Conditions: Insomnia Disorder
Keywords: insomnia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 971
Healthy volunteers: no

Brief summary:
The key objectives of this study are to determine, using sleep diaries, whether lemborexant at the doses 5 milligrams (mg) and 10 mg is superior to placebo on subjective sleep onset, subjective sleep efficiency, and subjective sleep maintenance in participants with insomnia disorder.

Detailed description:
This is a long-term (approximately 1 year), multicenter, randomized, controlled, double-blind, parallel group study of two doses of lemborexant and placebo in approximately 900 male or female participants with insomnia disorder. Approximately 40% of participants will be age 65 years or older. The study will last a maximum of 60 weeks, and will include a Screening Period, an approximately 54-week Treatment Period (during which study medication will be administered), and a 2-week Follow-up Period. All participants will receive lemborexant for at least 6 months and will receive placebo at some point during the study. Participants will not know which medication they receive (lemborexant or placebo) until the study has been completed, and will not know the timings at which the medication will change.

Arms:
arm 1: Lemborexant 5 mg will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep. arm 2: Lemborexant 10 mg will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep. arm 3: Lemborexant-matched placebo will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep.

Interventions: intervention 1: lemborexant intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol
(Per Protocol Amendment 06)
E2006-G000-303
Eisai
FINAL:  V8.0, 13 Aug 2018
Confidential
Page i of xiii
Revision History
Previous Version:  V7.0
Current Version:  V8.0 (per Amendment 06)
Date of Revisions:  13 Aug 2018
Change
Rationale
Affected Section(s)
Updated completed Phase 1 study 
information
Added results from 
Study E2006-A001-012

Section 7.1.2.2.1
Updated list of prohibited concomitant 
medications
To prohibit the use of  moderate 
cytochrome P450 3A (CYP3A) 
inhibitors 

Synopsis
o Concomitant Drug/
Therapy

Section 9.4.7.1

Section 9.4.7.2

Appendix 3
Revised summaries for efficacy and 
safety endpoints in Period 2 to be 
based on duration of exposure

Synopsis
o Secondary Endpoints
o Exploratory Endpoints
o Analysis Sets
o Definitions of Baseline
o Other Secondary Efficacy 
and Pharmacodynamic 
Analyses
o Exploratory Efficacy and 
Pharmacodynamic 
Analyses
o Safety Analyses

Section 9.7.1.1.2

Section 9.7.1.1.4

Section 9.7.1.2

Section 9.7.1.6

Section 9.7.1.6.2

Section 9.7.1.6.3

Section 9.7.1.8

Section 9.7.1.8.1

Section 9.7.1.8.2

Section 9.7.1.8.3

Section 9.7.1.8.4

Section 9.7.1.8.5
Revised Other Secondary Endpoint 
Analyses
Added Fatigue Severity Scale
analysis

Synopsis
o Other Secondary Efficacy 
and Pharmacodynamic 
Analyses

Section 9.7.1.6.2
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Clinical Study Protocol
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E2006-G000-303
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Page ii of xiii
Previous Version:  V7.0
Current Version:  V8.0 (per Amendment 06)
Date of Revisions:  13 Aug 2018
Change
Rationale
Affected Section(s)
Revised protocol signatories
Corrected signatory for study 
statistician

Protocol Signature Page
Correction of typos and spelling errors
Correction

Revision History

Synopsis
o
Interim Analysis
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Clinical Study Protocol
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E2006-G000-303
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FINAL:  V8.0, 13 Aug 2018
Confidential
Page iii of xiii
Previous Version:  V6.0
Current Version:  V7.0 (per Amendment 05)
Date of Revisions:  03 Aug 2018
Change
Rationale
Affected Section(s)
Updated blinding and interim analysis 
description
Clarify that no interim analysis 
is being performed and that 
when all subjects have 
completed Period 1, all data 
will be unblinded to the sponsor 
and that study sites and subjects 
will remain blinded until the 
study has been completed.

Section 2, Synopsis
o
Interim Analysis

Section 9.4.6

Section 9.7

Section 9.7.3
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Clinical Study Protocol
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Page iv of xiii
Previous Version:  V5.0
Current Version:  V6.0 (per Amendment 04)
Date of Revisions:  28 Jun 2018
Change
Rationale
Affected Section(s)
Corrected typos and redundant text
Correction for consistency

Synopsis
o Study Design
Added analysis of Treatment Period 1
Based on the results of pivotal 
Phase 3 Study E2006-G000-304 
and special safety studies, Eisai 
decided to include a database 
lock with interim analysis to 
assess efficacy in the double-
blind placebo-controlled 
treatment period.  All available 
safety data will also be assessed 

Synopsis
o Interim Analysis

Section 9.7

Section 9.7.3
Revised blinding statement
In the event of an interim 
analysis, Sponsor staff will be 
unblinded; however, site 
personnel, investigator, and 
subjects will remain blinded

Section 9.4.6
Revised information about study 
signatories
Correction

Protocol Signature Page
Updated analysis sets and analysis 
plan
To align with Regulatory 
Authority provision 
(International Council on 
Harmonisation of Technical 
Requirements for Registration 
of Pharmaceuticals for Human 
Use [ICH] E9 Addendum)

Synopsis
o
Analysis Sets
o Analysis of Primary 
Endpoint

Section 9.7.1.2

Section 9.7.1.6.1
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Page v of xiii
Previous Version:  V4.0
Current Version:  V5.0 (per Amendment 03)
Date of Revisions:  06 Mar 2017
Change
Rationale
Affected Section(s)
Revised approximate number of sites 
from 110 to 125
To facilitate study enrollment

Synopsis – Site(s)

Section 6

Figure 1
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

Table 3
Revised the requirement for a history 
of “difficulties with sleep onset and 
sleep maintenance” to “difficulties 
with sleep onset and/or sleep 
maintenance”
To permit broader inclusion of 
appropriate subjects

Synopsis – Study Design

Section 9.1

Section 9.1.1.1

Section 9.2.4
Deleted “or early morning awakening” 
from the requirements.  
Early morning awakening is not 
an inclusion criterion. 

Synopsis – Study Design

Section 9.1.1.1
Deleted the Munich Parasomnia Scale 
(MUPS) and revised text such that 
investigators will instead interview 
subjects regarding possible history of 
parasomnias. 
To bring more efficiency to 
screening for parasomnias, by
allowing investigators to use 
interview to screen for a history 
of REM-behavior disorder
sleep-eating, or sleep-related 
violent behaviour, and use 
clinical judgement, rather than 
automatically excluding 
subjects who endorse these 
items on the MUPS scale.

Synopsis – Study Design

Synopsis – Exclusion Criteria

Synopsis – Assessments

Section 4

Section 9.1.1.1

Section 9.3.2

Section 9.5.1.2.2

Table 3
Revised inclusion (#3,7, & 10) from 
sSOL ≥30 AND sWASO ≥60 minutes 
to sSOL ≥30 minutes AND/OR 
sWASO ≥60 minutes.
To permit broader inclusion of 
appropriate subjects

Synopsis – Inclusion Criteria

Section 9.3.1
Revised inclusion (#5) for regular 
bedtime from between 21:00 and 
24:00 to between 21:00 and 01:00, 
waketime from between 05:00 and 
09:00 to between 05:00 and 10:00
To permit broader inclusion of 
appropriate subjects

Synopsis – Inclusion Criteria

Section 9.3.1
Revised inclusion (#8) requiring  the 
subjects has a regular time spend in 
bed, either sleeping or trying to sleep, 
between 7 and 10 hours

Synopsis – Inclusion Criteria

Section 9.3.1
Revised inclusion (#9) requiring  
maximum duration of time spent in 
bed from  9 hours to  10 hours, on 
To permit broader inclusion of 
appropriate subjects

Synopsis – Inclusion Criteria

Section 9.3.1
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Page vi of xiii
Previous Version:  V4.0
Current Version:  V5.0 (per Amendment 03)
Date of Revisions:  06 Mar 2017
Change
Rationale
Affected Section(s)
Sleep Diary at Visit 2a  
Revised inclusion (#11) requiring 
reconfirmation of regular bedtimes 
and waketimes during Run-In Period
To permit broader inclusion of 
appropriate subjects

Synopsis – Inclusion Criteria

Section 9.3.1
Revised inclusion (#12) to delete 
requirement for no more than 2 nights 
with duration of time in bed >9 hours
in Run-In 
To permit broader inclusion of 
appropriate subjects

Synopsis – Inclusion Criteria

Section 9.3.1
Revised inclusion (#13) “TIB” to 
“staying in bed”
For clarity.

Synopsis – Inclusion Criteria

Section 9.3.1
Revised exclusion (#1) from ESS 
score “>10” to “>15” as an indicator 
of excessive daytime sleepiness, and 
require that scores of 11 to 15 be 
recorded as excessive daytime 
sleepiness in subject's Medical 
History)
To avoid low specificity of 
more stringent criterion, and  to 
record excessive sleepiness in 
medical history instead of 
excluding subjects

Synopsis – Exclusion Criteria

Section 9.3.2

Section9.5.1.2.1
Revised exclusion (#3) to remove 
MUPS assessment and allow 
evaluation based upon reporting of a 
history of sleep-related violent 
behavior or sleep driving, or any other 
complex sleep-related behavior (eg, 
making phone call or preparing and 
eating food while sleeping)
To permit broader inclusion of 
appropriate subjects

Synopsis – Exclusion Criteria

Section9.3.2
Revised exclusion (#9) for females of 
CBP from “…30 days before study 
entry and…” to “…30 days before 
study entry or …”
For clarity

Synopsis – Exclusion Criteria

Section9.3.2
Revised exclusion (#15) from 
“A prolonged QT/QT interval (QTc 
>450 ms)” to “A prolonged QT/QT 
interval corrected by Fridericia’s 
formula (QTcF) >450 ms”
For clarity and correction of 
error. 

Synopsis – Exclusion Criteria

Section9.3.2

Section9.5.1.5.1
Revised exclusion (#20) for suicidal 
behavior as per the C-SSRS from 
“lifetime” to “in the past 10 years”
To facilitate enrollment and 
align with other protocols in the 
program

Synopsis – Exclusion Criteria

Section9.3.2
Revised exclusion (#21) to specify 
major surgery.
To allow for the possibility of 
minor surgery that will not 
interfere with study assessments 

Synopsis – Exclusion Criteria

Section9.3.2
Revised definition of sSE
For clarity

Synopsis – Assessments

Section 9.5.1.3.1
Revised name and description of 
As requested by FDA, to 

Synopsis – Study Design
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E2006-G000-303
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Page vii of xiii
Previous Version:  V4.0
Current Version:  V5.0 (per Amendment 03)
Date of Revisions:  06 Mar 2017
Change
Rationale
Affected Section(s)
Adjudication Committee, and added 
seizures as adverse events to be 
adjudicated
include information on  seizures 
for adjudication as  symptoms 
of cataplexy 

Synopsis – Statistical Methods

Section9.2.3
Added requirement to question 
subjects as to whether they have had a 
fall, at each visit, and record 
supplemental information 
As requested by FDA. 

Table 3
Revised analyses for Primary, 
Secondary and Exploratory Efficacy
To align with regulatory 
recommendations for handling 
missing data

Synopsis – Statistical Methods

Section 9.7.1.6.1

Section 9.7.1.6.2

Section 9.7.1.6.3
Deleted text related to the Symptoms 
of Narcolepsy Screen
Correction of error. This screen 
is not employed in the study. 

Section 9.5.1.2.2
Provided window around Visits 6 
through 15. 
To correct the omission. 

Table 3
Revised definitions of prior and 
concomitant medications
To allow separate analyses for 
the Run-In Period, Treatment 
Period 1, and Treatment 
Period 2.

Section 9.7.1.5
Revised text regarding ECG 
interpretation categories
For clarity

Section 9.7.1.8.5
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 9.5.1.5.7
Revised List of Prohibited 
Concomitant Medications
To correct lists of strong 
CYP3A inhibitors and CYP3A 
inducers

Appendix 3
Added the requirement of a Data 
Safety Monitoring Board
Per the request of FDA

Synopsis – Study Design

Section 9.2.3
Converted Month 2 visit from phone 
to in-person visit.
Per the request of FDA

Synopsis – Study Design

Section 9.1.2.1

Table 3
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E2006-G000-303
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FINAL:  V8.0, 13 Aug 2018
Confidential
Page viii of xiii
Previous Version:  V3.0
Current Version:  V4.0 (per Amendment 02)
Date of Revisions:  25 Oct 2016
Change
Rationale
Affected Section(s)
Revised exclusion criteria 
regarding highly effective forms of 
contraception
Per VHP feedback

Synopsis:  Exclusion 
Criteria

Section 9.3.2
Revised Sleep Diary to Sleep 
Diary
Correction of typographical 
error

Synopsis: Additional 
Secondary Endpoints

Section 9.7.1.1.2
Revised inclusion and exclusion 
criteria to be checked at Screening 
and Baseline
Correction of errors

Appendix 2
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Page ix of xiii
Previous Version:  V2.0 (revised protocol)
Current Version:  V3.0 (per Amendment 01)
Date of Revisions:  29 Sep 2016
Change
Rationale
Affected Section(s)
Deleted colon after “Evaluate the 
safety and tolerability of LEM5 
and LEM10”
Correction of error 

Synopsis: Objectives

Section 8.2. 
Stated that enrollment of subjects 
<65 years may be limited if the 
percentage of enrolled subjects >65 
years is below expectations toward 
the end of the study
To ensure that approximately 
40% of subjects are age 65 
years or older

Synopsis: Study Design

Section 9.1
Revised “from Screening through 
end of Treatment Period” to “from 
Screening to the EOS Visit” for 
urine drug testing
Correction of error

Synopsis: Study Design 
Clarified that subjects who 
discontinue study medication but 
do not agree to return for study 
visits will undergo an EOS visit 
Clarification and correction; 
the term “Follow-up Visit” is 
not used elsewhere in the 
protocol 

Synopsis: Study Design

Section 9.5.2

Section 9.5.5
Clarified the dates that the study 
will begin and end enrollment
Clarification 

Synopsis: Study Design.

Section 9.1.
Clarified the term abstinence
Clarification as required by 
the VHP

Synopsis: Exclusion
Criteria

Section 9.3.2
Clarified excessive caffeine use
Clarification as required by 
the VHP

Synopsis: Exclusion 
Criteria

Section 9.3.2
Clarified that subjects who lack 
capacity and/or whose cognitive 
decline indicates disorientation to 
person/place/time and/or situation 
are excluded 
Clarification as required by 
the VHP

Synopsis: Exclusion 
Criteria

Section 9.3.2
Revised the washout interval 
between taking a prohibited 
medication and the 1st dose of 
study medication
Correction of inconsistency 
between text (incorrect) and 
Exclusion Criteria (correct)

Synopsis: Concomitant 
Drug/Therapy

Section 9.4.7.2
Specified that the statistical model 
will include region if necessary, 
that countries with small numbers 
of subjects may be pooled by 
region, and that regions will be 
grouped in consideration of the 
number and homogeneity of 
subjects from each region 
Clarification/specification as 
required by the VHP 

Synopsis: Statistical 
Methods

Section 9.7.1.6.1
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Page x of xiii
Previous Version:  V2.0 (revised protocol)
Current Version:  V3.0 (per Amendment 01)
Date of Revisions:  29 Sep 2016
Change
Rationale
Affected Section(s)
Relocated definition of SAP
Editorial quality

Synopsis, Statistical 
Methods
Specified that informed consent 
will be taken by personnel in 
accordance with national 
legislation
Specification required by the 
VHP  

Section 5.3
Clarified the reason why subjects 
should not eat a meal within 3 
hours before taking the study drug
Clarification as required by 
the VHP

Section 9.4.5
Deleted the statement that dose 
adjustment of an allowable 
medication is permitted for those 
drugs where monitoring and dose 
modulation are typical practice
Correction of error: dose 
modulation of all 
concomitant medications is 
permitted during the study.

Section 9.4.7.2
Specified that the neurological 
examination must be conducted by 
a clinician whose clinical 
experience ensures that an 
adequate assessment of domains 
underlying the exclusion criteria 
can be performed 
Specification as required by 
the VHP

Section 9.5.1.2.1
Deleted pharmacokinetic sample at 
EOS visit from Table 2. 
Correction of error: No PK 
sample with be taken at EOS

Section 9.5.1.5.3
Clarified that clinical lab tests 
and/or PK sampling will also be 
conducted at ET/EDD visits
Clarification

Section 9.5.1.5.3
Added visit number, physical 
examination, vital signs, weight, 
ECG, urine pregnancy test, and 
clinical laboratory tests to the EOS 
visit
Clarification. This 
information was previously 
in the footnote but not in the 
table.

Section 9.5.2
Deleted “ISI – Insomnia Severity 
Index” from abbreviations
Correction of duplication

Section 9.5.2
Specified that EOS must be 
conducted within ± 7 days of the 
schedule
Correction of error. The 
EOS, not the ET, must be 
conducted within this
timeframe.

Section 9.5.2
Clarified that the maximum 
duration Run-In Period must be 17 
days.
Clarification

Section 9.5.2
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Page xi of xiii
Previous Version:  V2.0 (revised protocol)
Current Version:  V3.0 (per Amendment 01)
Date of Revisions:  29 Sep 2016
Change
Rationale
Affected Section(s)
Specified that inclusion and 
exclusion criteria that must be 
evaluated at visits other than or in 
addition to Visit 1 are listed in 
Appendix 2
Clarification

Section 9.5.2
Deleted Symptoms of Narcolepsy 
Screen from Sleep Disorders 
Screening Battery
Correction of error 

Section 9.5.2
Specified that study drug 
compliance (tablet count) will be 
carried out at each clinic visit from 
Visit 3a through Visit 15
Clarification

Section 9.5.2
Replaced Xs with a broken arrow 
to indicate timepoints for prior and 
concomitant medications sleep 
diary, and adverse event collection
For clarity

Section 9.5.2
Renumbered superscripts that 
indicate footnotes
For consistency between 
superscripts and the 
footnotes to which they 
refer. 

Section 9.5.2
Delete “only” from footnote “u” 
(instructions for PK sampling at 
ET)
Correction of error (PK 
sampling will also take place 
at other time points)

Section 9.5.2
Specified that the investigator 
agrees to allow direct access to 
source documents and study 
facilities to sponsor 
representative(s), monitor(s) and 
auditor(s), and agree to inspection 
by regulatory authorities or 
IRB/IEC representative
Specification required by the 
VHP. 

Section 11.5
Revised the lists of strong CYP3A 
inhibitors and CYP3A inducers
Correction of errors.

Appendix 3
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Page xii of xiii
Previous Version:  V1.0 (original protocol)
Current Version:  V2.0 (revised protocol)
Date of Revisions:  15 Jul 2016
Change
Rationale
Affected Section(s)
Deleted requirement that a 
blood sample be taken at end of 
study for determination of 
lemborexant blood levels
Correction of error

Synopsis – Study Design

Section 9.1.2.4
Clarified that reconfirmation of 
bedtimes take place for the final 
7 nights of the Run-in Period
For clarity and consistency

Synopsis – Inclusion 
Criteria

Section 9.3.1
Specified that exclusion criteria 
include current diagnosis of 
obstructive sleep apnea (CPAP)
For clarity

Synopsis – Exclusion 
Criteria 

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
Provided examples of clinically 
significant disease that would 
exclude the subject from the 
study
For clarity

Synopsis—Exclusion 
Criteria 

Section 9.3.2
Stated that subjects taking 
sedating drugs that would 
interfere with occupation or 
activities will be excluded
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 1st 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
Added wording to clarify 
prohibitions on concomitant 
drugs during study
Clarification

Synopsis – Concomitant 
Drug Therapy

Section 9.4.7.2
Changed wording such that 
sleep diary will ask, not 
determine, alcohol consumption
For accuracy

Synopsis – Assessments

Section 9.5.1.3.1
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

Table 3 (footnote “r”)
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Page xiii of xiii
Change
Rationale
Affected Section(s)
Revised method for assessment 
of rebound insomnia
To emphasize assessment of 
rebound insomnia at individual 
subject level

Synopsis – Statistical 
Methods

Section 9.7.1.6.2
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 9.5.1.5.3

Table 3 (footnote “n”)
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 9.5.1.5.3
Corrected window of study 
days for Screening
To correct an error

Figure 1

Table 3
Clarified interval for reporting 
of follow-up SAE, pregnancy, 
or breastfeeding information
For clarity

Section 9.5.4.1

Section 9.5.4.2
Added sentence distinguishing 
between definitions of “study 
completer” per protocol versus 
for statistical analysis purposes
For clarity

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
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-G000-303
Study Protocol Title:
A 
Long-Term
Multicenter, 
Randomized, 
Double-Blind,
Controlled,
Parallel-Group Study of the Safety and Efficacy of Lemborexant in Subjects 
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
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2006/lemborexant
Indication:
Insomnia disorder
Phase:
Phase 3
Approval Date:
V1.0
Final, 29 Apr 2016 (original protocol)
V2.0
Final, 15 Jul 2016 (revised protocol)
V3.0
Final, 29 Sep 2016 (per Amendment 01)
V4.0
Final, 25 Oct 2016 (per Amendment 02)
V5.0
Final, 06 Mar 2017 (per Amendment 03)
V6.0
Final, 28 Jun 2018 (per Amendment 04)
V7.0
Final, 03 Aug 2018 (per Amendment 05)
V8.0
Final, 13 Aug 2018 (per Amendment 06)
IND Number:
111871
EudraCT Number:
2015-001463-39
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/lemborexant
Name 
of 
Active 
Ingredient: 
 
(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-
(3-fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide 
Study Protocol Title
A Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel-Group Study of the 
Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder
Investigator(s)
To be determined
Site(s)
Approximately 125 investigational sites in North America, South America, Europe, Asia, and 
Oceania (revised per Amendment 03)
Study Period and Phase of Development
Approximately 30 months
Phase 3
Objectives
Primary Objective 
Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to placebo
(PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in subjects with insomnia 
disorder
Key Secondary Objectives

Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective sleep efficiency 
(sSE) after 6 months of treatment in subjects with insomnia disorder

Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective wake after sleep 
onset (sWASO) after 6 months of treatment in subjects with insomnia disorder
Additional Secondary Objectives

Determine the efficacy of LEM5 and LEM10 compared to PBO on sSOL, sSE, sWASO, and 
subjective total sleep time (sTST):
-
over the 1st 7 nights of treatment 
-
after 1 month of treatment
-
after 3 months of treatment

Determine the efficacy of LEM5 and LEM10 compared to PBO on sTST at 6 months  

Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and LEM10 
compared to PBO as defined by response on sSOL or sWASO at 6 months and 12 months
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
Evaluate the safety and tolerability of LEM5 and LEM10

Evaluate the efficacy of LEM5 and LEM10 compared to PBO as measured by responses on the 
Insomnia Severity Index (ISI) and the Fatigue Severity Scale (FSS) after 6 months

Evaluate rebound insomnia following discontinuation of treatment 

Evaluate morning sleepiness during and following completion of treatment

Evaluate persistence of efficacy of LEM5 and LEM10 over 12 months 
Exploratory Objectives
The following will be explored for both LEM5 and LEM10 compared to PBO over Treatment 
Period 1 (Period 1) and over Treatment Period 2 (Period 2) with analyses dependent on whether 
subjects received active treatment or PBO during Period 1. (revised per Amendment 04)

Efficacy on quality of sleep 

Health outcomes on the EuroQOL version 5D-3L (EQ-5D-3L), Work Productivity and Activity 
Impairment Questionnaire – General Health (WPAI-GH), and Patient Global Impression –
Insomnia  (PGI-Insomnia)

Efficacy on sSOL, sSE, sWASO, sTST, ISI, and FSS

Withdrawal symptoms after completion of treatment (Period 2 only)
The following will be explored for LEM5 and LEM10:

