding 
pair.   
6.3.2 
Sleep Diary 
Each Sleep Diary parameter will be derived by calculating the average of weekly (7 days) 
diary parameter values.  For the follow-up period, if the first 7 nights overlaps with the last 7 
nights (eg, the follow-up period is less than 14 days in total), the last non-overlaps nights will 
be used in calculating the average value for the last 7 nights. 
For each Sleep Diary parameter at baseline, if no more than 2 of the 7 nights’ values are 
missing, the available values will be used to calculate the mean.  If more than 2 values are 
missing, the parameter will be considered missing for baseline.  For each Sleep Diary 
parameter during treatment period and follow-up period, if at least 4 of the 7 nights’ values 
are available, the available values will be used to calculate the mean.  If less than 4 values are 
available, the parameter will be considered missing for the corresponding time point.  
7 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
The following sample SAS statement provides the framework for the MI method: 
CONVERT DATASET INTO MONOTONE MISSING DATA PATTERN (IMPUTING ARBITRARY MISSING 
DATA): 
PROC MI data=<dataset> nimpute=30 seed=2359 out=<dataset1>; 
   VAR age BMI baseline… visit1-visit4; 
   MCMC chain=multiple nbiter=500 niter=300 impute=monotone; 
   BY treatment; 
RUN; 


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IMPUTE MISSING VALUES: 
PROC MI data=<dataset1> nimpute=1 seed=2359 out=<dataset2>; 
   CLASS treatment sex race region; 
   MONOTONE regression ( /details); 
   MNAR model (visit1-visit4/ modelobs=CCMV); 
   VAR treatment age sex race region BMI baseline….; 
   BY _imputation_; 
RUN; 
PERFORMING MMRM: 
PROC MIXED data=<dataset2>; 
   CLASS subject treatment agegrp visit; 
   MODEL value=treatment agegrp region visit visit*treatment / ddfm=kr; 
   REPEAT visit/sub=subject type=UN group=treatment; 
   LSMEANS visit*treatment; 
   ESTIMATE ‘5mg  –  ZOL Days 1_2’      treatment 0 -1 1 0  visit*treatment   0 0 -1 0 1 0 0 0/CL; 
   ESTIMATE ‘10mg – ZOL Days 1_2’      treatment 0 -1 0 1  visit*treatment   0 0 -1 0 0 0 1 0/CL;     
   ESTIMATE ‘5mg  –  ZOL Days 29_30’  treatment 0 -1 1 0  visit*treatment   0 0 0 -1 0 1 0 0/CL; 
   ESTIMATE ‘10mg – ZOL Days 29_30’  treatment 0 -1 0 1  visit*treatment   0 0 0 -1 0 0 0 1/CL;     
   BY _imputation_; 
   ODS output estimates=<dataset3>; 
RUN; 
COMBINE RESULTS: 
PROC MIANALYZE data=<dataset3>; 
   MODELEFFECTS estimate; 
   STDERR stderr; 
RUN; 
VARIABLE ORDER TO BE USED IN THE PROC MI PROCEDURES: 
To Create Monotone Missing Data Pattern 
• LPS: age, baseline BMI, baseline ISI, baseline log(sSOL), baseline log(LPS), log(LPS) at 
Day1, log(LPS) at Day2, log(LPS) at Day29, log(LPS) at Day30 
• SE: age, baseline BMI, baseline ISI, baseline sSE, baseline SE, SE at Day1, SE at Day2, 
SE at Day29, SE at Day30 
• WASO2H: age, baseline BMI, baseline ISI, baseline sWASO, baseline WASO2H, 
WASO2H at Day1, WASO2H at Day2, WASO2H at Day29, WASO2H at Day30 
• WASO: age, baseline BMI, baseline ISI, baseline sWASO, baseline WASO, WASO at 
Day1, WASO at Day2, WASO at Day29, WASO at Day30 
 