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10

Population pharmacokinetic (PK) modeling for lemborexant

PK/pharmacodynamic (PD) relationships between lemborexant concentrations and efficacy and 
safety variables
Study Design
E2006-G000-303 is a 12-month, multicenter, randomized, controlled, double-blind, parallel-group 
study of 2 doses of lemborexant in approximately 900 male or female subjects with insomnia 
disorder.  Approximately 40% of the population will be 65 years of age or older. Note: enrollment of 
subjects <65 years may be limited if the percentage of enrolled subjects >65 years is below 
expectations toward the end of the study.  (revised per Amendment 01)
The study will have 2 phases, the Prerandomization Phase and the Randomization Phase.
The 
Prerandomization Phase will comprise 3 periods that will last up to 35 days: a Screening Period, a 
Run-In Period and a Baseline Period.  The Randomization Phase will comprise a 6-month,
placebo-controlled treatment period (Period 1).  During the next 6 months (Period 2), subjects will 
receive only active treatment.  Subjects will be informed that they will receive PBO at some point 
during the study and that all will receive active drug for at least 6 months. They will not be informed 
of either the timing of these periods or the timing of the 2nd randomization. A 2-week Follow-Up 
Period will then take place, followed by an End of Study Visit (EOS). (revised per Amendment 03)
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 (once at Visit 1), clinical hematology 
and chemistry analysis and urinalysis, and suicidality, assessed using an electronic version of the 
Columbia-Suicide Severity Rating Scale (eC-SSRS). At each visit from Screening to the EOS Visit, 
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subjects will also undergo a urine drug screen.  (revised per Amendment 01)
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At the 1st
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 has a history of 
difficulties with sleep onset and/or sleep maintenance.  Screening assessments will include the ISI, 
and the Epworth Sleepiness Scale (ESS), the STOPBang, and the International Restless Legs Scale 
(IRLS) the latter 3 assessments collectively called the Sleep Disorders Screening Battery (SDSB).  
The FSS and health-related quality-of-life measures the EQ-5D-3L and the WPAI-GH will be 
administered.  Additional eligibility criteria will be assessed and safety assessments will be 
conducted.  (revised per Amendment 03)
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, 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 2nd Screening 
Visit (Visit 2a).  Subjects will return to the clinic and eligibility criteria will be determined.  Subjects 
who are not eligible based on Sleep Diary entries will return to the clinic for debriefing purposes and 
to return study equipment.  Visit 2a must occur between Day -17 and Day -14.  A urine drug test will 
be performed.  Subjects who continue to meet eligibility criteria will then receive PBO (single-blind) 
sufficient for 14 nights and will enter the Run-In Period which will last approximately 14 nights and a 
maximum of 17 nights. 
Run-In Period
The Run-In Period will begin once eligible subjects are dispensed PBO 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 time spent in bed trying to sleep 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.  
Baseline Period (Study Baseline)
On Day 1, the Run-In Period will end and the Baseline Period will begin.  Subjects will return to the 
clinic for this visit (Visit 3), and the ISI will be administered.  If subjects remain eligible, the FSS, 
EQ-5D-3L, and WPAI-GH will then be administered. Blood and urine samples will be collected for 
routine safety assessment, suicidality will be assessed using the eC-SSRS, and a urine drug test will 
be performed.  An ECG will be performed, and vital signs and weight will be assessed.  Subjects who 
complete the Baseline Period and continue to meet the eligibility criteria will be randomized and 
begin the Treatment Period. 
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Treatment Period (Periods 1 and 2)
Treatment Periods 1 and 2 (Periods 1 and 2) will begin on Day 1 and will continue for 12 months.  
Subjects will be randomized, in a double-blind manner, to receive LEM5 or LEM10, or PBO 
(approximately 1:1:1, stratified by country and age group (<65 years old; ≥65 years old). Study drug 
will be dispensed and subjects will be provided with instructions to continue completing the Sleep 
Diary and taking study drug daily at home according to the same schedule and with the same 
restrictions as during the Run-In Period.
Period 1 will begin with the 1st dose of randomized study medication. 
At the end of Month 6 (Period 2 Baseline), subjects who received PBO during Period 1 will undergo 
a 2nd randomization to receive either LEM5 or LEM10 (approximately 1:1, stratified by country and 
age group (<65 years old; ≥65 years old) during Period 2.  Subjects who received lemborexant during 
Period 1 will continue to receive lemborexant at the same dose level during Period 2.  Subjects will 
not be informed of the timing of the 2nd randomization (at the end of Month 6); allocation of dose 
will be double-blind.  (revised per Amendment 04)
Subjects will continue to complete the Sleep Diary every morning throughout both Periods 1 and 2.  
They will return to the clinic at the end of Months 1, 2, 3, 6, 9, and 12.  At each clinic visit, safety and 
tolerability will be assessed, including assessment of AEs, and a urine drug test will be carried out.  
At each clinic visit, except Month 12, the Sleep Diary will be reviewed for completeness, compliance 
will be check, and study drug will be dispensed.  At months 1, 3, 6, 9, and 12 the eC-SSRS will be 
administered. At the end of Months 1, 3, 6, 9, and 12, the ISI, FSS, the EQ-5D-3L and the 
PGI-Insomnia will be completed.  At the end of Months 3, 6, 9 and 12, the WPAI-GH will also be 
completed. At predefined visits, a blood sample will be collected for PK analysis. (revised per 
Amendment 03)
At the end of Months 4, 5, 7, 8, 10, and 11, the site will telephone the subject to assess AEs, record 
concomitant medications, and review Sleep Diary entries.  If any AE is clinically significant and 
requires follow-up, an Unscheduled Visit should be arranged as soon as possible.  (revised per 
Amendment 03)
Period 2 will end with the completion of the 12-month visit. For analysis purposes, a subject who 
completes assessments through Period 2 will be considered to have completed the study.
Follow-up Period
The Follow-up Period will begin at the end of Period 2. Subjects will discontinue study drug but will 
continue to complete the Sleep Diary each morning until the EOS visit.
Premature Discontinuation of Study Drug
The subject may elect to discontinue the study at any time for any reason.  Subjects who discontinue 
study drug prematurely at any time after randomization at Visit 3 (Study Baseline) will be 
encouraged to return to the site as soon as practicable (preferably within 7 days).  These subjects will 
be encouraged to continue to complete all study assessments (excepting PK samples, which will not 
be taken), including the Sleep Diary, and to return for all subsequent clinic visits, without the 
administration of study medication.   
Subjects who do not agree to this will undergo an Early Termination (ET) Visit and the EOS visit, as 
described in the Schedule of Procedures/Assessments.  (revised per Amendment 01)  Subjects who 
agree will undergo an Early Drug Discontinuation (EDD) Visit, during which all assessments will be 
conducted that would be made at an ET visit.  These subjects need not attend the next regularly 
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scheduled visit if this falls within the visit window of the next visit.  Subjects who discontinue early 
from study drug are considered on study as long as they return for their regularly scheduled visits.
Adjudication Committee (revised per Amendment 03)
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure.  A set of preferred terms 
constituting a customized Medical Dictionary for Regulatory Activities (MedDRA) query for 
cataplexy or seizure will be used to identify events for adjudication (including cataplexy, muscle 
fatigue, muscular weakness, muscle tone disorder, hypotonia, drop attacks, slurred speech, diplopia, 
falls, convulsions [standardized MedDRA query (SMQ) narrow and broad], atypical migraine, loss of 
consciousness, decreased consciousness, myoclonus, syncope, transient global amnesia, lipothymia, 
[faintness] and transient ischemic attack).  To assist in the preparation of narratives about such events 
and to support the committee’s adjudication process, investigators and site staff will be instructed to 
query subjects who report any of the above events for supplemental information using a questionnaire 
for events potentially related to cataplexy and the serious adverse event (SAE) form for any of the 
above events considered serious.  (revised per Amendment 03) 
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) will convene at regular intervals to monitor 
the overall safety of the study and to make recommendations to the sponsor related to study safety as 
appropriate.  The DSMB will be asked to review the cumulative safety data up to the date identified 
to make a determination of whether the trial is safe to proceed unchanged or to provide 
recommendations to the sponsor as to how to proceed.  The study will proceed, including 
randomization of additional subjects, during DSMB safety reviews.  Details will be provided in the 
DSMB Charter. (revised per Amendment 03)
End of Study
At least 14 days but no more than 18 days after the Treatment Period, subjects will return to the clinic 
for the EOS Visit.  At the EOS Visit, in addition to standard safety assessments and the eC-SSRS, a 
urine drug test will be conducted, the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire 
(T-BWSQ) will be administered and sleep diaries will be collected.  After the End of Study Visit, 
subjects’ participation in the study will be finished. 
Additional Study Information
The end of the study will be the date of the last study visit for the last subject.  As required by some 
regulatory agencies, the following estimates are provided: 

The study will begin enrollment in approximately November 2016 (revised per Amendments 01
and 03)

The estimated duration for each subject on study is anticipated to be a maximum of 60 weeks (a 
maximum 35-day Prerandomization Phase [that includes a Screening Period, a maximum 17-day
Run-In Period, and a Baseline Period] + 52 weeks of the Randomization Phase + a 1-week 
window + a 2-week Follow-Up Period). (revised per Amendment 03)

Approximately 900 subjects with insomnia disorder (18 years or older) will be randomized to 
receive LEM5 or LEM10 or PBO for 6 months.  After 6 months, subjects who previously 
received lemborexant will continue to receive lemborexant at the same dosage level for an 
additional 6 months, while subjects who previously received PBO will undergo a 2nd
randomization to receive LEM5 or LEM10 for 6 months.
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Number of Subjects
Approximately 1500 subjects will be screened to provide 900 randomized subjects. 
Inclusion Criteria 
1.
Male or female, age 18 years or older at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria 
for Insomnia Disorder, as follows:

Complains of dissatisfaction with nighttime sleep in the form of difficulty getting to sleep, 
difficulty staying asleep and/or awakening earlier in the morning than desired despite 
adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
At Screening:  History of sSOL ≥30 minutes on at least 3 nights per week in the previous 4 weeks 
AND/OR sWASO ≥60 minutes on at least 3 nights per week in the previous 4 weeks (revised per 
Amendment 03)
4.
At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 
9 hours 
5.
At 1st Screening Visit (Visit 1) and 2nd Screening Visit (Visit 2a): Reports regular bedtime, 
defined as the time the subject attempts to sleep, between 21:00 and 01:00 and regular waketime,
defined as the time the subject gets out of bed for the day, between 05:00 and 10:00 (revised per 
Amendment 03)
6.
At Screening and Study Baseline: ISI score ≥15 
7.
At the 2nd Screening Visit (Visit 2a):  Confirmation of current insomnia symptoms as determined 
from responses on the Sleep Diary completed on at least 7 consecutive mornings (minimum 5 of 
7 for eligibility), such that sSOL ≥30 minutes on at least 3 of the 7 nights and/or sWASO ≥60
minutes on at least 3 of the 7 nights (revised per Amendment 03)
8.
At 2nd Screening Visit (Visit 2a):  Confirmation of regular bedtimes and waketimes, as 
determined from responses on the Sleep Diary completed on a minimum of 7 consecutive 
mornings between the 1st and 2nd screening visit, such that the subject has a regular time spend 
in bed, either sleeping or trying to sleep, between 7 and 10 hours (revised per Amendment 03)
9.
At the 2nd Screening Visit (Visit 2a):  Confirmation of sufficient duration of time spent in bed, as 
determined from responses on the Sleep Diary completed on 7 mornings between the 1st and 2nd
screening visit, such that there are not more than 2 nights with duration of time spent in bed
<7 hours or >10 hours (revised per Amendment 03)
10. At Baseline (Visit 3a):  Reconfirmation of insomnia symptoms, as determined from responses on 
the Sleep Diary for the final 7 nights of the Run-in Period, such that sSOL ≥30 minutes on at 
least 3 of the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 7 nights (revised per 
Amendment 03)
11. At Baseline (Visit 3a):  Confirmation of regular bedtimes and waketimes,, such that the subject 
has a regular time spent in bed, either sleeping or trying to sleep, between 7 and 10 hours for the 
final 7 nights of the Run-In Period (revised per Amendment 03)
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12. At Baseline (Visit 3a):  Reconfirmation of regular bedtime, defined as the time the subject 
attempts to sleep, between 21:00 and 01:00 and regular waketime, defined as the time the subject 
gets out of bed for the day, between 05:00 and 10:00, for the final 7 nights of the Run-In period
(revised per Amendment 03)
13. Willing and able to comply with all aspects of the protocol, including staying in bed at least 
7 hours each night (revised per Amendment 03)
14. Willing to not start a behavioral or other treatment program for 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 the SDSB as follows:

STOPBang score ≥5

IRLS score ≥16

ESS score >15 (Scores of 11-15 require that excessive daytime sleepiness must be recorded 
in subject’s Medical History) (revised per Amendment 03)
2.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator 
indicate the need for referral for a diagnostic evaluation for the presence of narcolepsy.
3.
Reports a history of sleep-related violent behavior, or sleep driving, or any other complex sleep-
related behavior (eg, making phone call or preparing and eating food while sleeping) (revised per 
Amendment 03)
4.
For subjects who underwent diagnostic polysomnography (PSG) within 1 year before informed 
consent:

Age 18 to 64 years: Apnea-Hypopnea Index ≥10, or Periodic Limb Movements with Arousal 
Index  ≥10 

Age ≥65 years: Apnea-Hypopnea Index >15, or Periodic Limb Movements with Arousal 
Index >15
5.
Beck Depression Inventory – II (BDI-II) score >19 at Screening
6.
Beck Anxiety Inventory (BAI) score >15 at Screening
7.
Habitually naps more than 3 times per week
8.
Females who are breastfeeding or pregnant at Screening or Study Baseline (as documented by a 
positive serum beta-human chorionic gonadotropin [ß-hCG]).  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before the 1st
dose of study drug.
9.
Females of childbearing  who: 

Had unprotected sexual intercourse within 30 days before study entry or who do not agree to 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a 
contraceptive implant, injectable contraceptives, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study period or for
28 days after study drug discontinuation. Periodic abstinence (e.g., calendar, ovulation, 
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symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.  (revised per Amendments 01, 02, and 03)

Are currently abstinent, and do not agree to use a highly effective method (as described 
above) or refrain from sexual activity during the study period and for 28 days after study drug 
discontinuation. (revised per Amendment 02)

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study and for 28 days after study drug discontinuation.
(NOTES:  All females will be considered to be of childbearing  unless they are postmenopausal 
[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing].
For sites outside of the EU, it is permissible that if a highly effective method of contraception is 
not appropriate or acceptable to the subject, the subject must agree to use a medically acceptable 
method of contraception, ie, double-barrier methods of contraception such as condom plus 
diaphragm or cervical/vault cap with spermicide.) (revised per Amendment 02)
10. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
insomnia, or habitually consumes caffeine-containing beverages after 18:00 and is unwilling to 
forego caffeine after 18:00 for the duration of his/her participation in the study.  Subjects are 
excluded if, in the previous 3 months, they had symptoms that would meet DSM-5 criteria for 
caffeine intoxication, which includes consumption of a high dose of caffeine (significantly in 
excess of 250 mg) and ≥5 of the following symptoms: restlessness, nervousness, excitement, 
insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of 
thought and speech, tachycardia or cardiac arrhythmia, periods of high energy, or psychomotor 
agitation.  To be exclusionary, those symptoms must cause distress or impairment in social, 
occupational and other forms of functioning, and not be associated with other substance, mental 
disorder or medical condition.  (revised per Amendment 01)
11. History of drug or alcohol dependency or abuse within approximately the previous 2 years
12. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or 
more than 21 drinks containing alcohol per week (males), or unwilling to limit alcohol intake to 2 
or fewer drinks per day or forego having alcohol within 3 hours before bedtime for the duration 
of his/her participation in the study
13. Known to be human immunodeficiency virus (HIV) positive
14. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
15. A prolonged QT/QT interval corrected by Fridericia’s formula (QTcF >450 ms) as demonstrated 
by a repeated ECG at Screening (repeated only if initial ECG indicates a QTcF interval >450 ms)
(revised per Amendment 03)
16. Current evidence of clinically significant disease (eg, cardiac; respiratory including chronic 
obstructive pulmonary disease, acute and/or severe respiratory depression; severe hepatic 
insufficiency; gastrointestinal; renal including severe renal impairment; neurological [including 
subjects who lack capacity and/or whose cognitive decline indicates disorientation to 
person/place/time and/or situation] or 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. Subjects 
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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)
17. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the 
night
18. 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
19. Any suicidal ideation with intent with or without a plan at Screening or Study Baseline or within 
6 months of Study Baseline (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation 
section of the eC-SSRS)
20. Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the eC-SSRS)
(revised per Amendment 03)
21. Scheduled for major surgery during the study (revised per Amendment 03)
22. Used any prohibited prescription or over-the-counter medications within 1 week or 5 half lives, 
whichever is longer, before the 1st dose of study medication (Run-In Period).  (A list of 
prohibited or limited concomitant medications is presented in Appendix 3 of the protocol.)
23. 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 1st dose of study 
medication (Run-In Period)
24. Failed treatment with suvorexant (efficacy or safety) following treatment with an appropriate 
dose and of adequate duration in the opinion of the investigator
25. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between 
Screening and Study Baseline
26. A positive drug test at Screening, Run-In, or Baseline or unwilling to refrain from use of 
recreational drugs during the study 
27. Hypersensitivity to the study drug or any of the excipients 
28. Currently enrolled in another clinical trial or used any investigational drug or device within 
30 days or 5 times the half-life, whichever is longer preceding informed consent
29. Previously participated in any clinical trial of lemborexant
Study Treatments
LEM5, LEM10, or lemborexant-matched PBO taken orally in tablet form each night immediately 
before the time the subject intends to try to sleep
Run-In Period
All subjects will receive 1 lemborexant-matched PBO in a single-blind manner during the Run-In
Period immediately before the time the subject intends to try to sleep.
Randomization Phase (Periods 1 and 2)
During Period 1 (Day 1 through end of Month 6), all subjects will receive 1 tablet as described below, 
according to the treatment arm to which the subject has been randomized:

LEM5: 1 lemborexant 5-mg tablet

LEM10: 1 lemborexant 10-mg tablet
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
PBO: 1 lemborexant-matched PBO tablet
During Period 2 (Month 7 through 12), all subjects will receive 1 tablet as described below, according 
to the treatment arm to which the subject has been randomized

LEM5: 1 lemborexant 5-mg tablet

LEM10: 1 lemborexant 10-mg tablet
Duration of Treatment
A maximum of approximately 55.5 weeks: Up to 17 days of PBO during the Run-In Period and up to 
52 weeks of randomized treatment. 
Concomitant Drug/Therapy
Caffeine will be permitted in limited quantities during the study.  Subjects will be instructed to limit 
caffeine consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg caffeine per day. 
Subjects will be instructed to avoid caffeine after 18:00 on all days during the study.
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a maximum 
of 2 alcohol-containing drinks on any given day while in the study, and will be instructed not to 
consume any alcohol within 3 hours before bedtime. Because the definition of a standard drink 
varies among countries and regions, no definition of the volume or alcohol content of a standard 
drink is provided, with the exception of Japan.  For sites and subjects in Japan, a drink will be defined 
as 360 mL of beer, 150 mL of wine, or 50 mL of liquor.  Compliance with these restrictions will be 
monitored by specific questions in the Sleep Diary. If subjects cannot comply after counseling, they 
may be discharged from the study.
Prohibited medications (Appendix 3) should not be used during the study. A subject must not have 
used any prohibited prescription or over-the-counter medications within 1 week or 5 half lives, 
whichever is longer, before the 1st dose of study medication (Run-In Period). 
(revised per 
Amendment 01)
Prohibited medications include strong and moderate cytochrome P450 (CYP3A) inhibitors and all 
CYP3A inducers.  Prohibited therapies also include: any treatment for insomnia disorder, including 
any drugs or nonpharmacological treatment such as cognitive behavioral therapy; medications that 
are used for the purpose of inducing sleep (hypnotics) or inducing wakefulness (stimulants; except 
caffeine; see above) and medications that have known sedating effects or alerting effects. The 
prohibition applies even if the entire class to which that medication belongs is not prohibited (eg, 
anticonvulsants).  (revised per Amendment 06)
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, he/she must discontinue from the study, with 
the exception that certain prohibited medications may be used for a short duration (not to exceed 
2 weeks) to treat an acute condition if this is agreed with the Medical Monitor.  Note that strong and 
moderate CYP3A inhibitors and all CYP3A4 inducers will not be permitted at any time for any 
duration during the study. (revised per Amendment 06)
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Assessments
Screening Assessments (administered only at the 1st screening visit)
Sleep Disorders Screening Battery (SDSB) (revised per Amendment 03)
The SDSB will include the following, to be self-administered: (revised per Amendment 03)

STOPBang: a list of 8 questions to be answered Yes or No, which screens subjects for obstructive 
sleep apnea 

IRLS: a subjective scale comprising 10 questions, which measures disease severity of restless 
legs syndrome

ESS: a questionnaire that rates the 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
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 >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 >15 will be excluded from participation.
Efficacy Assessments
Electronic Sleep Diary
The Sleep Diary will be completed within an hour of morning waketime on each morning of the 
study from Screening through theFollow-Up Period.  This Sleep Diary will yield several self-reported 
measures of sleep that will be used to determine eligibility, as well as to assess efficacy.  In addition, 
the Sleep Diary will include questions that relate to morning sleepiness and to alcohol consumption. 
(revised per Amendment 03)
Sleep Parameters

sSOL: estimated minutes from the time the subject attempted to sleep until sleep onset 

sWASO: sum of estimated minutes of wake during the night after initial sleep onset until the time 
the subject stopped trying to sleep for the night

sTST: derived minutes of sleep from sleep onset until the time the subject stopped trying to sleep 
for the night

sSE: proportion of sTST per subjective time spent in bed, calculated as the interval from the time 
the subject reported attempting to sleep until the time the subject stopped trying to sleep for the 
night, and time spent asleep derived from time spent in bed minus sWASO (revised per 
Amendment 03)
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Quality of Sleep and Morning Sleepiness
The Sleep Diary will be used to assess the subject’s global perception of quality of sleep on the 
previous night with the following question: “How would you rate the quality of your sleep last 
night?”  Subjects will rate the quality of their sleep on a scale from 1 to 9, with 1 being extremely 
poor and 9 being extremely good. 
The Sleep Diary will be used to assess subjective ratings of morning sleepiness with the following 
question: “How sleepy/alert do you feel this morning?” Subjects will rate their sleepiness/alertness 
level on a scale from 1 to 9, with 1 being extremely poor and 9 being extremely good.
Alcohol Consumption
The Sleep Diary will include questions that ask about alcohol consumption the previous day, 
including within 3 hours before bedtime and/or exceeding the daily maximum of 2 alcoholic drinks 
per day. 
ISI
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.
FSS
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 will be taken at prespecified visits.  The time and date of the 2 most recent doses administered 
before each sample will be documented.
Pharmacodynamic Assessments
There are no assessments that are primarily PD.  For purposes of PK/PD modeling, selected efficacy 
and safety assessments will be used in lieu of PD assessments.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular laboratory 
evaluation for hematology, blood chemistry, and urine values; periodic measurement of vital signs, 
weight and ECGs; and the performance of physical examinations.  Safety will be assessed at every 
clinic visit throughout the study, including after the last dose of study drug, and at the End of Study, 
ET, EDD, and Unscheduled Visits.
eC-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.
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T-BWSQ
An assessment of withdrawal symptoms will be made using the T-BWSQ completed at the End of 
Study 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 03)
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 (PGI) – Insomnia 
The PGI-Insomnia 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 total sleep time) and 1 item related to perceived 
appropriateness of study medication strength.  The 1st 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).
Work Productivity and Activity Impairment Questionnaire – General Health (WPAI-GH)
The WPAI-GH collects data on absenteeism and presenteeism.  The scale comprises 6 items that are 
used to create the 4 scores shown below.  Outcomes are expressed as impairment percentages, with 
higher numbers indicating greater impairment and less productivity (ie, worse outcomes).

Percent work time missed due to health 

Percent impairment while working due to health 

Percent overall work impairment due to health

Percent activity impairment due to health
Bioanalytical Methods 
Plasma concentrations of lemborexant and its metabolites (M4, M9, and M10) will be measured using 
validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay methods.
Statistical Methods 
All statistical tests will be based on the 5% level of significance (2-sided). 
Where Sleep Diary endpoints are described, the time points refer to the mean of the final 7 nights 
before the visit unless otherwise stated. The following endpoints will be analyzed for LEM5 and 
LEM10 compared to PBO.  
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Primary Endpoint
Mean change from Study Baseline in sSOL at Month 6 
Secondary Endpoints
Key Secondary endpoints:

Mean change from Study Baseline in sSE at Month 6

Mean change from Study Baseline of sWASO at Month 6  
Additional Secondary Endpoints:

Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST, at the beginning of 
treatment (mean of the 7 nights after the 1st dose in Period 1), at Month 1 and at Month 3

Mean change from Study Baseline of sTST at Month 6 

Proportion of responders at Month 6 and Month 12, where sleep onset responder is defined as 
follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 months is ≤20 minutes, and 
sleep maintenance responder is defined as follows: sWASO at Study Baseline is ≥60 minutes and 
mean sWASO at 6 months is ≤60 minutes and shows a reduction of >10 minutes compared to 
Study Baseline.

Change from Study Baseline in daytime functioning, assessed as the total score from the 4 items 
on daytime functioning, on the ISI, at Months 1, 3, and 6

Change from Study Baseline on the FSS at Months 1, 3, and 6

Ratings on the morning sleepiness item of the Sleep Diary, for:
-
The mean change from Study Baseline of the 1st 7 mornings after the 1st dose in Period 1
and Period 2
-
The mean change from Study Baseline at: Month 1, Month 3, and Month 6 
-
The mean change from Study Baseline and from Period 2 Baseline (as appropriate) for 
subjects with 1, 3, 6, 9, and 12 months exposure (revised per Amendment 06)
-
The mean change from Screening for the 1st 7 mornings and 2nd 7 mornings of the 
Follow-up Period

Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up Period
(revised per Amendment 02)
-
Change from Screening of sSOL on each of the 1st 3 nights, mean sSOL of the 1st 7 nights, 
and mean sSOL of the 2nd 7 nights of the Follow-up Period
-
Change from Screening of sWASO on each of the 1st 3 nights, mean sWASO of the 1st
7 nights and mean sWASO of the 2nd 7 nights of the Follow-up Period
-
Proportion of subjects whose sSOL is longer than at Screening for each of the 1st 3 nights, or 
whose mean sSOL is longer than at Screening for 1st 7 nights or 2nd 7 nights of the 
Follow-up Period
-
Proportion of subjects whose sWASO is higher than at Screening for each of the 1st 3 nights, 
or whose mean sWASO is higher than at Screening for the 1st 7 nights or 2nd 7 nights of the 
Follow-up Period
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
Persistence of Effect 
-
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST at Months 3, 6,
9, and 12 compared to Month 1
-
Mean change from Treatment Period 2 Baseline (Month 6) of sSOL, sSE, sWASO, and sTST 
at Months 9 and 12 compared to Month 7 (the first month of treatment in Period 2)  (revised 
per Amendment 06)
-
Mean change from Study Baseline and Treatment Period 2 Baseline (as appropriate) of 
sSOL, sSE, sWASO, and sTST at 3 and 6 months exposure compared to 1 month of exposure  
(revised per Amendment 06)
Safety and Tolerability of Lemborexant

During Period 1, compared to PBO

For subjects exposed to lemborexant for 3, 6, 9, and 12 months (revised per Amendment 06)  
Exploratory Endpoints
The following endpoints will be explored for LEM5 and LEM10.  Except for PK endpoints, 
comparisons to PBO will be made.

Change from Study Baseline in the mean value of the item on quality of sleep from the Sleep 
Diary for: 
-
The 1st 7 mornings after the 1st dose in Period 1
-
Months 1, 3, and 6 

Change from Study Baseline and Period 2 Baseline (as appropriate) in the mean value of the item 
on quality of sleep from the Sleep Diary for:
-
Subjects with 1, 3, 6, 9, and 12 months exposure (revised per Amendment 06)

Change from Study Baseline in: 
-
EQ-5D-3L at Months 1, 3, and 6
-
WPAI-GH at Months 3 and 6

Change from Study Baseline and Period 2 Baseline (as appropriate) in:
-
EQ-5D-3L for subjects with 3, 6, 9, and 12 months exposure  (revised per Amendment 06)
-
WPAI-GH for subjects with 3, 6, 9, and 12 months exposure  (revised per Amendment 06)

Number and percentage of subjects with a rating of a positive medication effect on each 
PGI-Insomnia item (1) at Months 1, 3, and 6 (placebo-controlled Treatment Period 1), and (2) 
with 3, 6, 9, and 12 months exposure (Treatment Period 1 and Treatment Period 2 combined).  
(revised per Amendment 06)

Change from Study Baseline and Period 2 Baseline (as appropriate) of sSOL, sSE, sWASO, 
sTST with 1, 3, 6, 9, and 12 months exposure, and ISI and FSS with 3, 6, 9, and 12 months 
exposure  (revised per Amendment 06)

Mean score on the T-BWSQ of LEM5, and LEM10 compared to PBO at End of Study

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
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
PK of lemborexant using population modeling

Relationships between lemborexant PK, efficacy, and/or safety variables using PK/PD modeling
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of randomized study 
drug and had at least 1 postdose safety assessment.  

On-Treatment Safety Analysis Set:  On-Treatment Safety Analysis Set is the group of subjects 
who received at least 1 dose of lemborexant and had at least 1 postdose safety assessment.
(revised per Amendment 06)

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.

On-Treatment Full Analysis Set (FAS):  On-Treatment FAS is the group of subjects who received 
at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement. (revised 
per Amendment 06)

The Per Protocol 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).  (revised per Amendment 
01)

The 6-Months Completer Analysis Set is the group of subjects in the FAS who had all efficacy 
assessments up to and including Month 6 (ie, Week 1 and Months 1 to 6 visits) without missing 
primary or key secondary efficacy assessments at any of these visits.  (revised per Amendment 04)

The PK Analysis Set is the group of subjects who had at least 1 quantifiable lemborexant plasma 
concentration or its metabolites, with adequately documented dosing history.

The PK/PD Analysis Set is the group of subjects receiving either lemborexant or PBO who have 
efficacy or safety data with documented dosing history.
In addition, subjects receiving 
lemborexant should have at least 1 quantifiable lemborexant concentration data point as per the 
PK Analysis Set.
Efficacy Analyses
Definitions of Baseline
For the analyses of PBO-controlled endpoints (ie, Day 1 to Month 6), “Study Baseline” when applied 
to analysis endpoints is defined as the data captured during the Run-In Period (or during the Baseline 
Period).  For the analyses of data that are not placebo-controlled (ie, Month 7 to Month 12), data from 
Month 6 will be used as the “Period 2 Baseline”. (revised per Amendment 06)
For other endpoints, baseline data are captured during the Run-In and Baseline Period. Details will 
be specified in the SAP.  (revised per Amendment 01)
12-Month Lemborexant Exposure
Twelve-month (12-month) lemborexant exposure summaries will be summarized by treatment 
(LEM5, LEM10) and duration of exposure (1 month [30 days] where appropriate, 3 months [90 
days], 6 months [180 days], 9 months [270 days] and 12 months [365 days]). Treatment groups are 
LEM5 and LEM10, and include both (a) LEM Period 1 subjects on the On-Treatment Full Analysis 
Set using the change from Study Baseline and (b) LEM Period 2 subjects previously receiving PBO 
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on the On-Treatment Full Analysis Set using the change from Period 2 Baseline. (revised per 
Amendment 06)
Control of Type 1 Error
A sequential gate-keeping procedure including sSOL (primary endpoint), sSE and sWASO (key 
secondary endpoints) at Month 6 will control for type 1 error.  In order to move from 1 step to the 
next (steps a to f; below) the outcome must be significant at 0.05 (2-sided). 
a.
Change from Study Baseline at Month 6 in sSOL, LEM10 compared to PBO 
b.
Change from Study Baseline at Month 6 in sSOL, LEM5 compared to PBO 
c.
Change from Study Baseline at Month 6 in sSE, LEM10 compared to PBO 
d.
Change from Study Baseline at Month 6 in sSE, LEM5 compared to PBO 
e.
Change from Study Baseline at Month 6 in sWASO, LEM10 compared to PBO
f.
Change from Study Baseline at Month 6 in sWASO, LEM5 compared to PBO
This testing procedure controls the overall type 1 error rate of 0.05 for the primary and key secondary 
efficacy analyses.  (revised per Amendment 03).
Analysis for the Primary Endpoint
Null Hypothesis: For sSOL, no difference exists in the mean change from Study Baseline to Month 6 
of treatment with LEM10 and LEM5 as compared with PBO.
Alternative Hypothesis: For sSOL, a difference exists in the mean change from Study Baseline to 
Month 6 for LEM10 and LEM5 as compared with PBO.
The sSOL change from Study Baseline to Month 6 will be analyzed using the mixed effect model 
repeated measurement (MMRM) analysis on the FAS. The model will include all data and will be 
adjusted for the corresponding Study Baseline value, region, age group (<65 years old; ≥65 years 
old), treatment, time (average of the first 7 nights, Month 1, Month 3, and Month 6) and the 
interaction of treatment by time. 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 
not missing at random (MNAR) utilizing the complete case missing value pattern (CCMV - subjects 
who completed all 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.  Details of the pattern mixture model 
and MI method will be presented in SAP.  (revised per Amendments 03 and 04)
The following analyses will be considered as sensitivity analyses: (revised per Amendment 04)
•
Missing imputation assuming MNAR utilizing CCMV-7: The same MMRM method used in the 
primary analysis will be applied utilizing CCMV-7 (ie, up to 7 monotone missing patterns will be 
used for missing value imputation). (revised per Amendment 04)
•
Tipping point analysis: A range of shifts starting from the primary analysis (CCMV) 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 nonsignificant. (revised 
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per Amendment 04)
The following analyses will be considered as supplementary analyses (revised per Amendment 04):

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 based 
on 6-Months Completer Analysis Set (revised per Amendment 04).

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). (revised per 
Amendment 03)
Key Secondary Efficacy and Pharmacodynamic Analyses (revised per Amendment 03)
The change from Study Baseline of key secondary endpoints sSE and sWASO at Month 6 comparing 
LEM5 and LEM10 to PBO will be analyzed using the same analysis method as the primary endpoint.  
The missing values will be imputed 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% 
confidence interval (CI) of the treatment differences will also be provided.  (revised per 
Amendment 03)
Other Secondary Efficacy and Pharmacodynamic Analyses (revised per Amendment 03)
The other secondary efficacy endpoints (change from Study Baseline of the following for LEM5 and 
LEM10 compared to PBO; mean sSOL, mean sSE, mean sWASO and mean sTST at 1st 7 nights, 
Months 1 and 3; and mean sTST at Month 6; ISI total of 4 items of daytime functioning at Months 1, 
3, and 6, and FSS score at Months 1, 3, and 6) will be analyzed using the MMRM, assuming the 
missing values are missing at random (MAR).  The FSS will also be analyzed for responders,
including only those subjects who endorsed clinically significant fatigue at Study Baseline.  (revised 
per Amendments 03 and 06)
The proportion of responders, separately for sSOL and sWASO, will be analyzed using the Cochran-
Mantel-Haenszel test, adjusted for country and age group, after the 1st 7 nights and for the last 
7 nights of treatment at the end of Months 1, 3, 6, and 12, for LEM5 and LEM10 compared to PBO.
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.   
To assess rebound insomnia, both categorical analysis at the subject level and continuous analysis at 
the group mean level will be performed.  For each of the first 3 nights and each of the 2 weeks of the 
Follow-up Period the proportion of subjects whose corresponding value for sSOL or sWASO exceeds 
the corresponding Screening Period value by 5 minutes will be summarized by treatment group and 
compared to placebo. The percentage of ‘rebounders’ between each treatment and placebo group will 
be analyzed using a Cochran-Mantel-Haenszel (CMH) test, adjusted for country and age group.  
To assess statistical significance using the continuous data at the group mean level, the data will be 
analyzed using ANCOVA, adjusted for country, 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 
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bound of a 95% CI for the values during the Screening Period in the given treatment group, it will be 
considered strong evidence for rebound insomnia. If the LS means for sSOL and sWASO for the 
Follow-up Period are all lower than for the Screening Period, then no rebound insomnia is suggested.  
Otherwise, the degree to which the parameters worsen, and the time point(s) at which they worsen 
will be considered to evaluate whether clinically meaningful rebound insomnia is present.  
To evaluate morning sleepiness item on the Sleep Diary, the mean change from Study Baseline of the 
1st 7 mornings after the 1st dose in Period 1, Month 1, Month 3 and Month 6 will be analyzed using 
MMRM, assuming MAR.  Additionally, morning sleepiness change from both Study Baseline and 
Period 2 Baseline for the 1st 7 mornings after the 1st dose in Period 2, Month 9, and Month 12, and 
also the change from Screening of each of the 2 weeks of the Follow-Up Period will be summarized 
with mean and 95% CI's. (revised per Amendment 03)
Analyses for persistence versus loss of effect will be conducted for sSOL, sSE, sWASO and sTST at 
Months 3, 6, 9, and 12 compared to Month 1.  Loss of effect will be defined as present if the mean 
change from Study Baseline at Month 3 (or Months 6, 9, 12) is below the lower bound of the 95% CI 
at Month 1 for sSE or sTST and above the upper bound of the 95% CI at Month 1 for sSOL and 
sWASO.  Analyses for persistence versus loss of effect over Period 2 will be conducted for only the 
subjects randomized to PBO in Period 1 (those subjects will have been randomized to lemborexant in 
Period 2).  These analyses will compare sSOL, sSE, sWASO and sTST at Months 9 and 12 to these 
measures at Month 7.  Loss of effect will be defined as present if the mean change from Period 2
Baseline at Month 9 (or Month 12) is below the lower bound of the 95% CI at Month 7 for sSE or 
sTST and above the upper bound of the 95% CI at Month 7 for sSOL and sWASO.  Analyses for 
persistence versus loss of effect over duration of exposure will be conducted for On-Treatment Full 
Analysis Set subjects.  These analyses will compare 1 month duration of exposure on sSOL, sSE, 
sWASO and sTST at 3 and 6 months duration of exposure, for a) LEM Period 1 subjects using the 
change from Study Baseline and (b) LEM Period 2 subjects previously receiving PBO using the 
change from Period 2 Baseline, with loss of effect as defined above.  (revised per Amendment 06)
No multiplicity adjustment is planned for other secondary endpoints.  (revised per Amendment 03)
Exploratory Efficacy and Pharmacodynamic Analyses  
The change from Study Baseline for the mean score of the quality of sleep item on the Sleep Diary 
will be analyzed using MMRM, assuming MAR for the mean of the 1st 7 days of Period 1 and at 
Months 1, 3, and 6.  (revised per Amendment 03)
Health-related quality of life: the change from Study Baseline for the EQ-5D-3L scores (both total 
score and Visual Analog Scale score), and the four scores from WPAI-GH will be using MMRM, 
assuming MAR for Month 1 (EQ-5D-3L only) and Months 3 and 6 (both EQ-5D-3L and WPAI-GH).  
(revised per Amendment 03)
Each item on the PGI-Insomnia at Months 1, 3 and 6 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.  
Summaries of all efficacy endpoints will be performed for 12 months exposure.  Where appropriate, 
95% CIs around the mean change from Study Baseline or Period 2 Baseline (for Period 1 and Period 
2 data, respectively) will be presented.  (revised per Amendment 06)
No multiplicity adjustment is planned for the exploratory and PD endpoints. (revised per 
Amendment 03)
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Pharmacokinetic Analysis 
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, and 
M10 plasma concentration listings. The PK Analysis Set will be used for summaries of lemborexant 
M4, M9, and M10, 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 (eg, demographics, concomitant medications) on 
the PK of lemborexant will be evaluated. The PK model will be parameterized for oral clearance 
(CL/F) and volumes of distribution. 
Derived exposure parameters such as area under the 
concentration-time curve (AUC) and maximum plasma concentration (Cmax) of lemborexant and any 
other relevant parameters will be calculated from the model using the individual estimates
parameterized for oral clearance and dosing history.
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship between exposure to lemborexant and efficacy variables including but not 
limited to sSOL, sSE, and sWASO, and safety variables including but not limited to morning 
sleepiness and frequently occurring 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 and On-Treatment Safety 
Analysis Set, as appropriate.  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 ≥3), along with change 
from Study Baseline in laboratory safety test variables, ECGs, and vital sign and weight 
measurements, will be summarized by treatment group and visit using descriptive statistics.  This will 
be repeated for the 12-month LEM exposure (On-Treatment Safety Analysis Set), summarized by 
treatment group and duration of exposure.  (revised per Amendment 06)
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered cataplexy or 
seizure, somnolence, and related events, and preferred terms related to drug abuse liability, will be 
summarized.  The results of the deliberation of the Adjudication Committee will be reported 
separately.  (revised per Amendment 03)
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed by 
modeling methods if warranted.
Interim Analysis (revised per Amendments 04 and 05)
No interim analysis is planned for this study.  
Sample Size Rationale
The sample size was estimated for the comparison of LEM10 and LEM5 with PBO, with respect to 
the mean change from Study Baseline at the end of Month 6 of the mean sSOL, mean sSE, and mean 
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sWASO. This estimate was based on sequential gate-keeping procedure at the 0.05 α-level as 
described above. There is sufficient power for both the primary endpoint (sSOL) and key secondary 
endpoints (sSE and sWASO). 
On the basis of the dose finding study E2006-G000-201 (Study 201) for the lemborexant total 
summaries at Days 8 to 15, the standard deviation of change from Study Baseline for sSOL is 
assumed to be 33 minutes, for sSE is assumed to be 12% and for sWASO is assumed to be 
43 minutes.  The LS mean treatment differences at Days 8 to 15 from Study 201 were as follows: for 
sSE 9.5% for LEM10 and 5.5%, for LEM5; for sWASO -26.6 minutes for LEM10 and -11.3 minutes 
for LEM5.  As a result of the non-normal distribution of sSOL, the LS mean treatment difference is 
not available (geometric mean ratios were used).  Therefore, estimating treatment difference using 
medians at Days 8 to 15 from Study 201, leads to a median treatment difference of 
approximately -6.8 minutes for LEM10.  For LEM5, a median treatment difference is 
approximately -13.2 minutes. 
To detect a treatment difference in sSOL of at least -8.7 minutes, a sample size of 300 per treatment 
group at 5% (2-sided) level of significance has >90% power for comparing a dose of lemborexant 
with PBO. 
To detect a treatment difference in sSE of at least 5.5%, a sample size of 300 per treatment group at 
5% (2-sided) level of significance has >99% power for comparing a dose of lemborexant with PBO.
For sWASO, total 900 subjects (300 per treatment group) will give 90% power to detect a difference 
of -11.4 minutes for LEM5 and LEM10 compared to PBO.  The study is adequately powered to show 
the statistically significant difference from PBO for LEM10 as well as for LEM5.
The study also has adequate power for the secondary analysis of responders.  A sleep onset responder 
is defined as follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 months is ≤20 
minutes, and a sleep maintenance responder is defined as follows: sWASO at Study Baseline is ≥60 
minutes and mean sWASO at 6 months ≤60 minutes and shows a reduction of >10 minutes compared 
to Study Baseline. A total of 900 subjects gives >99% power to detect a treatment difference in sleep 
onset responder rates of 16% and sleep maintenance responder rates of 24.4%. 
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3
TABLE OF CONTENTS
1
TITLE PAGE.................................................................................................................... 1
2
CLINICAL PROTOCOL SYNOPSIS.............................................................................. 2
3
TABLE OF CONTENTS................................................................................................ 23
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................. 28
5
ETHICS........................................................................................................................... 31
5.1
Institutional Review Boards/Independent Ethics Committees ............................. 31
5.2
Ethical Conduct of the Study................................................................................ 31
5.3
Subject Information and Informed Consent.......................................................... 32
6
INVESTIGATORS AND STUDY PERSONNEL......................................................... 33
7
INTRODUCTION .......................................................................................................... 34
7.1
Indication .............................................................................................................. 34
7.1.1
Current Therapeutic Options....................................................................... 34
7.1.2
Lemborexant (E2006) ................................................................................. 34
7.1.2.1
Mechanism of Action.......................................................................... 34
7.1.2.2
Clinical Experience with Lemborexant .............................................. 35
7.1.2.2.1
Phase 1 .......................................................................................... 35
7.1.2.2.2
Phase 2 .......................................................................................... 36
7.1.2.3
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ................. 37
7.2
Study Rationale..................................................................................................... 37
8
STUDY OBJECTIVES................................................................................................... 38
8.1
Primary Objective ................................................................................................. 38
8.2
Secondary Objective(s)......................................................................................... 38
8.3
Exploratory Objective(s)....................................................................................... 38
9
INVESTIGATIONAL PLAN......................................................................................... 40
9.1
Overall Study Design and Plan............................................................................. 40
9.1.1
Prerandomization/Pretreatment Phase ........................................................ 42
9.1.1.1
Screening Period ................................................................................. 42
9.1.1.2
Run-In Period...................................................................................... 42
9.1.1.3
Baseline Period (Study Baseline)........................................................ 43
9.1.2
Randomization Phase.................................................................................. 43
9.1.2.1
Treatment Period 1 (Period 1)............................................................. 43
9.1.2.2
Treatment Period 2 (Period 2)............................................................. 44
9.1.2.3
Follow-Up Period................................................................................ 44
9.1.2.4
End of Study Visit............................................................................... 45
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9.1.2.5
Additional Study Information............................................................. 45
9.2
Discussion of Study Design, Including Choice of Control Groups...................... 45
9.2.1
Randomization............................................................................................ 45
9.2.2
Run-In ......................................................................................................... 46
9.2.3
Safety .......................................................................................................... 46
9.2.4
Efficacy....................................................................................................... 47
9.3
Selection of Study Population............................................................................... 47
9.3.1
Inclusion Criteria ........................................................................................ 47
9.3.2
Exclusion Criteria ....................................................................................... 49
9.3.3
Removal of Subjects from Therapy or Assessment.................................... 52
9.4
Treatment(s).......................................................................................................... 52
9.4.1
Treatment(s) Administered ......................................................................... 52
9.4.2
Identity of Investigational Product(s) ......................................................... 53
9.4.2.1
Chemical Name, Structural Formula of Lemborexant........................ 53
9.4.2.2
Comparator Drug ................................................................................ 53
9.4.2.3
Labeling for Study Drug ..................................................................... 53
9.4.2.4
Storage Conditions.............................................................................. 54
9.4.3
Method of Assigning Subjects to Treatment Groups.................................. 54
9.4.4
Selection of Doses in the Study .................................................................. 54
9.4.5
Selection and Timing of Dose for Each Subject......................................... 55
9.4.6
Blinding....................................................................................................... 55
9.4.7
Prior and Concomitant Therapy.................................................................. 55
9.4.7.1
Drug-Drug Interactions....................................................................... 56
9.4.7.2
Prohibited Concomitant Therapies and Drugs.................................... 56
9.4.7.2.1
Caffeine and Alcohol Restrictions................................................ 56
9.4.8
Treatment Compliance................................................................................ 57
9.4.9
Drug Supplies and Accountability.............................................................. 57
9.5
Study Assessments................................................................................................ 59
9.5.1
Assessments ................................................................................................ 59
9.5.1.1
Demography........................................................................................ 59
9.5.1.2
Screening and Baseline Assessments.................................................. 59
9.5.1.2.1
Medical History and Physical Examinations................................ 59
9.5.1.2.2
Sleep Disorders History and Screening Battery............................ 59
9.5.1.2.3
Beck Depression Inventory-II....................................................... 60
9.5.1.2.4
Beck Anxiety Inventory................................................................ 60
9.5.1.2.5
Viral Testing ................................................................................. 60
9.5.1.3
Efficacy Assessments.......................................................................... 60
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9.5.1.3.1
Electronic Sleep Diary.................................................................. 60
9.5.1.3.2
Insomnia Severity Index ............................................................... 61
9.5.1.3.3
Fatigue Severity Scale (FSS) ........................................................ 61
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments............................................................ 61
9.5.1.4.1
Pharmacokinetic Assessments ...................................................... 61
9.5.1.4.2
Pharmacodynamic Pharmacogenomic, and Other Biomarker 
Assessments .................................................................................. 62
9.5.1.5
Safety Assessments............................................................................. 62
9.5.1.5.1
Adverse Events and Events Associated with Special Situations .. 62
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................... 64
9.5.1.5.3
Laboratory Measurements ............................................................ 65
9.5.1.5.4
Vital Signs and Weight Measurements......................................... 67
9.5.1.5.5
Physical Examinations.................................................................. 68
9.5.1.5.6
Electrocardiograms ....................................................................... 68
9.5.1.5.7
Other Safety Assessments............................................................. 68
9.5.1.6
Other Assessments.............................................................................. 69
9.5.2
Schedule of Procedures/Assessments ......................................................... 70
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
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ........................... 77
9.5.4.3.2
Reporting of Study-Specific Events.............................................. 77
9.5.4.4
Expedited Reporting ........................................................................... 77
9.5.4.5
Breaking the Blind .............................................................................. 77
9.5.4.6
Regulatory Reporting of Adverse Events ........................................... 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
9.6.1
Data Collection ........................................................................................... 79
9.6.2
Clinical Data Management ......................................................................... 79
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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.......................................................................... 80
9.7.1.1.2
Secondary Endpoints .................................................................... 80
9.7.1.1.3
Safety Endpoints ........................................................................... 81
9.7.1.1.4
Exploratory Endpoints .................................................................. 81
9.7.1.2
Definitions of Analysis Sets................................................................ 82
9.7.1.3
Subject Disposition............................................................................. 83
9.7.1.4
Demographic and Other Baseline Characteristics .............................. 83
9.7.1.5
Prior and Concomitant Therapy.......................................................... 84
9.7.1.6
Efficacy Analyses ............................................................................... 84
9.7.1.6.1
Analysis for the Primary Endpoint ............................................... 85
9.7.1.6.2
Secondary Efficacy and Pharmacodynamic Analyses.................. 86
9.7.1.6.3
Exploratory Efficacy and Pharmacodynamic Analyses................ 88
9.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses.............................................................................................. 88
9.7.1.7.1
Pharmacokinetic Analyses............................................................ 88
9.7.1.7.2
Pharmacodynamic Analyses ......................................................... 88
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analysis.............................. 89
9.7.1.7.4
Pharmacogenomic Analyses ......................................................... 89
9.7.1.8
Safety Analyses................................................................................... 89
9.7.1.8.1
Extent of Exposure........................................................................ 89
9.7.1.8.2
Adverse Events ............................................................................. 90
9.7.1.8.3
Laboratory Values......................................................................... 91
9.7.1.8.4
Vital Signs and Weight ................................................................. 92
9.7.1.8.5
Electrocardiograms ....................................................................... 92
9.7.1.8.6
Other Safety Analyses................................................................... 93
9.7.1.9
Other Analyses.................................................................................... 93
9.7.2
Determination of Sample Size .................................................................... 93
9.7.3
Interim Analysis.......................................................................................... 94
9.7.4
Other Statistical/Analytical Issues .............................................................. 94
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................. 95
10
REFERENCE LIST ........................................................................................................ 96
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)...... 97
11.1
Changes to the Protocol ........................................................................................ 97
11.2
Adherence to the Protocol..................................................................................... 97
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11.3
Monitoring Procedures.......................................................................................... 97
11.4
Recording of Data................................................................................................. 98
11.5
Identification of Source Data................................................................................ 98
11.6
Retention of Records............................................................................................. 99
11.7
Auditing Procedures and Inspection ..................................................................... 99
11.8
Handling of Study Drug........................................................................................ 99
11.9
Publication of Results ......................................................................................... 100
11.10 Disclosure and Confidentiality ........................................................................... 100
11.11 Discontinuation of Study .................................................................................... 100
11.12 Subject Insurance and Indemnity........................................................................ 101
12
APPENDICES .............................................................................................................. 102
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests.......................................................................... 66
Table 2
Blood Sampling Schedule for All Laboratory and Pharmacokinetic 
Assessments .............................................................................................. 67
Table 3
Schedule of Procedures/Assessments ....................................................... 71
Table 4
Sample Size Calculations for Study E2006-G000-303............................. 94
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2006-G000-303 (revised per Amendment 03). 41
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.............................................. 103
Appendix 2
Inclusion/Exclusion Criteria Schedule.................................................... 105
Appendix 3
Prohibited Concomitant Medications ..................................................... 106
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
β-hCG
beta-human chorionic gonadotropin
BAI
Beck Anxiety Inventory
BDI
Beck Depression Inventory
BMI
body mass index
BP
blood pressure
CCMV
complete case missing value 
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum plasma concentration
CPAP
continuous positive airway pressure
CPMP
Committee for Proprietary Medicinal Products 
CRA
Clinical Research Associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia—Suicide Severity Rating Scale
CV
curriculum vitae
CYP
Cytochrome P450 
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic CRF
eC-SSRS
Columbia-Suicide Severity Scale, electronic version
EDC
electronic data capture
EDD
early drug discontinuation
EOS
end of study
EQ-5D-3L
EuroQOL version 5D-3L
ESS
Epworth Sleepiness Scale
ET
early termination
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSS
Fatigue Severity Scale
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Abbreviation
Term
GABA
γ-aminobutyric acid
GCP
Good Clinical Practice 
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
ICSD-2
International Classification of Sleep Disorders, Version 2
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
ISI
Insomnia Severity Index
IxRS
Interactive Randomization System
KSS
Karolinska Sleepiness Scale
LEM
lemborexant
LLN
lower limit of normal
LNH
low, normal, high
LPS
latency to persistent sleep
LS
least square
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputations
MMRM
mixed effect model repeated measurement
M-MSLT
modified multiple sleep latency test
MNAR
missing not at random
OX1R
orexin-1 receptor
OX2R
orexin-2 receptor
PBO
placebo 
PD
pharmacodynamic
PGI-Insomnia
Patient Global Impression - Insomnia
PI
Principal Investigator
PK
pharmacokinetic
PSG
polysomnography
QTc
Heart-rate-corrected QT interval 
QTcB
QT interval corrected for Bazett’s formula
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Abbreviation
Term
QTcF
QT interval corrected for Fridericia’s formula
RBC
red blood cell
REM
rapid eye movement
SAE
serious adverse event
SAP
statistical analysis plan
SDSB
Sleep Disorders Screening Battery
SMQ
standardized MedDRA query
SOC
system organ class
sSOL
subjective sleep onset latency
sSE
subjective sleep efficiency
sTST
subjective total sleep time
SUSAR
suspected unexpected serious adverse reaction
sWASO
subjective wake after sleep onset
T-BWSQ
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire
TEAE
Treatment-emergent adverse event
ULN
upper limit of normal
US
United States
WASO 
wake after sleep onset
WBC
white blood cell
WHO-DD
World Health Organization – Drug Dictionary
WPAI-GH
Work Productivity and Activity Impairment Questionnaire – General 
Health
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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, changes 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 
sponsor will provide the investigator with a brief report of the outcome of the study, which 
can be provided to the IRB/IEC if required.
At the end of the study, within 90 days the investigator should notify the IRB/IEC and the 
sponsor should notify the Competent Authority.  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 (ET)/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:

Principles of the World Medical Association Declaration of Helsinki 
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
ICH E6 Guideline for GCP of the European Agency for the Evaluation of Medicinal 
Products, Committee for Proprietary Medicinal Products (CPMP/ICH/135/95)

Title 21 of the United States Code of Federal Regulations (US 21 Code of Federal 
Regulations [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

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union country.  All suspected 
unexpected serious adverse reactions (SUSARs) will be reported, as required, to the 
Competent Authorities of all involved European Union member states

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law 
No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

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 appropriate 
designee must explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the  risks and benefits involved, any  discomfort,  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.  Informed consent will be taken by personnel in accordance with 
national legislation.  (revised per Amendment 01)
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 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 125 investigational sites in North America, South America, 
Europe, Asia, and Oceania.  The name and telephone and fax numbers of the medical 
monitor and other contact personnel at the sponsor and the contract research organization(s) 
(CRO[s]) are listed in the Investigator Study File provided to each site.  (revised per 
Amendment 03)
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7
INTRODUCTION
7.1
Indication 
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% of sufficient severity to merit
treatment.
7.1.1
Current Therapeutic Options 
Currently available pharmacological treatments used clinically for insomnia include 
benzodiazepines, non-benzodiazepine γ-aminobutyric acid (GABA)
-releasing agents 
including GABAA receptor positive-allosteric modulators, antidepressants, melatonin and 
melatonin agonists, and antihistamines, and other prescription and nonprescription 
medications with sedative properties.  Recently, there has been increased awareness of the 
need for sleep-promoting agents with new mechanisms of action.  
Towards this end, research findings have suggested that central nervous system orexin
receptors may be suitable targets for novel interventional strategies. This is supported by the 
recent approval of suvorexant, a drug in the same class as lemborexant which was shown in 
clinical trials to significantly improve sleep maintenance insomnia, but at the starting dose 
approved for use, showed suboptimal efficacy, particularly on sleep maintenance
(Herring et al., 2016).
7.1.2
Lemborexant (E2006)
The generic name for E2006 has been designated as lemborexant.
7.1.2.1
Mechanism of Action
Orexin neuropeptides (orexin-A and orexin-B) have been recognized as critical upstream 
controllers of most wake-promoting neurotransmitters via 2 G-protein-coupled receptors, the 
orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R).  On the basis of preclinical 
data, the OX2R has been speculated to be of greater importance for sleep/wake regulation 
than OX1R (Akanmu and Honda, 2005).  Dual receptor antagonists are, however, more 
effective 
for 
sleep 
promotion 
than 
antagonists 
for 
either 
receptor 
alone 
(Moriarty et al., 2012).  Lemborexant is a novel competitive dual orexin receptor antagonist, 
and therefore possesses a mechanism of action that may potentially be an effective treatment 
for insomnia disorder.  This mechanism of action is the basis for the recent marketing 
approval of suvorexant, also an orexin receptor antagonist.
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7.1.2.2
Clinical Experience with Lemborexant
7.1.2.2.1
PHASE 1
E2006-A001-001 (Study 001):  single ascending dose study.  This study included healthy 
subjects and otherwise healthy subjects with primary insomnia.  In addition to determining 
the safety and tolerability of single doses, the study provided preliminary evidence of 
efficacy in the target patient population.
E2006-A001-002 (Study 002):  multiple ascending dose study.  This study enrolled healthy 
adult and elderly subjects, each of whom was dosed with lemborexant or placebo 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 
(clinical phase completed, analysis and reporting in progress).  This study provided evidence 
of a lack of important differences in exposure and safety between Japanese and white 
subjects.
E2006-A001-004 (Study 004):  metabolism-based inducer/inhibitor study.  This study 
provided data demonstrating (1) strong inhibitors of cytochrome P450 (CYP3A) lead to 
moderately higher plasma concentrations of lemborexant; and (2) strong inducers of CYP3A 
lead to markedly lower plasma concentrations of lemborexant. The study also demonstrated 
a weak inhibitory effect of lemborexant on CYP2B6 activity and no effect of lemborexant to 
inhibit or induce 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 (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 AUC(0-inf) was increased by 18% following 
consumption of a high fat meal.
E2006-A001-012 (Study 012):  Drug-drug interaction study.  This study demonstrated that:  
(1) coadministration of a moderate CYP3A inhibitor (fluconazole) led to a moderate 
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interaction as demonstrated by a 1.6-fold increase in Cmax and 4.2-fold increase in AUC0-inf of 
lemborexant; (2) coadministration of lemborexant had no statistically significant effect on the 
PK of oral contraceptives (ethinyl estradiol and norethindrone), and these oral contraceptives 
did not alter the PK of lemborexant; and (3) coadministration of a gastric acid suppressant 
agent (famotidine) had a weak interaction with lemborexant as shown by a 27% decrease in 
Cmax and no impact on AUC0-inf of lemborexant.  (revised per Amendment 06)
E2006-A001-107 (Study 107):  This Phase 1 study was conducted to evaluate the effects of 
the 5 and 10 mg doses on next-morning residual sleepiness in subjects with insomnia 
disorder.  The study design was randomized, double-blind, and placebo-controlled with a 
3-way crossover.  Next-morning residual sleepiness was measured on a modified multiple 
sleep latency test (M-MSLT).  An active comparator, flurazepam 30 mg, was included to 
confirm assay sensitivity.  Results from neither 5 nor 10 mg indicated that 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 was more than -6 minutes, which was the 
prespecified criterion defining clinically meaningful next-morning residual sleepiness.  That 
is, neither dose level of E2006 resulted in a clinically meaningful reduction in average time 
to sleep onset in the morning hours, supporting the safety of these doses and their use in 
Phase 3 studies.
7.1.2.2.2
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.  The effects on LPS and WASO were maintained across 
the treatment period, and 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 2-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.
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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.
7.1.2.3
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure
Not applicable.
7.2
Study Rationale
Phase 1 and Phase 2 studies in the lemborexant clinical program have provided evidence for 
pharmacological efficacy at safe and well-tolerated doses (Section 7.1.2.2).  The present 
study is designed to provide evidence from a large sample of subjects with insomnia 
disorder, that lemborexant is effective at doses that are safe and well tolerated and that do not 
cause meaningful morning sleepiness.  This study will be part of the Phase 3 clinical study 
program, which is intended to support planned marketing applications.
Study 303 will also provide data on the safety of lemborexant over 12 months of treatment, 
in accordance with the ICH requirements for long-term administration. Study 303 will be 
conducted globally. The choice of countries will help ensure the enrollment of the requisite 
numbers of subjects from specific regions to facilitate the filing of regional Marketing 
Authorization Applications at the completion of the Phase 3 program.
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is:
Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to 
placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in 
subjects with insomnia disorder
8.2
Secondary Objective(s)
The key secondary objectives of the study are:

Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective sleep 
efficiency (sSE) after 6 months of treatment in subjects with insomnia disorder

Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective wake after 
sleep onset (sWASO) after 6 months of treatment in subjects with insomnia disorder
Additional secondary objectives of the study are:

Determine the efficacy of LEM5 and LEM10 compared to PBO on sSOL, sSE, sWASO, 
and subjective total sleep time (sTST):
-
over the 1st 7 nights of treatment 
-
after 1 month of treatment
-
after 3 months of treatment

Determine the efficacy of LEM5 and LEM10 compared to PBO on sTST at 6 months  

Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and 
LEM10 compared to PBO as defined by response on sSOL or sWASO at 6 months and 
12 months

Evaluate the safety and tolerability of LEM5 and LEM10

Evaluate the efficacy of LEM5 and LEM10 compared to PBO as measured by responses 
on the Insomnia Severity Index (ISI) and the Fatigue Severity Scale (FSS) after 6 months

Evaluate rebound insomnia following discontinuation of treatment 

Evaluate morning sleepiness during and following completion of treatment

Evaluate persistence of efficacy of LEM5 and LEM10 over 12 months
8.3
Exploratory Objective(s)
The following will be explored for both LEM5 and LEM10 compared to PBO over 
Treatment Period 1 (Period 1) and over Treatment Period 2 (Period 2) with analyses 
dependent on whether subjects received active treatment or PBO during Period 1 (revised per 
Amendment 04):
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
Efficacy on quality of sleep 

Health outcomes on the EuroQOL version 5D-3L (EQ-5D-3L), Work Productivity and 
Activity Impairment Questionnaire – General Health (WPAI-GH), and Patient Global 
Impression – Insomnia  (PGI-Insomnia)

Efficacy on sSOL, sSE, sWASO, sTST, ISI, and FSS

Withdrawal symptoms after completion of treatment (Period 2 only)
The following will be explored for LEM5 and LEM10:

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10

Population pharmacokinetic (PK) modeling for lemborexant

PK/pharmacodynamic (PD) relationships between lemborexant concentrations and 
efficacy and safety variables
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a 12-month, multicenter, randomized, controlled, double-blind, parallel-group 
study of 2 doses of lemborexant in approximately 900 male or female subjects with insomnia 
disorder (subjects who complain of difficulties with sleep onset and/or sleep maintenance).
Approximately 40% of the population will be 65 years of age or older.  Note: enrollment of 
subjects <65 years may be limited if the percentage of enrolled subjects >65 years is below 
expectations toward the end of the study.  (revised per Amendments 01 and 03)
The study will have 2 phases, the Prerandomization Phase and the Randomization Phase.
The Prerandomization Phase will comprise 3 periods and last up to 35 days: a Screening 
Period, a Run-In Period and a Baseline Period. The Randomization Phase will comprise a 
6-month, placebo-controlled treatment period (Period 1).
During the next 6 months 
(Period 2), subjects will receive only active treatment.  Subjects will be informed that they 
will receive PBO at some point during the study and that all will receive active drug for at 
least 6 months. They will not be informed of either the timing of these periods or the timing 
of the 2nd randomization.  A 2-week Follow-Up Period will then take place, followed by an 
End of Study Visit.  (revised per Amendment 03)
End of Study
The end of the study will be the date of the last study visit for the last subject.  As required by 
some regulatory agencies, the following estimates are provided: 

The study will begin enrollment in approximately November 2016 (revised per 
Amendments 01 and 03)

The estimated duration for each subject on study is anticipated to be a maximum 
of60 weeks (a maximum 35-day Prerandomization Phase [that includes a Screening 
Period, a maximum 17-day Run-In Period, and a Baseline Period] + 52 weeks of the 
Randomization Phase + a 1-week window + a 2-week Follow-Up Period). (revised per 
Amendment 03)

Approximately 900 subjects with insomnia disorder (18 years or older) will be 
randomized to receive LEM5 or LEM10 or PBO for 6 months.  After 6 months, subjects 
who previously received lemborexant will continue to receive lemborexant at the same 
dosage level for an additional 6 months, while subjects who previously received PBO 
will undergo a 2nd randomization to receive LEM5 or LEM10 for 6 months.
An overview of the study design is presented in Figure 1.
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Figure 1
Study Design for Study E2006-G000-303 (revised per Amendment 03)
R = randomization
Phase:
Period:
Start between 
Day -35 and 
Day -17
Baseline
R
Lemborexant 5 mg
Day 1
+2 weeks
Lemborexant 10 mg
Placebo
6 months
Start between 
Day -17 and 
Day -14, end 
on Day -1
Treatment Period 2 
Prerandomization
Follow-Up
Treatment Period 1 
Lemborexant 10 mg 
R
Lemborexant 5 mg 
12 months
Randomization
Screening
Run-In
No Study Drug
No Study Drug
No Study Drug
No Study Drug
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9.1.1
Prerandomization/Pretreatment Phase
9.1.1.1
Screening Period
The Screening Period will begin no more than 35 days before the subject is randomized.  At 
the 1st 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 has a history of difficulties with sleep onset and/or sleep maintenance.  
Screening assessments will include the ISI, the Epworth Sleepiness Scale (ESS), the 
STOPBang, and the International Restless Legs Scale (IRLS), the latter 3 assessments 
collectively called the Sleep Disorders Screening Battery (SDSB).
The FSS and 
health-related quality-of-life measures (EQ 5D-3L and WPAI-GH) will be administered.  
Safety assessments, including the electronic version of the Columbia-Suicide Severity Scale 
(eC-SSRS), will be conducted as described in Section 9.5.1.2.  Additional eligibility criteria 
will be assessed (see Appendix 2). (revised per Amendment 03)
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, 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 2nd Screening Visit (Visit 2a).  Subjects will return to the clinic and eligibility 
criteria will be determined.  Subjects who are not eligible based on Sleep Diary entries will 
return to the clinic for debriefing purposes and to return study equipment.  Visit 2a must 
occur between Day -17 and Day -14.  A urine drug test will be performed.  Subjects who 
continue to meet eligibility criteria will then receive PBO (single-blind) sufficient for 
14 nights and will enter the Run-In Period which will last approximately 14 nights and a 
maximum of 17 nights.   (revised per Amendment 03)
9.1.1.2
Run-In Period
The Run-in Period will begin once eligible subjects are dispensed PBO 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 time spent in bed trying to sleep 
throughout the study, according to the schedule determined by the study site and the subject.
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They will also be reminded that they must follow study restrictions with regard to timing of 
meals, and use of caffeine and alcohol.  
9.1.1.3
Baseline Period (Study Baseline)
On Day 1, the Run-in Period will end and the Baseline Period will begin.  Subjects will 
return to the clinic for this visit (Visit 3), and the ISI will be administered.  If subjects remain 
eligible, the FSS, EQ-5D-3L, and WPAI-GH will then be administered.  Blood and urine 
samples will be collected for routine safety assessment, the eC-SSRS will be completed, and 
a urine drug test will be performed (Table 3).  An electrocardiogram (ECG) will be 
performed, and vital signs and weight will be assessed.  Subjects who complete the Baseline 
Period and continue to meet the eligibility criteria will be randomized and begin the 
Treatment Period. 
9.1.2
Randomization Phase
Upon completion of baseline assessments on Day 1, subjects who remain eligible will enter 
the Randomization Phase. The purpose of the Randomization Phase will be (a) to assess the 
efficacy of lemborexant in subjects with insomnia disorder during treatment for at least 
6 months, and (b) to assess long-term safety in subject treated with lemborexant for up to 
12 months.  The Randomization Phase will begin on Day 1 and will continue for 12 months.  
A placebo-controlled treatment period (Period 1) will take place during the 1st 6 months of 
the Randomization Phase, immediately followed by a 2nd 6-month treatment period (Period 
2), during which only active study drug will be administered.
This will be immediately 
followed by a 2-week Follow-Up Period during which no study drug will be administered.
At the start of Period 1, subjects will be randomized, in a double-blind manner, to receive 
LEM5 or LEM10, or PBO (approximately 1:1:1).  Study drug will be dispensed and subjects 
will be provided with instructions to continue completing the Sleep Diary and taking study 
drug daily at home according to the same schedule and with the same restrictions as during 
the Run-in Period. At the start of Period 2, subjects who were randomized to receive PBO
during Period 1 will be randomized, in a double-blind manner, to receive LEM5 or LEM10 
(approximately 1:1).
All subjects will have routine safety monitored throughout the study, including 
treatment-emergent adverse events (TEAEs), 12-lead ECGs, vital signs, weight, and clinical 
hematology and blood chemistry labs.  Suicidality will be assessed at Screening, Baseline, 
during the Randomization Phase, EOS and the ET/Early Drug Discontinuation (EDD) Visits, 
using the eC-SSRS.
9.1.2.1
Treatment Period 1 (Period 1)
Period 1 will begin with the 1st dose of randomized study medication.  During Period 1, 
subjects will complete sleep diaries daily in the morning, within 1 hour of waketime; sleep 
diaries will be checked on a monthly basis.  The subjects will return to the clinic for the 
Month 1, 2, 3, and 6 visits.  In between these clinic visits, at the end of Months 4 and 5, study 
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site personnel will conduct a phone call to the subject to review any issues with completion 
of the Sleep Diary and to query concomitant medications and AEs.  (revised per 
Amendment 03)
At the Month 1 visit, standard safety assessments will be conducted, a blood sample will be 
collected for determination of plasma concentrations of lemborexant and its metabolites, the 
ISI, the FSS, the PGI-Insomnia, the EQ-5D-3L, and the eC-SSRS will be completed, unused 
study drug will be collected, study drug compliance will be assessed, and a new supply of 
study drug will be dispensed (Section 9.4.8). 
At the Month 2 visit, standard safety 
assessments will be conducted.  At the Month 3 visit, assessments will be same as those at 
the Month 1 visit, . At the end of Month 6, all assessments conducted at the Month 3 visit 
will be repeated, and the WPAI-GH will also be completed.  At completion of these
assessments, Period 1 will end and Period 2 will begin. For analysis purposes, a subject who 
completes assessments up to Month 6 will be defined as a Period 1 completer. (revised per 
Amendment 03)
9.1.2.2
Treatment Period 2 (Period 2)
At the end of Month 6 (Period 2 Baseline), subjects who received PBO during Period 1 will 
undergo a 2nd randomization to receive either LEM5 or LEM10 (approximately 1:1) during 
Period 2.  Subjects who received lemborexant during Period 1 will continue to receive 
lemborexant at the same dose level during Period 2. Subjects will not be informed of the 
timing of the 2nd randomization (at the end of Month 6); allocation of dose will be double 
blind. 
Subjects will continue to complete the Sleep Diary every morning.
Sleep diaries will be 
checked on a monthly basis.  The subjects will return to the clinic for the 9- and 12-month 
visits.  In between these clinic visits, at the end of Months 7, 8, 10, and 11, study site 
personnel will conduct a phone call to the subject to review any issues with completion of the 
Sleep Diary and to query concomitant medications and AEs.  
At each clinic visit, safety and tolerability will be assessed, the eC–SSRS will be completed, 
a urine drug test will be conducted, the Sleep Diary will be reviewed for completeness, 
compliance will be checked, and drug will be dispensed (except at the end of Month 12).  At 
the end of Months 9 and 12, the ISI, FSS, the EQ-5D-3L, the PGI-Insomnia and the 
WPAI-GH will be completed. At predefined visits, a blood sample will be collected for PK 
analysis.
Period 2 will end with the completion of the 12-month visit.  For analysis purposes, a subject 
who completes assessments through Period 2 will be defined as a study completer.
9.1.2.3
Follow-Up Period
The Follow-up Period will begin at the end of Period 2.  Subjects will cease to take study 
drug but will continue to complete the Sleep Diary each morning until the End of Study visit.
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9.1.2.4
End of Study Visit
At least 14 days but no more than 18 days after the Treatment Period, subjects will return to 
the clinic for the End of Study Visit.  
At the End of Study Visit, in addition to standard safety assessments and the eC-SSRS, a 
urine drug test will be conducted, the Tyrer Benzodiazepine Withdrawal Symptom 
Questionnaire (T-BWSQ) will be administered and sleep diaries will be collected (Table 3).  
After the End of Study Visit, subjects’ participation in the study will be finished. 
9.1.2.5
Additional Study Information
The end of the study will be the date of the last study visit for the last subject.  As required by 
some regulatory agencies, the following estimates are provided: 