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To Impute Missing Values 
• LPS: treatment, age, sex, race, region, baseline BMI, baseline ISI, baseline log(sSOL), 
baseline log(LPS), log(LPS) at Day1, log(LPS) at Day2, log(LPS) at Day29, log(LPS) at 
Day30 
• SE: treatment, age, sex, race, region, baseline BMI, baseline ISI, baseline sSE, baseline 
SE, SE at Day1, SE at Day2, SE at Day29, SE at Day30 
• WASO2H: treatment, age, sex, race, region, baseline BMI, baseline ISI, baseline 
sWASO, baseline WASO2H, WASO2H at Day1, WASO2H at Day2, WASO2H at 
Day29, WASO2H at Day30 
• WASO: treatment, age, sex, race, region, baseline BMI, baseline ISI, baseline sWASO, 
baseline WASO, WASO at Day1, WASO at Day2, WASO at Day29, WASO at Day30 
 
TIPPING POINT SENSITIVITY ANALYSIS: 
The following sample SAS statements and algorithm provide the framework for the Tipping 
Point Sensitivity Analysis: 
A tipping point sensitivity analysis will be conducted on the endpoints LPS (Log LPS), SE, 
WASO and WASO2H using the multiple imputation methodology as described in the section 
above but with the following modifications: 
1. The second MI procedure (monotone missing values) is to be modified to introduce an 
adjustable shift (i.e sensitivity parameter) to the imputed values for only the treatment 
groups LEM10 and LEM5, corresponding to a MAR assumption when the shift is zero. 
These shifts are to be applied to Day29 and Day30 only.  
 
PROC MI data=<dataset1> nimpute=1 seed=2359 out=<dataset2>; 
     
 
CLASS treatment sex race region; 
     
 
MONOTONE regression ( /details); 
     
 
MNAR adjust (visit3/ shift=<shift> adjustobs=(treatment=LEM5)); 
     
 
MNAR adjust (visit4/ shift=<shift> adjustobs=(treatment= LEM5)); 
     
 
MNAR adjust (visit3/ shift=<shift> adjustobs=(treatment=LEM10)); 
     
 
MNAR adjust (visit4/ shift=<shift> adjustobs=(treatment= LEM10)); 
     
 
VAR treatment age sex race region BMI baseline… V5 V6 V7 V8; 
     
 
BY _imputation_; 
RUN; 
2. If the MAR (shift=0) model has a p-value that is significant (<0.05), then the <shift> 
value will be systematically incremented until the resulting p-value is >=0.05. 
3. Step 2 may be repeated iteratively starting with the shift found just prior to p-value >0.05 
ending with the p-value>=0.05 found in Step 2, using smaller increments, until a shift is 
found where the rounded p-value has a value of 0.05 to a reasonable accuracy. 
4. The values for <shift> in Step 1 will be applied uniformly (same shift) to both LEM 5mg 
and LEM 10gm at both Day29 and Day 30. 


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5. The values for <shift> will correspond to worsening values for the endpoint according to 
the following: 
• Increasing positive shift values (LPS, WASO, WASO2H) 
• Increasing negative shift values (SE) 
 
6. The following specifies which comparisons are of interest when evaluating p-values for 
this procedure: 
• LEM 5mg and LEM10mg vs. Placebo (LPS, SE, WASO) 
• LEM 5mg and LEM 10mg vs. Zolpidem (WASO2H) 
 
8 
STATISTICAL SOFTWARE 
Statistical analyses will be performed using SAS version 9.4 (or later versions).  In the event 
that certain features graphical analyses cannot be implemented by SAS, other statistical 
software such as Splus can be employed.   
The conditional power calculated for the interim analysis will be performed using EAST® 
version 6 (or later versions). 
9 
MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings and graphs shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail. 
10 REFERENCES 
ICH Final Concept Paper E9(R1): Addendum to statistical principles for clinical trials on 
choosing appropriate estimands and defining sensitivity analyses in clinical trials dated 
22October 2014. 
Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G.  A structured approach to choosing 
estimands and estimators in longitudinal clinical trials.  Pharmaceutical Statistics 
2012,11:456-461, 10 September 2012. 
Rubin, DB.  Multiple Imputation for Nonresponse in Surveys.  New York: John Wiley & 
Sons; 1987. 
 