The study will begin enrollment in approximately November 2016   (revised per 
Amendment 03)

The estimated duration for each subject on study is anticipated to be a maximum of
60 weeks (a maximum 35-day Prerandomization Phase [that includes a Screening Period 
, a maximum 17-day Run-In Period, and a Baseline Period] + 52 weeks of the 
Randomization Phase + a 1-week window + a 2-week Follow-Up Period). (revised per 
Amendment 03)

Approximately 900 subjects with insomnia disorder (18 years or older) will be 
randomized to receive LEM5 or LEM10 or PBO for 6 months.  After 6 months, subjects 
who previously received lemborexant will continue to receive lemborexant at the same 
dosage level for an additional 6 months, while subjects who previously received PBO 
will undergo a 2nd randomization to receive LEM5 or LEM10 for 6 months.
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  bias during data collection and evaluation of endpoints. In addition, 
in order to avoid bias, subjects will be informed only that all will receive PBO at some point 
in the study, and that all will receive active study drug for at least 6 months. They will not be 
informed that they will receive PBO during the run-in, and will not be informed of the timing 
of Periods 1 and 2, nor of the timing of the 2nd randomization (at the start of Period 2).
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9.2.2
Run-In 
Insomnia trials are associated with large placebo effects (McCall et al., 2003).  This study 
will include a run-in period in which all subjects receive PBO (single-blind) to exclude 
subjects who no longer meet the study-specific criteria for insomnia disorder. 
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 and/or restrictions on alcohol 
consumption before bedtime.  In this regard, it is necessary for the subjects to be taking PBO 
and to obtain Sleep Diary data for approximately 14 nights to adequately evaluate whether 
they continue to meet the study-specific criteria for insomnia disorder and continue to 
comply with the study restrictions.  (revised per Amendment 03)
9.2.3
Safety
To allow for a long-term safety evaluation, the present study will take place over a 12-month 
interval during which study drug will be taken daily by subjects, within 5 minutes before the 
subject intends to sleep.
To allow for correlation of plasma drug levels with safety, population PK-safety modelling
will be conducted.
ADJUDICATION COMMITTEE (REVISED PER AMENDMENT 03)
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 [faintness] and transient ischemic attack). To assist in the 
preparation of narratives about such events and to support the committee’s adjudication 
process, investigators and site staff will be instructed to query subjects who report any of the 
above events for supplemental information using a questionnaire for events potentially 
related to cataplexy and the serious adverse event (SAE) form for any of the above events 
considered serious.  (revised per Amendment 03)
DATA SAFETY MONITORING BOARD (REVISED PER AMENDMENT 03)
An independent Data Safety Monitoring Board (DSMB) will convene at regular intervals to 
monitor the overall safety of the study and to make recommendations to the sponsor related 
to study safety as appropriate.  The DSMB will be asked to review the cumulative safety data 
up to the date identified to make a determination of whether the trial is safe to proceed 
unchanged or to provide recommendations to the sponsor as to how to proceed.  The study 
will proceed, including randomization of additional subjects, during DSMB safety reviews.  
Details will be provided in the DSMB Charter. (revised per Amendment 03) 
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9.2.4
Efficacy
To allow for evaluation of efficacy in insomnia disorder, this study will enroll only subjects 
who complain of difficulties with sleep onset and/or sleep maintenance.  (revised per 
Amendment 03)
Subjective measures of sleep efficacy (sSOL and sWASO, derived from sleep diaries) will be 
the primary basis for assessment of efficacy on sleep.  Study 201 showed that these measures 
yield results similar to those from objective PSG measurements.  Sleep diary data provide 
information on the clinical impact of treatment from the subject’s own perspective. 
To allow for extensive assessments of efficacy, safety, and the impact of lemborexant 
treatment on insomnia disorder, a variety of other test instruments will also be employed.  
The ISI, which was also administered during Study 201, and the FSS will be administered.  
Other test instruments will be included to provide information on the functional 
consequences of insomnia disorder and on their possible improvement with treatment. 
9.3
Selection of Study Population
Approximately 1500 subjects who have self-reported insomnia will be screened to provide 
900 randomized subjects in North America, South America, Europe, Asia, and Oceania.
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Male or female, age 18 years or older at the time of informed consent
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria for Insomnia Disorder, as follows:

Complains of dissatisfaction with nighttime sleep in the form of difficulty getting to 
sleep, difficulty staying asleep and/or awakening earlier in the morning than desired 
despite adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3. At Screening:  History of sSOL ≥30 minutes on at least 3 nights per week in the previous 
4 weeks AND/OR sWASO ≥60 minutes on at least 3 nights per week in the previous 
4 weeks (revised per Amendment 03)
4. At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, 
between 7 and 9 hours 
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5. At 1st Screening Visit (Visit 1) and 2nd Screening Visit (Visit 2a): Reports regular 
bedtime, defined as the time the subject attempts to sleep, between 21:00 and 01:00 and 
regular waketime, defined as the time the subject gets out of bed for the day, between 
05:00 and 10:00 (revised per Amendment 03)
6. At Screening and Study Baseline: ISI score ≥15 
7. At the 2nd Screening Visit (Visit 2a):  Confirmation of current insomnia symptoms as 
determined from responses on the Sleep Diary completed on at least 7 consecutive 
mornings (minimum 5 of 7 for eligibility), such that sSOL ≥30 minutes on at least 3 of 
the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 7 nights (revised per 
Amendment 03)
8. At the 2nd Screening Visit (Visit 2a):  Confirmation of regular bedtimes and waketimes, 
as determined from responses on the Sleep Diary completed on a minimum of 
7 consecutive mornings between the 1st and 2nd screening visit, such that the subject has 
a regular time spend in bed, either sleeping or trying to sleep, between 7 and 10 hours 
(revised per Amendment 03)
9. At the 2nd Screening Visit (Visit 2a):  Confirmation of sufficient duration of time spent 
in bed, as determined from responses on the Sleep Diary completed on 7 mornings 
between the 1st and 2nd screening visit, such that there are not more than 2 nights with 
duration of time spent in bed <7 hours or >10 hours (revised per Amendment 03)
10. At Baseline (Visit 3a):  Reconfirmation of insomnia symptoms, as determined from 
responses on the Sleep Diary for the final 7 nights of the Run-in Period, such that sSOL 
≥30 minutes on at least 3 of the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 
7 nights (revised per Amendment 03)
11. At Baseline (Visit 3a):  Confirmation of regular bedtimes and waketimes such that the 
subject has a regular time spent in bed, either sleeping or trying to sleep, between 7 and 
10 hours for the final 7 nights of the Run-In Period (revised per Amendment 03)
12. At Baseline (Visit 3a):  Reconfirmation of regular bedtime, defined as the time the 
subject attempts to sleep, between 21:00 and 01:00 and regular waketime, defined as the 
time the subject gets out of bed for the day, between 05:00 and 10:00, for the final 7 
nights of the Run-In period (revised per Amendment 03)
13. Willing and able to comply with all aspects of the protocol, including  staying in bed for 
at least 7 hours each night (revised per Amendment 03)
14. Willing to not start a behavioral or other treatment program for insomnia during the 
subject’s participation in the study
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9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
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 the SDSB as follows:

STOPBang score ≥5

IRLS score ≥16

ESS score >15 (Scores of 11-15 require excessive daytime sleepiness must be 
recorded in subject's Medical History)  (revised per Amendment 03)
2. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicate the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
3.
Reports a history of sleep-related violent behavior, or sleep driving, or any other
complex sleep-related behavior, eg, making phone calls, or preparing and eating food 
while asleep (revised per Amendment 03)
4. For subjects who underwent diagnostic PSG within 1 year before informed consent:

Age 18 to 64 years: Apnea-Hypopnea Index ≥10, or Periodic Limb Movements with 
Arousal Index ≥10 

Age ≥65 years: Apnea-Hypopnea Index >15, or Periodic Limb Movements with 
Arousal Index >15
5. Beck Depression Inventory – II (BDI-II) score >19 at Screening
6. Beck Anxiety Inventory (BAI) score >15 at Screening
7. Habitually naps more than 3 times per week
8. Females who are breastfeeding or pregnant at Screening or Study Baseline (as 
documented by a positive serum beta-human chorionic gonadotropin [ß-hCG]).  A 
separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the 1st dose of study drug.
9. Females of childbearing  who: 

Had unprotected sexual intercourse within 30 days before study entry or who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a contraceptive implant, injectable contraceptives, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) 
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throughout the entire study period or for 28 days after study drug discontinuation.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  (revised per 
Amendments 01, 02, and 03)

Are currently abstinent, and do not agree to use a highly effective method (as 
described above) or refrain from sexual activity during the study period and for 
28 days after study drug discontinuation. (revised per Amendment 02)

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation.
(NOTES:  All females will be considered to be of childbearing  unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery
at least 1 month before dosing].
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, the subject must agree to use 
a medically acceptable method of contraception, ie, double-barrier methods of 
contraception such as condom plus diaphragm or cervical/vault cap with spermicide.)  
(revised per Amendment 02)
10. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s 
insomnia, or habitually consumes caffeine-containing beverages after 18:00 and is 
unwilling to forego caffeine after 18:00 for the duration of his/her participation in the 
study.  Subjects are excluded if, in the previous 3 months, they had symptoms that would 
meet DSM-5 criteria for caffeine intoxication, which includes consumption of a high 
dose of caffeine (significantly in excess of 250 mg) and ≥5 of the following symptoms: 
restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal 
disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or 
cardiac arrhythmia, periods of high energy, or psychomotor agitation.  To be 
exclusionary, those symptoms must cause distress or impairment in social, occupational 
and other forms of functioning, and not be associated with other substance, mental 
disorder or medical condition.  (revised per Amendment 01)
11. History of drug or alcohol dependency or abuse within approximately the previous 
2 years
12. Reports habitually consuming more than 14 drinks containing alcohol per week (females) 
or more than 21 drinks containing alcohol per week (males), or unwilling to limit alcohol 
intake to 2 or fewer drinks per day or forego alcohol within 3 hours before bedtime for 
the duration of his/her participation in the study
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13. Known to be human immunodeficiency virus (HIV) positive
14. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
15. A prolonged QT/QT interval corrected by Fridericia’s formula (QTcF >450 ms) as 
demonstrated by a repeated ECG at Screening (repeated only if initial ECG indicates a 
QTcF interval >450 ms) (revised per Amendment 03)
16. Current evidence of clinically significant disease (eg, cardiac; respiratory including 
chronic obstructive pulmonary disease, acute and/or severe respiratory depression; severe 
hepatic insufficiency;
gastrointestinal; renal
including severe renal impairment;
neurological [including subjects who lack capacity and/or whose cognitive decline 
indicates disorientation to person/place/time and/or situation] or 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. 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)
17. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during 
the night
18. 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
19. Any suicidal ideation with intent with or without a plan at Screening or Study Baseline or 
within 6 months of Study Baseline (ie, answering “Yes” to questions 4 or 5 on the 
Suicidal Ideation section of the eC-SSRS)
20. Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the 
eC-SSRS) (revised per Amendment 03)
21. Scheduled for major surgery during the study (revised per Amendment 03)
22. Used any prohibited prescription or over-the-counter concomitant medications within 
1 week or 5 half lives, whichever is longer, before the 1st dose of study medication 
(Run-In Period). (A list of prohibited or limited concomitant medications is presented in
Appendix 3.)
23. 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 1st dose of study 
medication (Run-In Period)
24. Failed treatment with suvorexant (efficacy or safety) following treatment with an 
appropriate dose and of adequate duration in the opinion of the investigator
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25. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or 
between Screening and Study Baseline
26. A positive drug test at Screening, Run-In, or Baseline or unwilling to refrain from use of 
recreational drugs during the study (revised per Amendment 03)
27. Hypersensitivity to the study drug or any of the excipients 
28. Currently enrolled in another clinical trial or used any investigational drug or device 
within 30 days or 5 times the half-life, whichever is longer preceding informed consent
29. 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.  For subjects who discontinue study drug prematurely after 
randomization at Visit 3, the procedures are described in Section 9.5.5.  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) page.  In addition, the date of last dose of study drug(s) will be recorded.  
9.4
Treatment(s)
9.4.1
Treatment(s) Administered
LEM5, LEM10, or lemborexant-matched PBO taken orally in tablet form each night 
immediately before the time the subject intends to try to sleep
Run-In Period

Days –17 and Day –1: PBO matched to lemborexant
Randomization Phase (Periods 1 and 2) 
During Period 1 (Day 1 through end of Month 6), all subjects will receive 1 tablet as 
described below, according to the treatment arm to which the subject has been randomized:

LEM5: 1 lemborexant 5-mg tablet

LEM10: 1 lemborexant 10-mg tablet

PBO: 1 lemborexant-matched PBO tablet
During Period 2 (Month 7 through 12), all subjects will receive 1 tablet as described below, 
according to the treatment arm to which the subject has been randomized
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
LEM5: 1 lemborexant 5-mg tablet

LEM10: 1 lemborexant 10-mg tablet
9.4.2
Identity of Investigational Product(s)
Lemborexant (E2006) tablets and PBO to match lemborexant tablets will be manufactured by 
Eisai Manufacturing Ltd. and will be provided in strengths of 5 and 10 mg, identical in 
appearance.  Tablets will be packaged in a double-blind manner.  Each subject's treatment 
will be contained in a 17-day blister pack which includes 3 days overage (17 tablets) for the 
Run-In Period (Day -17 to -1), or a 1 month blister pack with 4 days overage (35 tablets) to 
allow for flexible visit scheduling.  
A list of subjects receiving each study drug batch number will be provided in the study 
report.
9.4.2.1
Chemical Name, Structural Formula of 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-fluoro
pyridin-2-yl)cyclopropanecarboxamide

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
9.4.2.2
Comparator Drug
PBO to match lemborexant as described in Section 9.4.2 will be used as a comparator 
drug in the study.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
The following information has to be provided:

For clinical study use only

Name and address of the sponsor

Chemical name/drug identifier

Lot number/batch number

Storage conditions, expiration date if necessary
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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.
9.4.3
Method of Assigning Subjects to Treatment Groups
At Study Baseline (Day 1), subjects will be assigned to treatments based on a 
computer-generated randomization scheme that will be reviewed and approved by an 
independent statistician.  The ratio of randomization to LEM5, LEM10, or to PBO, will be 
approximately 1:1:1, and stratified by country and age group (<65 years old; ≥65 years old).  
At the 2nd randomization, those previously randomized to PBO will be randomized to either 
LEM5 or LEM10 on an approximately 1:1 basis with the same stratification as in the 1st
randomization.  The randomization schemes and identification for each subject will be 
included in the final clinical study report for this study.  
9.4.4
Selection of Doses in the Study
In Study 201, all doses studied met the 1st 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 2nd 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 small 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 and 10 mg showed significant efficacy measured by sSE, as well 
as decreases in sSOL.  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 sWASO was less for 5 mg, there was a significant proportion of subjects whose 
sWASO 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 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 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 LEM5 and LEM10 in the Phase 2 study, these dose levels were selected for the 
current study.
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9.4.5
Selection and Timing of Dose for Each Subject
Throughout the Run-In Period and Treatment Periods 1 and 2, study drug will be taken at 
home immediately before the subject intends to sleep, on a time schedule that is as consistent 
as possible.  Subjects should not eat a meal within 3 hours before taking the study drug. In 
addition to being a principle of good sleep hygiene, the rationale underlying this requirement 
is based on the mild food effect noted in Section 7.1.2.2.1. (revised per Amendment 01)
9.4.6
Blinding
During the Run-In Period, the subject will be blinded to the treatment, but study personnel 
will be aware that the treatment consists of PBO (ie, single-blind). Subjects will be informed
that all will receive PBO at some point, and that all will receive active drug for at least 
6 months. They will not be informed of either the timing of these periods or the timing of the 
2nd randomization.
During Period 1 (ie, placebo-controlled, double-blind), 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 (ie, double-blind).  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 procedures. When all subjects have completed Period 1, 
all data will be unblinded to the sponsor.  Study sites and subjects will remain blinded until 
the study has been completed  (revised per Amendments 04 and 05)
A master list that identifies the treatment (ie, dose level) associated with each blister pack
will be maintained in a sealed envelope to be stored in a secure area with limited access, by 
the clinical supply vendor, the vendor for the Interactive Randomization System (IxRS) and 
the sponsor.  In the event that emergency conditions require knowledge of the study 
treatment given, the blind may be broken via the code breaker facility within the IxRS.  
Emergency procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, 
before breaking the blind, the investigator should consult with the sponsor to ascertain the 
necessity of breaking the code. 
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
Prior and Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The 
investigator will record on the AE
CRF 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 
Condition CRF.
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9.4.7.1
Drug-Drug Interactions
Co-administration with strong and moderate CYP3A inhibitors may moderately increase 
exposure to lemborexant, and CYP3A inducers may markedly decrease lemborexant 
exposure.   drug interactions with lemborexant are described in further detail in the 
Investigator’s Brochure; prohibited concomitant medications are described in Section 9.4.7.2
and listed in Appendix 3.  (revised per Amendment 06)
9.4.7.2
Prohibited Concomitant Therapies and Drugs 
Prohibited medications (Appendix 3) should not be used during the study.  A subject must 
discontinue any prohibited prescription or over-the-counter medications within 1 week or 
5 half lives, whichever is longer, before the 1st dose of study medication (Run-In Period).    
(revised per Amendment 01)
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 Section 9.4.7.2.1) 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). 
(revised per 
Amendment 06)
If a medication is not on the list of prohibited medications (Appendix 3) 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.
Note that strong and moderate CYP3A inhibitors and all CYP3A4 inducers will not be 
permitted at any time for any duration during the study. (revised per Amendment 06)
If a subject starts any prohibited medication or a new treatment/modality for insomnia 
disorder, 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.  This provision continues to apply if a 
subject discontinues study medication but remains in the study (ie, continues to attend study 
visits and complete study assessments; see Section 9.5.5).
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.  
9.4.7.2.1
CAFFEINE AND ALCOHOL RESTRICTIONS 
Caffeine will be permitted in limited quantities during the study.  Subjects will be instructed 
to limit caffeine consumption to ≤4 cups of caffeinated beverages per day, or ≤400 mg 
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caffeine per day.  Subjects will be instructed to avoid caffeine after 18:00 on all days during 
the study.
Alcohol will be permitted in limited quantities during the study.  Subjects may consume a 
maximum of 2 alcohol-containing drinks on a given day while in the study, and will be 
instructed not to consume any alcohol within 3 hours before bedtime. Because the definition 
of a standard drink varies among countries and regions, no definition of the volume or 
alcohol content of a standard drink is provided, with the exception of Japan.  For sites and 
subjects in Japan, a drink will be defined as 360 mL of beer, 150 mL of wine, or 50 mL of 
liquor.  Compliance with these restrictions will be monitored by specific questions on the 
Sleep Diary.  If subjects cannot comply after counseling, they may be discharged from the 
study.
9.4.8
Treatment Compliance
Compliance will be assessed by examination of blister packs returned to the investigator at 
the end of the Run-In and Treatment Periods.  
All subjects will be reminded of the importance of taking study medication as directed, ie, 
the correct number of tablets every night 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.  
At Study Baseline, if the subject continues to meet eligibility criteria but the treatment 
compliance check indicates that the subject has missed any doses of study medication, 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
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A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572
Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 
1572, where applicable
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV
A signed and dated clinical trials agreement
A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study. 
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, and (e) documentation of 
returns to the sponsor.  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, Medicines 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 by the subject and together with unused study drugs that were 
shipped to the site but not dispensed to subjects are to be returned to the sponsor’s designated 
central or local depot(s) during the study or at the conclusion of the study, unless provision is 
made by the sponsor for destruction of study drugs and containers at the site.  Destruction at 
the site will only occur under circumstances where regulation or supply type prohibits the 
return of study drugs to the central or local depot(s).  Approval for destruction to occur at the 
site must be provided by the sponsor in advance.  Upon completion of drug accountability 
and reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed and sealed and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
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Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic 
information will include birth year, 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 
date of each subject’s date of birth will be masked where necessary as “January 1”.
9.5.1.2
Screening and Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history within 5 years, except for history of any sleep 
disorder, which should be lifetime, must be noted in the Medical History and Current 
Medical Conditions CRF.  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 AE as specified in Section 9.5.1.5.1 means that only a 
worsening in daytime sleepiness during the study should be reported as an Adverse Event.  
Lifetime psychiatric history will also be obtained.  A full physical examination will be 
performed, excluding a urogenital examination unless there are special circumstances and at 
the discretion of the investigator.  The physical examination will include a brief neurological 
examination to assess possible impairment in major functions (ie, motor, cerebellar, sensory, 
major pathological reflexes). The neurological examination must be conducted by a clinician 
whose clinical experience ensures that an adequate assessment of domains underlying the 
exclusion criteria can be performed.  (revised per Amendments 01 and 03)
9.5.1.2.2
SLEEP DISORDERS HISTORY AND SCREENING BATTERY 
A lifetime history of sleep disorders will be obtained only at the 1st Screening Visit.  For 
insomnia complaints, this history will include clinical, qualitative assessment and/or 
confirmation that subjects meet diagnostic criteria for insomnia disorder.  The history will 
also include information regarding habitual sleep timing, bedtime routines, and other aspects 
of sleep hygiene to determine eligibility and to exclude subjects whose insomnia symptoms 
appear to be due to poor sleep hygiene or to frequent napping, for example.
For the detection of other sleep disorders, the SDSB will be administered (see below).  
(revised per Amendment 03)
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The SDSB will include the following, to be self-administered by subjects: (revised per 
Amendment 03)

The STOPBang: a list of 8 questions to be answered Yes or No, which screens subjects 
for obstructive sleep apnea (Chung et al., 2008)

The IRLS: a subjective scale comprising 10 questions, which measures disease severity 
of restless legs syndrome (Abetz et al., 2006)

The ESS: a questionnaire that rates the 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)
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 (Arnau et al., 2001).  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 >19 will be 
excluded from participation.
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.  
(Carney et al., 2011).  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 >15 will be 
excluded from participation.
9.5.1.2.5
VIRAL TESTING
At the Screening Visit, a 6-mL blood sample will be taken for detection of hepatitis B surface 
antigen and hepatitis C antibodies.  (revised per Amendment 03)
9.5.1.3
Efficacy Assessments
9.5.1.3.1
ELECTRONIC SLEEP DIARY
An electronic sleep diary was developed for the purposes of the Phase 3 clinical program.  
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.
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.  This Sleep Diary will 
yield several self-reported measures of sleep that will be used to determine eligibility, as well 
as to assess efficacy.  In addition, the Sleep Diary will include questions that relate to 
morning sleepiness and to alcohol consumption.  (revised per Amendment 03)
SLEEP PARAMETERS

sSOL: estimated minutes from the time the subject attempted to sleep until sleep onset 
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
sWASO: sum of estimated minutes of wake during the night after initial sleep onset until
the time the subject stopped trying to sleep for the night

sTST: derived minutes of sleep from sleep onset until the time the subject stopped trying 
to sleep for the night

sSE: proportion of sTST per subjective time spent in bed, calculated as the interval from 
the time the subject reports attempting to sleep until the time the subject stopped trying to 
sleep for the night, and time spent asleep derived from time spent in bed minus sWASO 
(revised per Amendment 03)
QUALITY OF SLEEP AND MORNING SLEEPINESS
The Sleep Diary will be used to assess the subject’s global perception of quality of sleep on 
the previous night with the following question: “How would you rate the quality of your 
sleep last night?”  Subjects will rate the quality of their sleep on a scale from 1 to 9, with 1 
being extremely poor and 9 being extremely good. 
The Sleep Diary will be used to assess subjective ratings of morning sleepiness with the 
following question: “How sleepy/alert do you feel this morning?” Subjects will rate their 
sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor and 9 being 
extremely good.
ALCOHOL CONSUMPTION
The Sleep Diary will include questions that ask about alcohol consumption the previous day, 
including within 3 hours before bedtime and/or exceeding the daily maximum of 2 alcoholic 
drinks per day. 
9.5.1.3.2
INSOMNIA SEVERITY INDEX
The ISI is a 7-item, self-report questionnaire assessing the nature, severity, and impact of 
insomnia (Bastien et al., 2001). The dimensions evaluated are severity of: sleep onset, sleep 
maintenance, early-morning awakening problems, sleep dissatisfaction, interference of sleep 
difficulties with daytime functioning, noticeability of the sleep problems by others, and 
distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each item 
(from 0=no problem to 4=very severe problem) yielding a total score from 0 to 28.
9.5.1.3.3
FATIGUE SEVERITY SCALE (FSS)
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 (Krupp et al., 1989). Higher scores indicate greater fatigue.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (4 mL per blood draw) will be obtained at prespecified visits for plasma 
concentrations of lemborexant and its metabolites M4, M9, and M10.  When these blood 
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samples are obtained, the time of the 2 most recent doses administered before each sample 
will be documented. The handling and shipment of blood samples will be described in a 
manual to be provided to the study sites.  Plasma concentrations of lemborexant and 
metabolites M4, M9, and M10 will be quantified by liquid chromatography with tandem 
mass spectrometry methodology using a previously validated assay.
Blood for determination of plasma concentrations should also be drawn at the 1st report of an
SAE or a severe unexpected AE and at its resolution.
9.5.1.4.2
PHARMACODYNAMIC PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
PHARMACODYNAMIC ASSESSMENTS
There are no assessments that are primarily PD.  For purposes of PK/PD modeling, selected 
efficacy and safety assessments will be used in lieu of PD assessments.
PHARMACOGENOMIC ASSESSMENTS
Not applicable.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic 
measurement of vital signs, weight and ECGs; and the performance of physical 
examinations.  Safety will be assessed at every clinic visit throughout the study, including 
after the last dose of study drug, and at the End of Study, ET, EDD, and Unscheduled Visit.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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(s) is lemborexant.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
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An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding of 
study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit.  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 CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.  (revised per 
Amendment 03)
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.7 for a description of the 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 electronic CRF (eCRF).  
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
ASSESSING SEVERITY OF ADVERSE EVENTS
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
ASSESSING RELATIONSHIP TO STUDY TREATMENT
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Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
CLASSIFICATION OF CAUSALITY
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
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 1 of the outcomes in the definition of SAE 
listed above should also be considered SAEs.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding and AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events with special situations are to be captured 
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using the SAE procedures but are to be considered as SAEs only if they meet 1 of the above 
criteria.  All AEs associated with special situations are to be reported on the CRF whether or 
not they meet the criteria for SAEs.  All SAEs must be followed to resolution or, if resolution 
is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “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 1st report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Blood and urine samples will be collected for the clinical laboratory tests as listed in Table 1.  
Clinical laboratory tests are to be performed according to the schedule in Table 2.  Subjects 
should be in a seated or supine position during blood collection.  
Viral testing for hepatitis B and C will be conducted from a blood sample obtained at 
Screening. The specific test for hepatitis B is the surface antigen panel (HBsAg) with 
confirmation as needed.  The specific tests for hepatitis C are the hepatitis C virus (HCV) 
antibody immunoglobulin G (IgG), with confirmation as needed using the HCV score.   
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 3).  These samples will be tested for common 
drugs of abuse: eg, cocaine, cannabinoids, phencyclidine, opioids (as a group), 
benzodiazepines, barbiturates, and amphetamines.
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Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Blood Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function parameters
blood urea/blood urea nitrogen, creatinine
Other
alumin, calcium, cholesterol, globulin, glucose, iron, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Serum pregnancy tests and urine drug tests will be collected for screening purposes.  A 
dipstick will be used for urine pregnancy testing and urine drug testing, to be performed at 
time points shown in the Schedule of Procedures/Assessments (Table 3).  The total blood 
volume to be drawn for laboratory measures in the study (Table 2) will be indicated on the 
ICF.
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Table 2
Blood 
Sampling 
Schedule 
for 
All 
Laboratory 
and 
Pharmacokinetic Assessments
Volumea per Sample 
Collection
(mL)
Collection Time points
Total Volumea
Collected 
(mL)
Clinical laboratory testsb
12
Screening
Study Baseline
Month 1
Month 3
Month 6
Month 9
Month 12
End of Study
96
Pregnancy testing
6
Screening
6
Viral tests
6
Screening
6
Pharmacokinetic samplingb
(revised per Amendment 01)
4
Month 1
Month 3
Month 6
Month 9
Month 12
23
Total (revised per Amendment 01)
128 mL
a:
Estimated volume.
b:
Clinical laboratory tests and/or pharmacokinetic sampling will also be conducted at ET/EDD visits, and may also 
be obtained at unscheduled visits at the discretion of the investigator.  (revised per Amendment 01)
Clinical laboratory tests during the study will be performed by a central laboratory.
All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  Laboratory certification as available will be included in the final clinical study 
report for this study. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], and body temperature [in centigrade] will be 
obtained at the visits designated on the Schedule of Procedures/Assessments (Table 3) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been in a 
sitting position for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  Validated methods will be used for all vital sign 
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measurements, and values will be recorded.  Height (cm), and weight (kg) will also be 
measured.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the  effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations (full or brief) will be performed as designated on the Schedule of 
Procedures/Assessments (Table 3).  At Screening and at the EOS/ET visit, a full physical 
examination will be conducted, including evaluation of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, skin.  The full physical examination 
will include a brief neurological examination to assess possible impairment in major 
functions (ie, motor, cerebellar, sensory, major pathological reflexes).  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region
and at the discretion of the investigator.  At other study visits as designated in Table 3, a brief 
physical examination will be conducted to assess health status by brief evaluation of the 
head, eyes, ears, nose, throat, heart, lungs, abdomen, and extremities, and other physical 
conditions of note.  Documentation of the physical examinations, including the brief 
neurological examinations, will be included in the source documentation at the site.  Only 
changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the AE CRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
ECGs will be obtained as designated on the Schedule of Procedures/Assessments (Table 3). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Reporting of Serious Adverse Events [Section 9.5.4.1]).
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Suicidality will be assessed using a self-rated electronic version of the C-SSRS (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.
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 
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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 03)
PREGNANCY TESTS FOR WOMEN OF CHILD-BEARING 
A serum β-hCG test will be performed at Screening for premenopausal women and 
postmenopausal women who have been amenorrheic for less than12 consecutive months.  
Subsequently, urine pregnancy tests will be conducted for these subjects as specified in the 
Schedule of Procedures/Assessments (Table 3).
9.5.1.6
Other Assessments
HEALTH-RELATED QUALITY OF LIFE 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’ 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 total sleep time) and 1 item related to perceived appropriateness of 
study medication strength.  The 1st 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).
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE – GENERAL HEALTH
The WPAI-GH collects data on absenteeism and presenteeism.  The scale comprises 6 items 
that are used to create the 4 scores shown below.  Outcomes are expressed as impairment 
percentages, with higher numbers indicating greater impairment and less productivity (ie,
worse outcomes).

Percent work time missed due to health 

Percent impairment while working due to health 

Percent overall work impairment due to health

Percent activity impairment due to health
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9.5.2
Schedule of Procedures/Assessments 
Table 3 presents the Schedule of Procedures/Assessments for this study.
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Table 3
Schedule of Procedures/Assessments
(revised per Amendments 01 and 03)
Phase
Prerandomization
Randomization
Period
Screening
Run-
Ina
Study 
Baseline
Treatment Period 1a
Treatment Period 2a
Follow-Up
ET/
EDDb
UNSc
Visitd
1
2a
2b
3a
3b
4d
5d,
6d
7d,e
8d,e
9d
10d,e
11d,e
12d
13d,e
14d,e
15d
EOS
16
Day
–35 
to
–17
-17 to 
-14f
thru -
1
1
Monthg
–
–
1
2
3
4
5
6
7
8
9
10
11
12
(Wk 
52 to 
54)
(End 
Wk 
54)
Procedures/
Assessments
Informed consent
X
Demographics
X
Inclusion/exclusion criteriah
X
X
X
Sleep Disorders Screening Batteryi
X
Sleep, medical, and psychiatric history
X
Physical examinationj
X
X
X
X
X
X
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
Insomnia Severity Index
X
X
X
X
X
X
X
Fatigue Severity Scale
X
X
X
X
X
X
X
Prior and concomitant medication(s)
Beck Depression Inventory - II 
X
Beck Anxiety Inventory
X
12-lead ECGk
X
X
Xl
Xl
Xl
Xl
Xl
Xl
Urine pregnancy testm
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test (β-hCG)m
X
Urine drug testn
X
X
X
X
X
X
X
X
X
X
Xn
Xn
Serology (Hepatitis B and C)o
X
Clinical laboratory testsp
X
X
X
X
X
X
X
X
X
X
eC-SSRS
X
X
X
X
X
X
X
X
X
Sleep diaryq
Dispense study drug
X
X
X
X
X
X
X
Retrieve unused study drug
X
X
X
X
X
X
X
Study drug compliancer
X
X
X
X
X
X
X
Randomization
Xa,s
Xa
EQ-5D-3L
X
X
X
X
X
X
X
WPAI-GH
X
X
X
X
X
X
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Table 3
Schedule of Procedures/Assessments
(revised per Amendments 01 and 03)
Phase
Prerandomization
Randomization
Period
Screening
Run-
Ina
Study 
Baseline
Treatment Period 1a
Treatment Period 2a
Follow-Up
ET/
EDDb
UNSc
Visitd
1
2a
2b
3a
3b
4d
5d,
6d
7d,e
8d,e
9d
10d,e
11d,e
12d
13d,e
14d,e
15d
EOS
16
Day
–35 
to
–17
-17 to 
-14f
thru -
1
1
Monthg
–
–
1
2
3
4
5
6
7
8
9
10
11
12
(Wk 
52 to 
54)
(End 
Wk 
54)
Procedures/
Assessments
PGI-Insomnia
X
X
X
X
X
T-BWSQ
X
Adverse eventst
Lemborexant PK sampling (plasma)u
X
X
X
X
X
Xv
X
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Footnotes for Table 3 (revised per Amendments 01 and 03)
AE = adverse event; ß-hCG = beta-human chorionic gonadotropin; ECG = electrocardiogram; eC-SSRS = electronic Columbia-Suicide Severity Rating Scale; EDD = 
Early Drug Discontinuation; EOS = End of Study; EQ-5D-3L = EuroQOL version 5D-3L; ET = early termination; PGI-Insomnia = Patient Global Impression - Insomnia; 
PK = pharmacokinetics; T-BWSQ = Tyrer Benzodiazepine Withdrawal Symptom Questionnaire; UNS = unscheduled, WPAI-GH = Work Productivity and Activity 
Impairment Questionnaire – General Health.
a:
Subjects will not be informed that placebo will be administered during the Run-In Period.  They will also not be informed of the timing of the placebo-controlled 
period (Period 1) or the active-treatment (only) period (Period 2), and will not be informed of the timing of the 2nd randomization for subjects who received 
placebo during Period 1.  
b:
These assessments will be conducted at EOS, ET and EDD (except the T-BWSQ, which will not be conducted at EDD).  Subjects who discontinue study drug 
prematurely at any time after randomization at Visit 3 (Study Baseline) will be encouraged to return to the site as soon as practicable (preferably within 7 days).  
These subjects will be encouraged to continue to complete all study assessments (excepting PK samples, which will not be taken), including the Sleep Diary, and 
to return for all subsequent clinic visits, without the administration of study medication.  Subjects who do not agree to this will undergo an ET Visit and an EOS
Visit.  Subjects who do agree to continue with study procedures without the administration of study drug will undergo an EDD Visit.  (revised per Amendment 
01)  These subjects need not attend the next regularly scheduled visit if this falls within the visit window of the next visit.  Subjects who discontinue early from 
study drug are considered on study as long as they return for their regularly scheduled visits. 
c:
Assessments during an UNS to be performed at the discretion of the investigator.
d:
Visits 4, 5, and 6 are to be conducted within 4 days of the schedule.  Visits 7 through 15, and EOS to be done within 7 days of the schedule. (revised per 
Amendments 01 and 03)
e:
The site will telephone the subject to assess AEs, to record concomitant medications and to review the sleep diaries.  If any AE is clinically significant and 
requires follow-up, a clinic visit should be arranged (Unscheduled Visit).
f:
The Run-In Period may start between Day -17 and Day -14 and must continue for approximately 14 consecutive days and a maximum of 17 days. (revised per 
Amendment 01)
g:
Defined as a calendar month.
h:
Inclusion and exclusion criteria to be evaluated at visits other than or in addition to Visit 1 are listed in Appendix 2 (revised per Amendment 01).
i:
Sleep Disorders Screening Battery comprises: STOPBang, International Restless Legs Scale, and Epworth Sleepiness Scale,. (revised per Amendments 01
and 03).
j:
A full physical examination will be carried out at Screening and EOS (ET at the discretion of the investigator) and will include a brief neurological examination.  
A brief physical examination will be carried out at other visits.
k:
The ECG should be repeated if an abnormality is observed .
l:
If subject has a normal ECG baseline reading, but during any visit thereafter the QT is measured as >450 ms, 3 consecutive ECGs separated by 5 to 10 minutes 
will be performed to confirm the abnormality.
m:
Female subjects of child-bearing  only. 
n:
Urine drug test to be conducted at Unscheduled Visits at the discretion of the investigator and at ET only for subjects who withdraw because of an Adverse 
Event.
o:
Viral screening for hepatitis B (HBsAg) and hepatitis C (HCV antibody IgG) will be conducted.
p:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
q:
Subjects should complete the Sleep Diary, within 1 hour of waketime, each day throughout the study until EOS.  Sleep diaries should be reviewed for eligibility: 
for the 7 consecutive days immediately before Visit 2, and for the Run-In Period at Visit 3.  Thereafter, the Sleep Diary should be reviewed for completeness 
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once a month. (revised per Amendment 03)
r:
Study drug compliance (tablet count) will be carried out at each clinic visit from Visit 3a through Visit 15.  (revised per Amendments 01 and 03)
s:
All other Baseline Period procedures must be completed and subject eligibility confirmed before randomization takes place and study drug is dispensed.
t:
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 9.2.3, Adjudication Committee. (revised per Amendment 03)
u:
PK: A single blood sample (approximately 4 mL) for plasma concentrations of lemborexant and its metabolites M4, M9, and M10 will be taken at each specified 
visit.  The date and time of the 2 most recent doses administered before each sample will be documented.
v:
PK sample will be collected at ET visit (not at EOS).  (revised per Amendment 01)
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9.5.3
Appropriateness of Measurements
Completion of sleep diaries by subjects is considered to be an appropriate method to measure 
changes in subjective sleep parameters, thereby allowing assessments of secondary efficacy 
in this study.  The advantages of the electronic Sleep Diary to be used in this study include 
that the questions and instructional text have been adapted from sleep diaries that were 
developed by clinicians and researchers with expertise in insomnia disorder, and have 
undergone linguistic validation and cognitive debriefing to optimize their use in this study. 
The Sleep Diary will include questions to assess the subject’s rating of sleep quality each 
night and sleepiness/alertness level in the morning.  
The ISI has been widely used to evaluate the subjective impact of insomnia severity on 
psychosocial functioning, which is one type of daytime functioning impairment experienced 
by those with insomnia disorder.  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, EQ-5D-3L and WPAI-GH will also be 
employed.  These measures have been used in studies evaluating the impact of treatment for 
insomnia on patients’ global perceptions of sleep quality and quality of life. Together these 
measures will provide a broad evaluation of the effects of lemborexant on each patient’s 
sleep, daytime functioning, quality of life and productivity.
The safety assessments performed in this study, including clinical laboratory analyses, vital 
sign parameters, electrocardiograms, and assessment of AEs are standard evaluations to 
ensure subject safety.  The C-SSRS, a standardized assessment required by regulatory 
authorities, will be used to evaluate any effects of lemborexant on suicidality.  Additional 
safety-related assessments include evaluation of morning sleepiness and rebound insomnia, 
which will be measured using the validated Sleep Diary.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours after the time the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution 
or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be 
related to the study treatment or any protocol-required procedure should be reported to the 
sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
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For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
or the responsible CRO, to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see
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 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
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9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event 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.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators or as regionally required, the head of the medical 
institution and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
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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
SUSARs 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.  The 
subject may elect to discontinue the study at any time for any reason.  Subjects who 
discontinue study drug prematurely at any time after randomization at Visit 3 (Study 
Baseline) will be encouraged to return to the site as soon as practicable (preferably within 
7 days). These subjects will be encouraged to continue to complete all study assessments 
(excepting PK samples, which will not be taken), including the Sleep Diary, and to return for 
all subsequent clinic visits, without the administration of study medication.   
Subjects who agree will undergo an EDD Visit, during which all assessments will be 
conducted that would be made at an ET visit (except the T-BWSQ).  These subjects need not 
attend the next regularly scheduled visit if this falls within the visit window of the next visit.  
Subjects who discontinue early from study drug are considered on study as long as they 
return for their regularly scheduled visits. 
Subjects who do not agree to this will undergo an ET Visit and an EOS Visit, as described in 
the Schedule of Procedures/Assessments (Table 3).  (revised per Amendment 01)
Subjects who withdraw because of an AE should also undergo a urine drug test.  
If the investigator or sponsor discontinues a subject from the study prematurely, the 
investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and will provide appropriate referral for medical treatment and other 
necessary measures for the subject.  A subject who has ceased to return for visits will be 
followed up by mail, phone, or other means to gather information such as the reason for 
failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.  This information will be recorded in the CRF.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons:  AE(s), lost to follow-up, subject choice, lack of therapeutic effect, or 
administrative/other.  Discontinuations due to noncompliance with alcohol restrictions will 
be assigned to “administrative/other”.  In addition to the primary reason, the subject may 
indicate 1 or more of secondary reasons for discontinuation.  Study disposition information 
will be collected on the Subject Disposition CRF.
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A subject removed from the study for any reason will not be replaced.  In some 
circumstances, a subject who screen fails before the Run-In period may be rescreened 
following consultation with the Sponsor.  Any such subject will be assigned a new subject 
identification number.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs.
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.4.3.1.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.
9.6.1
Data Collection
Data required by the protocol will be collected in a validated data management system that is 
compliant with all regulatory requirements.  These data include eCRFs, computer tablets and 
electronic sleep diaries. As defined by ICH guidelines, the CRF is a printed, optical, or 
electronic document designed to record all of the protocol-required information to be 
reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
Details of the statistical analyses will be included in a separate SAP.  All statistical analyses 
will be performed by the sponsor or designee after the database is locked and released for 
unblinding.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  (revised per Amendments 04 and 05)
9.7.1
Statistical and Analytical Plans
The statistical analyses are described in this section.  Further details of the analytical plan 
will be provided in the SAP which will be finalized before database lock and treatment 
unblinding.
All statistical tests will be based on the 5% level of significance (2-sided).
9.7.1.1
Study Endpoints
The following endpoints will be analyzed for LEM5 and LEM10 compared to PBO.  
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint will be the mean change from Study Baseline in sSOL at Month 6.
9.7.1.1.2
SECONDARY ENDPOINTS
The key secondary endpoints will be:

Mean change from Study Baseline in sSE at Month 6

Mean change from Study Baseline of sWASO at Month 6  
Additional secondary endpoints will be:

Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST, at the 
beginning of treatment (mean of the 7 nights after the 1st dose in Period 1), at Month 1 
and at Month 3

Mean change from Study Baseline of sTST at Month 6 

Proportion of responders at Month 6 and Month 12, where sleep onset responder is 
defined as follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 months is 
≤20 minutes, and sleep maintenance responder is defined as follows: sWASO at Study 
Baseline is ≥60 minutes and mean sWASO at 6 months is ≤60 minutes and shows a 
reduction of >10 minutes compared to Study Baseline.

Change from Study Baseline in daytime functioning, assessed as the total score from the 
4 items on daytime functioning, on the ISI, at Months 1, 3, and 6

Change from Study Baseline on the FSS at Months 1, 3, and 6

Ratings on the morning sleepiness item of the Sleep Diary, for:
-
The mean change from Study Baseline of the 1st 7 mornings after the 1st dose in 
Period 1 and Period 2
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-
The mean change from Study Baseline at: Month 1, Month 3, and Month 6 
-
The mean change from Study Baseline and from Period 2 Baseline (as appropriate)
for subjects with 1, 3, 6, 9 and 12 months exposure (revised per Amendment 06)
-
The mean change from Screening for the 1st 7 mornings and 2nd 7 mornings of the 
Follow-up Period

Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up 
Period (revised per Amendment 02)
-
Change from Screening of sSOL on each of the 1st 3 nights, mean sSOL of the 1st
7 nights, and mean sSOL of the 2nd 7 nights of the Follow-up Period
-
Change from Screening of sWASO on each of the 1st 3 nights, mean sWASO of the 
1st 7 nights and mean sWASO of the 2nd 7 nights of the Follow-up Period
-
Proportion of subjects whose sSOL is longer than at Screening for each of the 1st 3 
nights,  or whose mean sSOL is longer than at Screening for 1st 7 nights or 2nd 7 
nights of the Follow-up Period
-
Proportion of subjects whose sWASO is higher than at Screening for each of the 1st
3 nights, or whose mean sWASO is higher than at Study Baseline for the 1st 7 nights 
or 2nd 7 nights of the Follow-up Period

Persistence of Effect 
-
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST at 
Months 3, 6, 9, and 12 compared to Month 1
-
Mean change from Period 2 Baseline (Month 6) of sSOL, of sSE, of sWASO and of 
sTST at Months 9 and 12 compared to Month 7 (the 1st month of treatment in 
Period 2)
-
Mean change from Study Baseline and Treatment Period 2 Baseline (as appropriate) 
of sSOL, sSE, sWASO and sTST at 3 and 6 months exposure compared to 1 month of 
exposure  (revised per Amendment 06)
9.7.1.1.3
SAFETY ENDPOINTS
Safety and Tolerability of Lemborexant

During Period 1, compared to PBO

For subjects exposed to lemborexant for 3, 6, 9, and 12 months  (revised per 
Amendment 06)
9.7.1.1.4
EXPLORATORY ENDPOINTS
The following endpoints will be explored for LEM5 and LEM10.  Except for PK endpoints, 
comparisons to PBO will be made.

Change from Study Baseline in the mean value of the item on quality of sleep from the 
Sleep Diary for:
-
The 1st 7 mornings after the 1st dose in Period 1
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-
Months 1, 3, and 6

Change from Study Baseline and Period 2 Baseline (as appropriate) in the mean value of 
the item on quality of sleep from the Sleep Diary for:
-
Subjects with 1, 3, 6, 9, and 12 months exposure (revised per Amendment 06)

Change from Study Baseline in: 
-
EQ-5D-3L at Months 1, 3, and 6
-
WPAI-GH at Months 3 and 6

Change from Study Baseline and Period 2 Baseline (as appropriate) in:
-
EQ-5D-3L in subjects with 3, 6, 9, and 12 months exposure  (revised per 
Amendment 06)
-
WPAI-GH in subjects with 3, 6, 9, and 12 months exposure  (revised per 
Amendment 06)

Number and percentage of subjects with a rating of a positive medication effect on each 
PGI-Insomnia item (1) at Months 1, 3, and 6 (placebo-controlled Treatment Period 1),
and (2) with 3, 6, 9, and 12 months exposure (Treatment Period 1 and Treatment Period 2 
combined)  (revised per Amendment 06)

Change from Study Baseline and Period 2 Baseline (as appropriate) of sSOL, sSE, 
sWASO, sTST with 1, 3, 6, 9, and 12 months exposure, and ISI and FSS with 3, 6, 9, and 
12 months exposure.  (revised per Amendment 06)

Mean score on the T-BWSQ of LEM5, and LEM10 compared to PBO at End of Study

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10

PK of lemborexant using population modeling

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 subjects who received at least 1 dose of 
randomized study drug and had at least 1 postdose safety assessment.

On-Treatment Safety Analysis Set:  On-Treatment Safety Analysis Set is the group of 
subjects who received at least 1 dose of lemborexant and had at least 1 postdose safety 
assessment  (revised per Amendment 06)

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.

On-Treatment Full Analysis Set (FAS):  On-Treatment FAS is the group of subjects who 
received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy
measurement. (revised per Amendment 06)
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
The Per Protocol 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 6-Months Completer Analysis Set is the group of subjects in the FAS who had all 
efficacy assessments up to and including Month 6 (ie, Week 1 and Months 1 to 6 visits) 
without  missing primary or key secondary efficacy assessments at any of these visits.  
(revised per Amendment 04)

The PK Analysis Set is the group of subjects who have at least 1 quantifiable 
lemborexant plasma concentration or its metabolites, with adequately documented dosing 
history.