 


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


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 43 of 50 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Phosphate, serum-low 
(hypophosphatemia)  
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL 
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
life-threatening 
consequences 
Potassium, serum-high (hyperkalemia) >ULN – 5.5 mmol/L  
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
hospitalization indicated 
>7.0 mmol/L 
life-threatening 
consequences 
Potassium, serum-low (hypokalemia)  
<LLN – 3.0 mmol/L 
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
<3.0 – 2.5 mmol/L 
hospitalization indicated 
<2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
>300 – 500 mg/dL 
>3.42 – 5.7 mmol/L  
>500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
>1000 mg/dL 
>11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
>ULN – 10 mg/dL  
≤0.59 mmol/L without 
physiologic 
consequences  
N/A 
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences  
>10 mg/dL 
>0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
 
 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 44 of 50 
 
Appendix 2 
Derivations of Efficacy Endpoints from Electronic 
Sleep Diary 
The following 7 questions are captured in the electronic Sleep Diary: 
Q1: What time did you try to go to sleep? 
Q2: How long did it take you to fall asleep? 
Q3: How many times did you wake up, not counting your final awakening? 
Q4: In total, how long did these awakenings last? 
Q5: What time was your final awakening? 
Q6: After your last awakening, how much longer did you try to sleep? 
Q7: What time did you get out of bed for the day? 
The efficacy endpoints from electronic Sleep Diary are defined as follows: 
• sSOL= Q2 
• sWASO = Q4 + Q7 – Q5 
• sTST = TIB – time spent awake [where TIB = Q7 – Q1; and time spent awake = Q2 + Q4 
+ Q7 – Q5] 
• sSE = sTST/TIB (as defined above) 
 
 
 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 45 of 50 
 
Appendix 3 
List of Abuse Liability Events 
 
Code 
PT 
10061422 
Abnormal behaviour 
10000125 
Abnormal dreams 
10063746 
Accidental death 
10000381 
Accidental overdose 
10000383 
Accidental poisoning 
10001022 
Acute psychosis 
10054196 
Affect lability 
10001443 
Affective disorder 
10001488 
Aggression 
10001497 
Agitation 
10001666 
Alice in wonderland syndrome 
10001854 
Altered state of consciousness 
10053549 
Altered visual depth perception 
10001949 
Amnesia 
10061423 
Amnestic disorder 
10002368 
Anger 
10002511 
Anhedonia 
10002711 
Anterograde amnesia 
10002820 
Antisocial behaviour 
10002855 
Anxiety 
10002942 
Apathy 
10003472 
Asocial behaviour 
10003739 
Attention-seeking behaviour 
10049848 
Balance disorder 
10004224 
Belligerence 
10005885 
Blunted affect 
10050012 
Bradyphrenia 
10057668 
Cognitive disorder 
10061046 
Communication disorder 
10010219 
Compulsions 
10010297 
Confabulation 
10067494 
Confusional arousal 
10010305 
Confusional state 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 46 of 50 
 
10050093 
Consciousness fluctuating 
10010947 
Coordination abnormal 
10012177 
Deja vu 
10012218 
Delirium 
10012239 
Delusion 
10012335 
Dependence 
10077805 
Depersonalisation/derealisation disorder 
10012374 
Depressed mood 
10012378 
Depression 
10012411 
Derailment 
10012422 
Derealisation 
10013142 
Disinhibition 
10013395 
Disorientation 
10013457 
Dissociation 
10013462 
Dissociative disorder 
10013468 
Dissociative identity disorder 
10013496 
Disturbance in attention 
10061108 
Disturbance in social behaviour 
10013573 
Dizziness 
10061111 
Drug abuser 
10013659 
Drug administered at inappropriate site 
10052237 
Drug detoxification 
10066053 
Drug diversion 
10052804 
Drug tolerance 
10052806 
Drug tolerance increased 
10079381 
Drug use disorder 
10013752 
Drug withdrawal convulsions 
10013753 
Drug withdrawal headache 
10013754 
Drug withdrawal syndrome 
10013887 
Dysarthria 
10054940 
Dyslogia 
10014551 
Emotional disorder 
10049119 
Emotional distress 
10048779 
Energy increased 
10015535 
Euphoric mood 
10070246 
Executive dysfunction 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 47 of 50 
 