The PK/PD Analysis Set is the group of subjects receiving either lemborexant or PBO
who have efficacy or safety data with documented dosing history. In addition, subjects 
receiving lemborexant should have at least 1 quantifiable lemborexant concentration data 
point as per the PK Analysis Set.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized. Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination. Subjects who prematurely discontinued from study treatment will also be 
presented and summarized by primary reason for premature treatment discontinuation.  Other 
reasons for study treatment and study terminations will also be summarized.  These 
tabulations will be produced for all randomized subjects by treatment group.  
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic 
variables include age, height, weight, and BMI; categorical variables include sex, age group 
(<65 years old; ≥65 years old), BMI group (less than 18.5, 18.5 to less than 25, 25 to 30, 
above 30), race and ethnicity.
Characteristics of insomnia at Study Baseline will be summarized using sSOL, sSE, sWASO, 
sTST, ISI, and FSS.  The BDI-II and BAI scores will also be summarized at Study Baseline.
The demographic data will be summarized by subgroups of age group, sex, BMI group and
race.  The above tables will be produced for the FAS if it differs from the Safety Analysis 
Set.
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.  
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO-DDE/HD Mar 2014 or latest 
version).  The number (percentage) of subjects who took prior and concomitant medications 
will be summarized on the Safety Analysis Set by treatment group, Anatomical Therapeutic 
Chemical (ATC) class, and WHO-DD preferred term (PT).  (revised per Amendment 03)
Separate analyses will be provided for the Run-In Period, Treatment Period 1 and Treatment 
Period 2. (revised per Amendment 03)
For the Run-In Period, a prior medication is defined as a medication that stopped before the 
1st dose of study medication in the Run-In Period. For Treatment Period 1, a prior medication 
is defined as a medication that stopped before the 1st dose of study medication in Treatment 
Period 1. For Treatment Period 2, a prior medication is defined as a medication that stopped 
before the 1st dose of study medication in Treatment Period 2. (revised per Amendment 03)
For the Run-In Period, a concomitant medication is defined as a medication that started on or 
before the 1st dose of study medication in the Run-In Period and continued during some or all 
of the Run-In Period. For Treatment Period 1, a concomitant medication is defined as a 
medication that started on or before the 1st dose of study medication in Treatment Period 1 
and continued during some or all of that treatment period.
For Treatment Period 2, a 
concomitant medication is defined as a medication that started on or before the 1st dose of 
study medication in Treatment Period 2.  (revised per Amendment 03)
9.7.1.6
Efficacy Analyses
Where Sleep Diary endpoints are described, the time points refer to the mean of the final 
7 nights before the visit unless otherwise stated.
Subjects who discontinue the treatment prematurely will be encouraged to continue to 
complete the assessments at the protocol defined times (retrieved drop out) until the 
scheduled time of termination. When available, these data will be used for efficacy analyses. 
If there are a substantial proportion of early withdrawals, a sensitivity analysis of the primary 
endpoint will be conducted.
Definitions of Baseline
For the analyses of PBO-controlled endpoints (ie, Day 1 to Month 6), “Study Baseline” is 
defined as the data captured during the Run-In Period (or during the Baseline Period).  For 
the analyses of data that are not placebo-controlled (ie, Month 7 to Month 12), data from 
Month 6 visit will be used as the “Period 2 Baseline”. (revised per Amendment 06)
For other endpoints, baseline data are captured during the Run-In and Baseline Period.  
Details will be specified in the SAP.
12-Month Lemborexant Exposure
Twelve-month (12-month) lemborexant exposure summaries will be summarized by 
treatment (LEM5, LEM10) and duration of exposure (1 month [30 days] where appropriate,
3 months [90 days], 6 months [180 days], 9 months [270 days] and 12 months [365 days]). 
Treatment groups are LEM5 and LEM10, and include both (a) LEM Period 1 subjects on the 
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On-Treatment Full Analysis Set using the change from Study Baseline and (b) LEM Period 2 
subjects previously receiving PBO on the On-Treatment Full Analysis Set using the change 
from Period 2 Baseline. (revised per Amendment 06)
Control of Type 1 Error
A sequential gate-keeping procedure including sSOL (primary endpoint), sSE and sWASO 
(key secondary endpoints) at Month 6 will control for type 1 error.  In order to move from 
1 step to the next (steps a to f; below) the outcome must be significant at 0.05 (2-sided). 
a.
Change from Study Baseline at Month 6 in sSOL, LEM10 compared to PBO 
b. Change from Study Baseline at Month 6 in sSOL, LEM5 compared to PBO 
c.
Change from Study Baseline at Month 6 in sSE, LEM10 compared to PBO 
d. Change from Study Baseline at Month 6 in sSE, LEM5 compared to PBO 
e.
Change from Study Baseline at Month 6 in sWASO, LEM10 compared to PBO
f.
Change from Study Baseline at Month 6 in sWASO, LEM5 compared to PBO
This testing procedure controls the overall type I error rate of 0.05 for the primary and key 
secondary efficacy analyses. (revised per Amendment 03).
9.7.1.6.1
ANALYSIS FOR THE PRIMARY ENDPOINT
Null Hypothesis: For sSOL, no difference exists in the mean change from Study Baseline to 
Month 6 of treatment with LEM10 and LEM5 as compared with PBO.
Alternative Hypothesis: For sSOL, a difference exists in the mean change from Study 
Baseline to Month 6 for LEM10 and LEM5 as compared with PBO. 
The sSOL change from Study Baseline to Month 6 will be analyzed using the mixed effect 
model repeated measurement (MMRM) analysis on the FAS. The model will include all data 
and will be adjusted for the corresponding Study Baseline value, region, age group (<65 
years old, ≥65 years old), treatment, time (average of the first 7 nights, Month 1, Month 3,
and Month 6) and the interaction of treatment by time.  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 
imputation (MI) assuming the missing values are missing not at random (MNAR) utilizing 
the complete case missing value pattern (CCMV - subjects who completed all 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.  Details of pattern mixture 
model and MI method will be presented in SAP.  (revised per Amendment 03)
The following analyses will be considered as sensitivity analyses (revised per 
Amendment 04):
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•
Missing imputation assuming MNAR utilizing CCMV-7: The same MMRM method used 
in the primary analysis will be applied utilizing CCMV-7 (ie, up to 7 monotone missing 
patterns will be used for missing value imputation). (revised per Amendment 04)
•
Tipping point analysis: A range of shifts starting from the primary analysis (CCMV) 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)
The following analyses will be considered as supplementary analyses (revised per 
Amendment 04):

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 based on 6-Months Completer Analysis Set. (revised per Amendment 04).

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). (revised per Amendment 03)
9.7.1.6.2
SECONDARY EFFICACY AND PHARMACODYNAMIC ANALYSES
Key Secondary Efficacy Analyses (revised per Amendment 03)
The change from Study Baseline of key secondary endpoints sSE and sWASO at Month 6 
comparing LEM5 and LEM10 to PBO will be analyzed using the same analysis method as 
the primary endpoint.  The missing values will be imputed 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% confidence interval (CI) of the treatment differences will 
also be provided.  (revised per Amendment 03)
Other Secondary Efficacy Analyses (revised per Amendment 03)
The other secondary efficacy endpoints (change from Study Baseline of the following for 
LEM5 and LEM10 compared to PBO; mean sSOL, mean sSE, mean sWASO and mean 
sTST at 1st 7 nights, Months 1 and 3; and mean sTST at Month 6; ISI total of 4 items of 
daytime functioning at Months 1, 3, and 6, and FSS score at Months 1, 3, and 6) will be 
analyzed using MMRM, assuming MAR.  The FSS will also be analyzed for responders,
including only those subjects who endorsed clinically significant fatigue at Study Baseline.  
(revised per Amendments 03 and 06)
The proportion of responders, separately for sSOL and sWASO, will be analyzed using the 
Cochran-Mantel-Haenszel test, adjusted for country and age group, after the 1st 7 nights and 
for the last 7 nights of treatment at the end of Months 1, 3, 6 and 12, for LEM5 and LEM10 
compared to PBO.
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 
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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.
To assess rebound insomnia, both categorical analysis at the subject level and continuous 
analysis at the group mean level will be performed.  For each of the first 3 nights and each of 
the 2 weeks of the Follow-up Period the proportion of subjects whose corresponding value 
for sSOL or sWASO exceeds the corresponding Screening Period value by 5 minutes will be 
summarized by treatment group and compared to placebo. The percentage of ‘rebounders’ 
between each treatment and placebo group will be analyzed using a Cochran-Mantel-
Haenszel test, adjusted for country and age group.  
To assess statistical significance using the continuous data at the group mean level, the data 
will be analyzed using ANCOVA, adjusted for country, 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.  Otherwise, the degree to 
which the parameters worsen, and the time point(s) at which they worsen will be considered 
to evaluate whether clinically meaningful rebound insomnia is present.  
To evaluate morning sleepiness item on the Sleep Diary, the mean change from Study 
Baseline of the 1st 7 mornings after the 1st dose in Period 1, Month 1, Month 3 and Month 6 
will be analyzed using MMRM, assuming MAR.  Additionally, morning sleepiness change 
from both Study Baseline and Period 2 Baseline for the 1st 7 mornings after the 1st dose in 
Period 2, Month 9, and Month 12, and also the change from Screening of each of the 2 weeks 
of the Follow-Up Period will be summarized with mean and 95% CI's. 
(revised per 
Amendment 03)
Analyses for persistence versus loss of effect will be conducted for sSOL, sSE, sWASO and 
sTST at Months 3, 6, 9, and 12 compared to Month 1.  Loss of effect will be defined as 
present if the mean change from Study Baseline at Month 3 (or Months 6, 9, 12) is below the 
lower bound of the 95% CI at Month 1 for sSE or sTST and above the upper bound of the 
95% CI at Month 1 for sSOL and sWASO.  Analyses for persistence versus loss of effect 
over Period 2 will be conducted for only the subjects randomized to PBO in Period 1 (those 
subjects will have been randomized to lemborexant in Period 2).  These analyses will 
compare sSOL, sSE, sWASO and sTST at Months 9 and 12 to these measures at Month 7.  
Loss of effect will be defined as present if the mean change from Period 2 Baseline at 
Month 9 (or Month 12) is below the lower bound of the 95% CI at Month 7 for sSE or sTST 
and above the upper bound of the 95% CI at Month 7 for sSOL and sWASO. Analyses for 
persistence versus loss of effect over duration of exposure will be conducted for 
On-Treatment Full Analysis Set subjects.  These analyses will compare 1 month duration of 
exposure on sSOL, sSE, sWASO and sTST at 3 and 6 months duration of exposure, for (a) 
LEM Period 1 subjects using the change from Study Baseline and (b) LEM Period 2 subjects 
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previously receiving PBO using the change from Period 2 Baseline, with loss of effect as 
defined above.  (revised per Amendment 06)
No multiplicity adjustment is planned for other secondary endpoints. (revised per 
Amendment 03)
9.7.1.6.3
EXPLORATORY EFFICACY AND PHARMACODYNAMIC ANALYSES
The change from Study Baseline for the mean score of the quality of sleep item on the Sleep 
Diary will be analyzed using MMRM, assuming MAR for the mean of the 1st 7 days of 
Period 1 and at Months 1, 3, and 6.  (revised per Amendment 03)
Health-related quality of life: the change from Study Baseline for the EQ-5D-3L scores (both 
total score and Visual Analog Scale score), and the four scores from WPAI-GH will be using 
MMRM, assuming MAR for Month 1 (EQ-5D-3L only) and Months 3 and 6 (both 
EQ-5D-3L and WPAI-GH).  (revised per Amendment 03)
Each item on the PGI-Insomnia at Months 1, 3, and 6 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.  
Summaries of all efficacy endpoints will be performed for 12 months exposure.  Where 
appropriate, 95% CIs around the mean change from Study Baseline or Period 2 Baseline (for 
Period 1 and Period 2 data, respectively) will be presented.  (revised per Amendment 06)
No multiplicity adjustment is planned for the exploratory and pharmacodynamic endpoints.  
(revised per Amendment 03)
9.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual lemborexant and its metabolites M4, M9, 
and M10 plasma concentration listings.  The PK Analysis Set will be used for summaries of 
lemborexant M4, M9, and M10, 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 
(eg, demographics, concomitant medications) on the PK of lemborexant will be evaluated. 
The PK model will be parameterized for oral clearance (CL/F) and volumes of distribution. 
Derived exposure parameters such as AUC and Cmax of lemborexant and any other relevant 
parameters will be calculated from the model using the individual estimates parameterized 
for oral clearance and dosing history.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
There are no variables in this study that are primarily designated as PD variables.  These 
analyses are described in the Secondary Efficacy and Pharmacodynamic Analysis 
Section 9.7.1.6.2 and Exploratory and Pharmacodynamic Analyses Section 9.7.1.6.3.
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9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
The PK/PD relationship between exposure to lemborexant and the efficacy variables 
including but not limited to sSOL, sSE, and sWASO, and the safety variables including but 
not limited to morning sleepiness and frequently occurring 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.
9.7.1.7.4
PHARMACOGENOMIC ANALYSES
Not applicable.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the relevant Safety Analysis Set and On-
Treatment Safety Analysis Set, as appropriate. (revised per Amendment 06)
12-Month Lemborexant Exposure
For visit-based Safety data (ie, laboratory values, vital signs, ECGs, etc),  data will be 
summarized by treatment (LEM5, LEM10) and duration of exposure (1 month, 3 months, 
6 months, 9 months, and 12 months). Treatment groups are LEM5 and LEM10, and include 
both (a) LEM Period 1 subjects on the On-Treatment Safety Analysis Set using the change 
from Study Baseline, and (b) LEM Period 2 subjects previously receiving PBO on the On-
Treatment Safety Analysis Set using the change from Period 2 Baseline.  (revised per 
Amendment 06)
Summaries of exposure and AEs will be summarized for:

Period 1 data, where treatment groups are PBO, LEM5 and LEM10 on the Safety 
Analysis Set

12-month LEM exposure, where treatment groups are LEM5 and LEM10, and include 
both (a) LEM Period 1 subjects on the On-Treatment Safety Analysis Set, and (b) LEM 
Period 2 subjects previously receiving PBO on the On-Treatment Safety Analysis Set.  
(revised per Amendment 06)
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.  Period 1 data with LEM5 or LEM10 will be 
summarized for:
the number (percent) of subjects who completed 1 month (30 or more 
days), 3 months (90 or more days), and 6 months (180 or more days). Twelve-month (12-
month) exposure with LEM5 or LEM10 will be summarized for: the number (percent) of 
subjects who completed 3 months (90 or more days), 6 months (180 or more days), 9 months 
(270 days), and 12 months (365 or more days) of dosing.  (revised per Amendment 06)
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Compliance will be calculated on the basis of number of tablets dispensed, lost and returned.  
Summaries will provide descriptive summary statistics and number (percentage) of subjects 
below 80%, between 80% and 120%, and >120%.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) 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 (LLT) closest to the verbatim term.  The 
linked MedDRA preferred term (PT) and primary system organ class (SOC) are also 
captured in the database.
A TEAE is defined as an AE that emerges during treatment (including the Run-In Period), 
having been absent at pretreatment (before the Run-In Period) or 

Reemerges during treatment, having been present at pretreatment (before the Run-In
Period) but stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Separately, for 12-month exposure analysis, LEM Period 2 subjects previously receiving
PBO on the On-Treatment Safety Analysis Set will have a separate definition for TEAE in 
Period 2, where an AE is defined as (revised per Amendment 06):

Emerges during Period 2 having been absent prior to Period 2 treatment, or

Reemerges during treatment, having been present prior to Period 2 treatment but stopped 
before Period 2 treatment, or 

Worsens in severity during Period 2 treatment relative to the pre Period 2 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 using the Safety Analysis Set and, where appropriate, the 
On-Treatment 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 experienced more than 1 TEAE within a specific SOC and PT.  
The number (percentage) of subjects with TEAEs during the Run-In Period, and after the 
Run-In Period will be summarized separately.
The number (percentage) of subjects with 
TEAEs during the Period 1 (Safety Analysis Set) and 12-month LEM exposure (On-
Treatment Safety Analysis Set) will also be summarized separately.
(revised per 
Amendment 06)
All the following summaries will be repeated for Period 1 and 12-month LEM exposure.  
(revised per Amendment 06)
The number (percentage) of subjects with TEAEs will also be summarized by maximum 
severity (mild, moderate, or severe).
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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 cataplexy-related events, as 
well as somnolence and related events, and drug abuse liability will be summarized 
separately. The number of adjudicated events based on the report of the Adjudication 
Committee will also reported separately.
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered 
cataplexy or seizure, somnolence, and related events, and preferred terms related to drug 
abuse liability, will be summarized.  The results of the deliberation of the Adjudication 
Committee will be reported separately.  (revised per Amendment 03)
9.7.1.8.3
LABORATORY VALUES
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  
Abnormal laboratory values will be identified as those outside (above or below) the normal 
range.  Reference (normal) ranges for laboratory parameters will be included in the CSR for 
this study.  Descriptive summary statistics (eg, mean, SD, median, minimum, maximum for 
continuous variables, and number and percentage for categorical variables) for the laboratory 
parameters and changes from Study Baseline will be evaluated by treatment group and visit. 
This will also be repeated for the 12-month LEM exposure (On-Treatment Safety Analysis 
Set), summarized by treatment group and duration of exposure.  (revised per Amendment 06)
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 Month 6 by treatment group.  This will also be repeated for the 12-
month LEM exposure (On-Treatment Safety Analysis Set), summarized by treatment group 
and duration of exposure. (revised per Amendment 06)
Clinical laboratory results post-Study Baseline will be evaluated for markedly abnormal 
values.  A laboratory test will be considered markedly abnormal if the result worsens to meet 
Eisai grading criteria for laboratory values limit of Grade 2 or higher.  If the Grade 2 limit is 
missing, the Grade 1 limit will be considered.  Appendix 1 presents the Eisai grading criteria 
for laboratory values that were used to identify subjects with markedly abnormal laboratory 
values.  For the incidence of markedly abnormal laboratory values, each subject may be 
counted once in the laboratory parameter value high and in the laboratory parameter low 
categories as applicable.
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9.7.1.8.4
VITAL SIGNS AND WEIGHT
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiration rate, temperature) and weight, and changes from Study Baseline will be presented 
by visit and treatment group.  
Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range.  Categorical analyses of 
subjects (number and percent) who fall outside the below clinically notable vital sign ranges 
will also be presented for change from Study Baseline (Safety Analysis Set), by treatment 
group and by time point.  This will also be repeated for the 12-month LEM exposure (On-
Treatment Safety Analysis Set), summarized by treatment group and duration of exposure.  
(revised per Amendment 06)
Variable
Criterion Valuea
Change Relative to Study 
Baselinea
Clinically 
Notable 
Range
Heart rate
>120 bpm
Increase of 15 bpm
H
<50 bpm
Decrease of ≥15 bpm
L
Systolic BP
>180 mmHg
Increase of ≥20 mmHg
H
<90 mmHg
Decrease of ≥20 mmHg
L
Diastolic BP
>105 mmHg
Increase of ≥15 mmHg
H
<50 mmHg
Decrease of ≥15 mmHg
L
BP = blood pressure, H = high, L = low
a.
Clinically notable means that a value must meet the criterion value and must attain the specified 
magnitude of change relative to Study Baseline.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from Study Baseline (Safety Analysis 
Set) will be presented by treatment group and visit.  This will also be repeated for the 12-
month LEM exposure (On-Treatment Safety Analysis Set), summarized by treatment group 
and duration of exposure.  (revised per Amendment 06)
Shift tables will present changes from Study Baseline in ECG interpretation (categorized as 
normal and abnormal) by time point. (revised per Amendment 03)
For each subject, the maximum observed QTcF, the corrected QT interval calculated using 
Bazett’s formula (QTcB), and the maximum prolongation from Study Baseline in QTcF will 
be compiled. 
Categorical analyses of subjects (number and percent) with maximum 
observed QTcF values >450 ms, >480 ms, and >500 ms and maximum prolongations (from 
Study Baseline) in QTcF >30 ms and >60 ms will be presented by treatment group and by 
time point.  Categorical analyses of subjects (number and percent) with maximum observed 
PR values >220 ms, and QRS values >120 ms will be presented by treatment group and by 
time point.  This will also be repeated for the 12-month LEM exposure (On-Treatment Safety 
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Analysis Set), summarized by treatment group and duration of exposure.  (revised per 
Amendment 06)
9.7.1.8.6
OTHER SAFETY ANALYSES
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 as appropriate.  Urine 
drug test results and pregnancy test results will also be listed.
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.
9.7.1.9
Other Analyses
Secondary and exploratory endpoints may be additionally presented graphically or analyzed 
by modeling methods if warranted.  
9.7.2
Determination of Sample Size
The sample size was estimated for the comparison of LEM10 and LEM5 with PBO, with 
respect to the mean change from Study Baseline at the end of Month 6 of the mean sSOL, the 
mean sSE and mean sWASO. This estimate was based on sequential gate-keeping procedure
at the 0.05 α-level as described above. There is sufficient power for both the primary 
endpoint (sSOL) and key secondary endpoints (sSE and sWASO). 
On the basis of the dose finding study E2006-G000-201 (Study 201) for the lemborexant 
total summaries at Days 8 to 15, the standard deviation of change from Study Baseline for 
sSOL is assumed to be 33 minutes, for sSE is assumed to be 12% and for sWASO is assumed 
to be 43 minutes.  The LS mean treatment differences at Days 8 to 15 from Study 201 were 
as follows: for sSE 9.5% for LEM10 and 5.5%, for LEM5; for sWASO -26.6 minutes for 
LEM10, and -11.3 minutes for LEM5.  As a result of the non-normal distribution of sSOL, 
the LS mean treatment difference is not available (geometric mean ratios were used).  
Therefore, estimating treatment difference using medians at Days 8 to 15 from Study 201, 
leads to a median treatment difference of approximately -6.8 minutes for LEM10.  For 
LEM5, a median treatment difference is approximately -13.2 minutes. 
To detect a treatment difference in sSOL of at least -8.7 minutes, a sample size of 300 per 
treatment group at 5% (2-sided) level of significance has >90% power for comparing a dose 
of lemborexant with PBO. 
To detect a treatment difference in sSE of at least 5.5%, a sample size of 300 per treatment 
group at 5% (2-sided) level of significance has >99% power for comparing a dose of 
lemborexant with PBO.
For sWASO, total 900 subjects (300 per treatment group) will give 90% power to detect a 
difference of -11.4 minutes for LEM5 and LEM10 compared to PBO (Table 4).  The study is 
adequately powered to show the statistically significant difference from PBO for LEM10 as 
well as for LEM5.
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Table 4
Sample Size Calculations for Study E2006-G000-303
Alpha=0.05
Difference 
between Active 
and 
Placebo 
CfB (min)
Power = 80%
Power =90%
Sample size 
per group
Overall 
3 
group 
sample size
Sample 
size 
per group
Overall 
3 
group sample 
size
sSOL (SD=33)
-6.8
371
1113
496
1488
-7.6
300
900
398
1194
-8
269
807
359
1077
-8.7
229
687
300
900
-9
213
639
284
852
-10
172
516
230
690
-11
143
429
191
573
sWASO (SD=43)
-9
360
1080
481
1443
-9.9
300
900
398
1194
-10
292
876
390
1170
-11
241
723
323
969
-11.4
225
675
300
900
-12
203
609
271
813
CfB = change from baseline, sSOL = subjective sleep onset latency, sWASO = subjective wake after sleep 
onset.
The study also has adequate power for the secondary analysis of responders.  A sleep onset 
responder is defined as follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 
months is ≤20 minutes, and a sleep maintenance responder is defined as follows: sWASO at 
Study Baseline is ≥60 minutes and mean sWASO at 6 months is ≤60 minutes and shows a 
reduction of >10 minutes compared to Study Baseline.  A total of 900 subjects gives >99% 
power to detect a treatment difference in sleep onset responder rates of 16% and sleep 
maintenance responder rates of 24.4%.
The above sample size also meets regulatory safety requirements.  Even with early 
discontinuation rates as high as 50% at Month 6 (ie, 150 subjects remaining) and 60% by 
Month 12 (ie, 120 subjects remaining in each treatment group), the requirement for 
100 subjects in each of the elderly and non-elderly age-groups to complete 12-months of 
treatment on 5 or 10 mg lemborexant will be met.  In addition, 420 total subjects would have 
completed 6 months of treatment of 5 mg or 10 mg lemborexant.
9.7.3
Interim Analysis
No interim analysis is planned for this study.  (revised per Amendments 04 and 05)
9.7.4
Other Statistical/Analytical Issues
Not applicable.
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9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
Abetz L, Arbuckle R, Allen RP, Garcia-Borreguero D, Hening W, Walters AS, et al. The 
reliability, validity and responsiveness of the International Restless Legs Syndrome Study 
Group rating scale and subscales in a clinical-trial setting.  Sleep Med. 2006;7:340–9.
Akanmu MA, Honda K.
Selective stimulation of orexin receptor type 2 promotes 
wakefulness in freely behaving rats. Brain Res. 2005;1048:138-45.
Arnau RC, Meagher MW, Norris MP, Bramson R.
Psychometric evaluation of the Beck 
Depression Inventory-II with primary care medical patients.  Health Psychology 
2001;20(2):112-9.
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med 2001;2:297-307.
Carney CE, Moss TG, Harris AL, Jack D, Edinger JD, Krystal AD.  Should We Be Anxious 
When Assessing Anxiety Using the Beck Anxiety Inventory in Clinical Insomnia Patients?  J 
Psychiatr Res 2011;45(9):1243–9.
Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, et al. STOP 
Questionnaire A Tool to Screen Patients for Obstructive Sleep Apnea. Anesthesiology 
2008;108:812–21.
Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. Suvorexant in 
patients with insomnia: results from two 3-month randomized controlled clinical trials.  
Biological Psychiatry 2016;79:136–48.
Johns MW. 
Reliability and factor analysis of the Epworth Sleepiness Scale. 
Sleep 
1992;15(4):376-81.
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD.  The fatigue severity scale.  
Application to patients with multiple sclerosis and systemic lupus erythematosus.  Arch 
Neurol 1989;46(10):1121-3.
McCall WV, D’Agostino R., Dunn A. A meta-analysis of sleep changes associated with 
placebo in hypnotic clinical trials. Sleep Medicine 2003;4 (1): 57–62.
Moriarty SR, Revel FG, Malherbe P, Moreau J-L, Vallado D, Wettstein JG, et al.
Dual 
hypocretin receptor antagonism is more effective for sleep promotion than antagonism of 
either receptor alone. PLoS ONE. 2012;7(7):e39131.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia–Suicide Severity Rating Scale: Initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. 
Am J Psychiatry 
2011;168(12):1266–77.
Tyrer P, Murphy S, Riley P. 
The benzodiazepine withdrawal symptom questionnaire.  
J Affective Disorders 1990;19:53–61.
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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 or appropriate 
study team member 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 will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with GCP and local regulations.  All records at the site are subject to inspection 
by the appropriate Regulatory Authorities and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:
Subject clinical records 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production
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Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, ECGs, rhythm strips, EEGs) regardless of how these images are stored, 
including microfiche and photographic negatives
Quality of life, or medical history questionnaires completed by subjects
Records of telephone contacts
Diaries or evaluation checklists
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
Data entered into the electronic data capture (EDC) system must be accurate and complete.  
Responsible site personnel will enter the data required by the protocol in the eCRFs in 
accordance with the eCRF Completion Guidelines provided by the Sponsor. All the eCRF 
data collected in the EDC system will be archived in CDs and will be forwarded to the 
Sponsor at the end of the study.