10016256 
Fatigue 
10016275 
Fear 
10016322 
Feeling abnormal 
10016330 
Feeling drunk 
10016338 
Feeling jittery 
10016344 
Feeling of despair 
10016352 
Feeling of relaxation 
10016754 
Flashback 
10016759 
Flat affect 
10016777 
Flight of ideas 
10017062 
Formication 
10019063 
Hallucination 
10019070 
Hallucination, auditory 
10019072 
Hallucination, olfactory 
10062824 
Hallucination, synaesthetic 
10019074 
Hallucination, tactile 
10019075 
Hallucination, visual 
10019079 
Hallucinations, mixed 
10019133 
Hangover 
10020400 
Hostility 
10048533 
Hypervigilance 
10020937 
Hypoaesthesia 
10021212 
Ideas of reference 
10021402 
Illogical thinking 
10021403 
Illusion 
10049564 
Impaired driving ability 
10071176 
Impaired reasoning 
10049976 
Impatience 
10021567 
Impulsive behaviour 
10021588 
Inappropriate affect 
10021630 
Incoherent 
10021703 
Indifference 
10022523 
Intentional overdose 
10074903 
Intentional product misuse 
10023118 
Jamais vu 
10023236 
Judgement impaired 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 48 of 50 
 
10024264 
Lethargy 
10024825 
Loose associations 
10025429 
Magical thinking 
10026749 
Mania 
10027175 
Memory impairment 
10061284 
Mental disorder 
10027374 
Mental impairment 
10048294 
Mental status changes 
10027940 
Mood altered 
10027951 
Mood swings 
10028330 
Muscle rigidity 
10028747 
Nasal necrosis 
10028765 
Nasal septum perforation 
10028766 
Nasal septum ulceration 
10028896 
Needle track marks 
10061862 
Neonatal complications of substance abuse 
10029216 
Nervousness 
10029412 
Nightmare 
10033295 
Overdose 
10033664 
Panic attack 
10033670 
Panic reaction 
10033775 
Paraesthesia 
10033848 
Paramnesia 
10033864 
Paranoia 
10061910 
Parasomnia 
10063117 
Paroxysmal perceptual alteration 
10034719 
Personality change 
10061355 
Poisoning 
10067669 
Prescription form tampering 
10069330 
Product tampering 
10070592 
Product used for unknown indication 
10037211 
Psychomotor hyperactivity 
10037213 
Psychomotor retardation 
10049215 
Psychomotor skills impaired 
10061920 
Psychotic disorder 
10053632 
Reactive psychosis 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 49 of 50 
 
10038001 
Rebound effect 
10038743 
Restlessness 
10038965 
Retrograde amnesia 
10039897 
Sedation 
10040026 
Sensory disturbance 
10061567 
Sensory level abnormal 
10041052 
Sluggishness 
10041317 
Somatic delusion 
10062684 
Somatic hallucination 
10041349 
Somnolence 
10041953 
Staring 
10042264 
Stupor 
10067688 
Substance abuser 
10070964 
Substance use 
10079384 
Substance use disorder 
10072387 
Substance-induced mood disorder 
10072388 
Substance-induced psychotic disorder 
10042635 
Suspiciousness 
10043114 
Tangentiality 
10043431 
Thinking abnormal 
10043495 
Thought blocking 
10052214 
Thought broadcasting 
10043496 
Thought insertion 
10043497 
Thought withdrawal 
10070863 
Toxicity to various agents 
10044380 
Transient global amnesia 
10056326 
Transient psychosis 
10049414 
Treatment noncompliance 
10048010 
Withdrawal syndrome 
MedDRA 20.1 
 
 
 
 


Statistical Analysis Plan 
E2006-G000-304 
 
 
Eisai 
Final V3.0:  05Feb2018 
Confidential 
Page 50 of 50 
 
SIGNATURE PAGE 
 
Author(s):   
 
 
 
 
[electronic signature in eDMS] 
 
 
 
 
  
Neuroscience Business Group, Eisai Inc. 
 
 
Date 
Approval: 
 
 
 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neuroscience Business Group, Eisai Inc. 
 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neuroscience Business Group, Eisai Inc. 
 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
  
 
Neuroscience Business Group, Eisai Inc. 
 
Date 
 
 
 
 
 
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