All corrections made to data entered in the eCRFs will require a reason for change

The Principal Investigator will review all eCRF data entered in the EDC system and will 
electronically sign off to attest to the review

Data reported on the eCRF that are derived from source documents should be consistent 
with the source documents, and if not, the discrepancy should be explained

The Principal Investigator will use a subject identification number to identify subjects in 
the study
Data corrections made to eCRF data entered in the EDC system will be verified by CRA 
personnel using source documents.
The expectation for timely completion of eCRFs can be found in the eCRF Completion 
Guidelines. All sites should complete data entry for all visits in accordance with these 
Guidelines. Entry of all data from the Month 6 visit, and all corresponding data, must in no 
case be completed later than 2 weeks after the Month 6 visit.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  The 
investigator agrees to allow direct access to source documents and study facilities to sponsor 
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representative(s), monitor(s) and auditor(s), and agree to inspection by regulatory authorities 
or IRB/IEC representative.  (revised per Amendment 01)
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 CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence) and subject source 
data.  In addition, upon request, the sponsor will send a list of treatment codes by study 
subject to the investigator after the clinical database for this study has been locked. The site 
should plan to retain study documents, as directed by the sponsor, for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study 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 designated contractor or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
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11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
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.
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11.12 Subject Insurance and Indemnity
The sponsor will provide insurance in accordance with local guidelines and requirements for 
subject participation in this study.
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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
Fasting glucose value:
>160 – 250 mg/dL
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
>500 mg/dL;
>27.8 mmol/L;
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
>ULN – 8.9 mmol/L 
>8.9 – 13.9 mmol/L 
hospitalization indicated 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
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: 28 May 2009 (v4.03: 14 Jun  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.
(revised per Amendment 02)
Visit Name
V1
V2a
V3a
Screening
Screening
Screening/
Baseline 1
Inclusion Criterion 
Number
1, 2, 3, 4, 5, 6, 
13, 14
7, 8, 9
6, 10, 11, 12, 13, 14
Exclusion Criterion 
Number
1 – 29
8, 22, 23,26
8, 15, 17, 19, 21, 25, 
26
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Appendix 3
Prohibited Concomitant Medications
If a medication is not presented in the list below, but does fit into a class of medications 
noted in the list, the medical monitor must be consulted to determine whether it is permitted. 
Category
Medication
Anticholinergics (centrally-acting)
-
Anticonvulsants with known sedating effects
Barbiturates 
Benzodiazepines 
GABA analogues 
Hydantoins 
Phenyltriazines
Antihistamines (centrally-acting H1, including 
over the counter) (revised per Amendment 03)
Diphenhydramine HCl
Carbinoxamine 
Doxylamine 
Dimenhyrinate 
Triprolidine 
Bromopheniramine 
Chlorphenamine 
Hydroxazine
Antihistamines with known sedating effects
Non-sedating, eg, Claritin ™ is not 
prohibited
Anxiolytics with known sedating effects
Lorazepam 
Alprazolam 
Buspirone
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Category
Medication
Strong CYP3A inhibitors
(revised per Amendments 01 and 03)
Amiodarone 
Bocepravir
Clarithomycin 
Cobicistat
Conivaptan
Danoprevir
Diltizem
Elteravir
Fluvoxamine 
Grapefruit juice
Idelalisib
Indinavir
Itraconazole 
Ketoconazole 
Lopinavir
Mibefradil 
Nefazodone 
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telapravir
Telethromycin
Tipranavir
Troleandomycin 
Voriconazole
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Category
Medication
Moderate CYP3A inhibitors (revised per 
Amendment 06)
Amprenavir
Aprepitant
Atazanavir
Casopitant
Cimetidine
Ciprofloxacin
Clotrimazole
Crizotinib
Cyclosporin
Darunavir
Dronadarone
Erythromycin
Faldaprevir
Fluconazole
Fluvoxamine
Imatinib
Netupitant
Tofisopam
Verapamil
CYP3A inducers
(revised per Amendments 01 and 03)
Avasimibe
Bosentan
Carbamazepine 
Efavirenz
Enzaluteamide
Etravirine
Lersivirine
Modafinil
Mitotane
Nafcillin
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin
St John’s Wort 
Troglitazone
Talviraline
Thioridazine
Hypnotics
Melatonin 
Prescribed or OTC
Herbal preparations with sedating effects
-
MAOIs
-
Opioid Analgesics
-
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Category
Medication
Muscle relaxants (centrally-acting) with known 
sedating effects
GABA analogues 
Hydantoins 
Phenyltriazines
Stimulants
Amphetamines 
Modafinil 
Armodafinil
Methylfenidate
Other
Warfarin, heparin, ticlopidine
Non-stimulant diet pills
Systemic isoretinoin
Systemic glucocorticoids
Tryptophan
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-G000-303
Study Protocol Title:
A Long-Term Multicenter, Randomized, Double-Blind, Controlled, 
Parallel-Group Study of the Safety and Efficacy of Lemborexant in 
Subjects With Insomnia Disorder
Investigational Product
Name:
E2006/lemborexant
IND Number:
111871
EudraCT Number:
2015-001463-39
SIGNATURES
Authors:
Neurology Business Group
Eisai Ltd.
Date
Neurology Business Group
Eisai Inc. (revised per Amendment 04)
Date
Neurology Business Group
Eisai Inc.
Date
Neurology Business Group
Eisai Ltd. (revised per Amendments 04 and 06)
Date
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_003.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2006-G000-303
Study Protocol 
Title:
A Long-Term Multicenter, Randomized, Double-Blind, Controlled, 
Parallel-Group Study of the Safety and Efficacy of Lemborexant in 
Subjects With Insomnia Disorder
Date:
21 August 2018
Version:
Final Version 2.0
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Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................................7
1
INTRODUCTION ...........................................................................................................10
1.1
Study Objectives ....................................................................................................10
1.1.1
Primary Objective........................................................................................10
1.1.2
Secondary Objectives...................................................................................10
1.1.3
Exploratory Objectives ................................................................................11
1.2
Overall Study Design and Plan..............................................................................11
2
DETERMINATION OF SAMPLE SIZE........................................................................12
3
STATISTICAL METHODS............................................................................................14
3.1
Study Endpoints.....................................................................................................14
3.1.1
Primary Endpoint.........................................................................................14
3.1.2
Secondary Endpoints ...................................................................................14
3.1.3
Exploratory Endpoints .................................................................................16
3.1.4
Other Endpoints ...........................................................................................17
3.2
Study Subjects........................................................................................................17
3.2.1
Definitions of Analysis Sets.........................................................................17
3.2.2
Subject Disposition......................................................................................18
3.2.3
Protocol Deviations......................................................................................18
3.2.4
Demographic and Other Baseline Characteristics .......................................18
3.2.4.1
Medical History .................................................................................19
3.2.5
Prior and Concomitant Therapy...................................................................19
3.2.6
Treatment Compliance.................................................................................20
3.3
Data Analysis General Considerations ..................................................................20
3.3.1
Pooling of Centers........................................................................................20
3.3.2
Adjustments for Covariates..........................................................................20
3.3.3
Multiple Comparisons/Multiplicity .............................................................20
3.3.4
Examination of Subgroups...........................................................................21
3.3.5
Handling of Missing Data, Dropouts, and Outliers .....................................21
3.3.6
Other Considerations ...................................................................................23
3.4
Efficacy Analyses ..................................................................................................24
3.4.1
Primary Efficacy Analyses ..........................................................................24
3.4.1.1
Multiple Imputation ...........................................................................25
3.4.1.2
Subgroup Analyses ............................................................................26
3.4.1.3
Sensitivity Analyses...........................................................................26
3.4.1.4
Supplementary Analyses....................................................................27
3.4.2
Secondary Efficacy Analyses ......................................................................28
3.4.2.1
Key Secondary Efficacy Analyses.....................................................28
3.4.2.2
Sensitivity Analyses for Key Secondary Efficacy Analyses .............30
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3.4.2.3
Supplementary Analyses for Key Secondary Efficacy Analyses ......30
3.4.2.4
Other Secondary Efficacy Analyses ..................................................31
3.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...............................................................................................34
3.5.1
Pharmacokinetic Analyses...........................................................................34
3.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....35
3.6
Safety Analyses......................................................................................................35
3.6.1
Treatment Definitions..................................................................................35
3.6.2
Extent of Exposure.......................................................................................36
3.6.3
Adverse Events ............................................................................................36
3.6.3.1
Selected Adverse Events....................................................................38
3.6.3.2
Subgroup Analysis of TEAE .............................................................38
3.6.4
Laboratory Values........................................................................................39
3.6.4.1
Subgroup Analysis of Laboratory Values..........................................40
3.6.5
Vital Signs....................................................................................................40
3.6.6
Electrocardiograms ......................................................................................41
3.6.7
Other Safety Analyses..................................................................................42
3.6.7.1
Columbia-Suicide Severity Rating Scale (C-SSRS)..........................42
3.6.7.2
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (T-
BWSQ)...............................................................................................42
3.7
Other Analyses.......................................................................................................42
3.7.1
EQ-5D-3L ....................................................................................................42
3.7.2
Patient Global Impression (PGI) - Insomnia ...............................................43
3.7.2.1
WPAI-GH ..........................................................................................43
3.8
Exploratory and Pharmacodynamic Analyses .......................................................44
4
INTERIM ANALYSES...................................................................................................44
4.1
DSMB (Data Safety Monitoring Board)................................................................44
4.2
Interim Analysis.....................................................................................................44
5
CHANGES IN THE PLANNED ANALYSES...............................................................44
6
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................45
6.1
Efficacy Data Handling..........................................................................................45
6.1.1
Baseline Efficacy .........................................................................................45
6.1.2
Derivation of Primary and Key Secondary Endpoints for Sleep Diary.......45
6.1.3
Visit Windowing..........................................................................................46
6.2
SAFETY DATA HANDLING ..............................................................................47
6.2.1
Baseline Safety.............................................................................................47
6.2.2
Handling of Missing Safety data, Drop-outs, and Outliers..........................47
6.2.3
Visit Windowing..........................................................................................48
7
PROGRAMMING SPECIFICATIONS ..........................................................................48
8
STATISTICAL SOFTWARE..........................................................................................52
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9
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................52
10
REFERENCES ................................................................................................................52
LIST OF IN-TEXT TABLES
Table 1
Summary of Changes (Version 2)................................................................5
Table 2
Sample Size Calculations for Study E2006-G000-303..............................13
Table 3
Multiple Imputation Methods ....................................................................22
Table 4
Estimands...................................................................................................23
Table 5
Monotone Missing Patterns for Primary Efficacy Analysis ......................27
Table 6
Monotone Missing Patterns for Secondary Efficacy Analysis ..................30
Table 7
Selected Laboratory Parameters for Subgroup Analysis ...........................40
Table 8
Vital Sign Criteria......................................................................................41
Table 9
Windowing Rules for Efficacy Endpoints from Sleep Diary ....................46
Table 10
Windowing Rules for Safety Endpoints ....................................................48
LIST OF IN-TEXT FIGURES
Figure 1
Schematic Diagram of Study Design.........................................................12
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results
53
Appendix 2
List of Potential Cataplexy Events.............................................................55
Appendix 3
List of Abuse Liability Events...................................................................56
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Table 1
Summary of Changes (Version 2)
Change
Rationale
Throughout the document: Editorial 
comments are made to correct typos
For clarification purposes.
Section 3 Added wording on multiple 
database locks and reporting
Due to changes in planned reporting.
Section 3.1.2 “Secondary Endpoints” and 
Section 3.1.3 “Exploratory Endpoints”
Wording adjusted to look at endpoints for 
duration of exposure, not timepoints during 
Period 2
Section 3.2.1 “Definitions of Analysis Sets”: 
The definition of 6-Months Completer 
Analysis Set, On-Treatment Safety Analysis 
Set and On-Treatment Full Analysis Set are
added.
Detail added.
Section 3.4 “Efficacy Analyses”
Description of 12-month LEM exposure 
summaries detailed
Section 3.4.1.4 “Supplementary Analyses” 
and Section 3.4.2.3 ” Supplementary
Analyses for Key Secondary Efficacy 
Analyses”: 
The supplementary analysis is added to 
incorporate feedback from regulatory 
authorities.
Section 3.4.1.4 “Other Secondary Efficacy 
Measures” 
Clarity added on responder and persistence 
of loss of effect. Description of 12-month 
LEM exposure summaries detailed. FSS 
responder analysis added.
Section 3.6.1 “Treatment Definitions”
Description of 12-month LEM exposure 
summaries detailed.  Up to 12 month and up 
to 6 month treatment definitions removed.
Section 3.6.2 “Extent of Exposure”
Updated to include 9 month exposure 
summary.
Section 3.6.3 “Adverse Events”
Up to 12 month and up to 6 month treatment 
definitions removed.
Section 3.6.3.1 “Selected Adverse Events”: 
The summary of potential cataplexy and its 
definition (Appendix 2) are added. 
Detail of definition of potential cataplexy 
added. Up to 12 month and up to 6 month 
treatment definitions removed.
Section 3.6.3.2 “Subgroup Analysis of 
TEAE” and Section 3.6.4.1 “Subgroup 
Analysis of Laboratory values” are added.
Further subgroups for safety analyses added.
Up to 12 month and up to 6 month treatment 
definitions removed.
3.6.4 “Laboratory Values”, 3.6.4.1 
“Subgroup Analysis of Laboratory Values”, 
Description of 12-month LEM exposure 
summaries detailed.  
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Table 1
Summary of Changes (Version 2)
Change
Rationale
3.6.5 “Vital Signs”, 3.6.6 
“Electrocardiograms”, 3.7.1 “EQ-5D-3L”, 
3.7.2 “Patient Global Impression (PGI) –
Insomnia”, 3.7.2.1 “WPAI-GH”
Section 7 “Programming Specifications”: 
The description of a planned tipping point 
analysis has been included
Further detail of tipping point analysis 
required.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
ATC
anatomical therapeutic class
AUC
area under the concentration-time curve
BAI
Beck Anxiety Inventory
BDI-II
Beck Depression Inventory - II
BMI
body mass index
CI
confidence interval
CL
total clearance
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CSR
clinical study report
CV
coefficient of variation
ECG
electrocardiogram
ESS
Epworth Sleepiness Scale
eCRF
electronic case report form
eC-SSRS
electronic Columbia-Suicide Severity Rating Scale
EOS
end of study
ESS
Epworth Sleepiness Scale
FAS
full analysis set
FDA
Food and Drug Administration
FSS
Fatigue Severity Scale
IRLS
International Restless Legs Scale
ISI
Insomnia Severity Index
LDA
longitudinal data analysis
LEM5
lemborexant, 5-mg dose
LEM10
lemborexant, 10-mg dose
LNH
low-normal-high
LS
least squares
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Abbreviation
Term
MAR
missing at random
MCMC
Monte Carlo Markov Chain 
MI
Multiple Imputation
MNAR 
missing not at random
MedDRA
Medical Dictionary for Regulatory Activities
NREM
non-REM sleep
PAB
performance assessment battery
PBO
placebo
PD
pharmacodynamic
PGI
Patient Global Impression
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PT
preferred term
QTcB
QT interval calculated using Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SD
Standard deviation
SE
sleep efficiency
SOC
system organ class
SDSB
Sleep Disorders Screening Battery
sSE
subjective sleep efficiency
sSOL
subjective sleep onset latency
sTIB
subjective time in bed
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
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Abbreviation
Term
US
United States
VAS
visual analog scale
WASO
wake after sleep onset
WBC
white blood cells
WPAI-GH
Work Productivity and Activity Impairment Questionnaire –
General Health
TLG
tables, listings, and graphs
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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-G000-303.  
This document is prepared on the basis of the final study protocol version 6.0 (dated 13 Aug
2018). The reader is referred to the study protocol, the electronic case report form (eCRF), 
general eCRF completion guidelines, and various data collection instruments employed in the 
study for details of study design, conduct and data collection.  
This SAP is to be reviewed and approved prior to study database lock.  If any updates are 
made upon blinded review of study data, or for any other reasons in the course of the study, 
such modifications and rationale are likewise to be documented and approved prior to 
unblinding of the study database. 
1.1
Study Objectives
1.1.1
Primary Objective
The primary objective of the study is to:
Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to 
placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in 
subjects with insomnia disorder
1.1.2
Secondary Objectives
Key Secondary Objectives
•
Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective sleep 
efficiency (sSE) after 6 months of treatment in subjects with insomnia disorder
•
Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective wake 
after sleep onset (sWASO) after 6 months of treatment in subjects with insomnia 
disorder
Additional Secondary Objectives
•
Determine the efficacy of LEM5 and LEM10 compared to PBO on sSOL, sSE, 
sWASO, and subjective total sleep time (sTST):
-
over the 1st 7 nights of treatment 
-
after 1 month of treatment
-
after 3 months of treatment
•
Determine the efficacy of LEM5 and LEM10 compared to PBO on sTST at 6 months  
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•
Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and 
LEM10 compared to PBO as defined by response on sSOL or sWASO at 6 months and 
12 months
•
Evaluate the safety and tolerability of LEM5 and LEM10
•
Evaluate the efficacy of LEM5 and LEM10 compared to PBO as measured by responses 
on the Insomnia Severity Index (ISI) and the Fatigue Severity Scale (FSS) after 6 
months
•
Evaluate rebound insomnia following discontinuation of treatment 
•
Evaluate morning sleepiness during and following completion of treatment
•
Evaluate persistence of efficacy of LEM5 and LEM10 over 12 months
1.1.3
Exploratory Objectives
The following will be explored for both LEM5 and LEM10 compared to PBO over Period 1 
and over Period 2 with analyses dependent on whether subjects received active treatment or 
PBO during Period 1:
•
Efficacy on quality of sleep 
•
Health outcomes on the EuroQOL version 5D-3L (EQ-5D-3L), Work Productivity and 
Activity Impairment Questionnaire – General Health (WPAI-GH), and Patient Global 
Impression – Insomnia (PGI-Insomnia)
•
Efficacy on sSOL, sSE, sWASO, sTST, ISI, and FSS
•
Withdrawal symptoms after completion of treatment (Period 2 only)
The following will be explored for LEM5 and LEM10:

Plasma concentrations of lemborexant and its metabolites M4, M9, and M10

Population pharmacokinetic (PK) modeling for lemborexant 

PK/pharmacodynamic (PD) relationships between lemborexant concentrations and 
efficacy and safety variables
1.2
Overall Study Design and Plan
This study was a 12-month, multicenter, randomized, controlled, double-blind, parallel-group 
study of 2 doses of lemborexant in approximately 900 male and female subjects with 
insomnia disorder (subjects who complain of difficulties with sleep onset and/or sleep 
maintenance).  Approximately 40% of the population was planned to be 65 years of age or 
older.
The study had 2 phases, the Prerandomization Phase and the Randomization Phase.  The 
Prerandomization Phase comprised 3 periods and lasted up to 35 days: a Screening Period, a 
Run-In Period, and a Baseline Period.  The Randomization Phase comprised a 6-month, 
placebo-controlled treatment period (Period 1) followed by a further 6 months in which
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subjects received only active treatment (Period 2).  Subjects were informed that they were to
receive PBO at some point during the study and that all would receive active drug for at least 
6 months.  They were not informed of either the timing of these periods or the timing of the 
2nd randomization.  A 2-week Follow-Up Period was then to take place, followed by an End 
of Study Visit.  The study design is shown in Figure 1.
Figure 1
Schematic Diagram of Study Design
R = randomization
2
DETERMINATION OF SAMPLE SIZE
The sample size was estimated for the comparison of LEM10 and LEM5 with PBO, with 
respect to the mean change from Study Baseline at the end of Month 6 of the mean sSOL, the 
mean sSE and mean sWASO.  This estimate was based on a sequential gate-keeping 
procedure at the 0.05 α-level in Section 3.3.3.  There was sufficient power for both the 
primary endpoint (sSOL) and key secondary endpoints (sSE and sWASO). 
On the basis of the dose-finding study E2006-G000-201 (Study 201), across various
lemborexant doses (1 to 25 mg) at Days 8 to 15, the standard deviation of change from Study 
Baseline for sSOL was assumed to be 33 minutes; for sSE was assumed to be 12%; and for 
sWASO was assumed to be 43 minutes.  The LS mean treatment differences at Days 8 to 15 
from Study 201 were as follows: for sSE 9.5% for LEM10 and 5.5%, for LEM5; for 
sWASO -26.6 minutes for LEM10, and -11.3 minutes for LEM5.  As a result of the 
non-normal distribution of sSOL, the LS mean treatment difference is not available 
(geometric mean ratios were used).  Therefore, estimating treatment difference using 
medians at Days 8 to 15 from Study 201, leads to a median treatment difference of 
approximately -6.8 minutes for LEM10.  For LEM5, a median treatment difference was
approximately -13.2 minutes. 
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To detect a treatment difference in sSOL of at least -8.7 minutes, a sample size of 300 per 
treatment group at 5% (2-sided) level of significance had >90% power for comparing a dose 
of lemborexant with PBO. 
To detect a treatment difference in sSE of at least 5.5%, a sample size of 300 per treatment 
group at 5% (2-sided) level of significance had >99% power for comparing a dose of 
lemborexant with PBO.
For sWASO, a total of 900 subjects (300 per treatment group) gave 90% power to detect a 
difference of -11.4 minutes for LEM5 and LEM10 compared to PBO (Table 2).  The study 
was adequately powered to show the statistically significant difference from PBO for LEM10 
as well as for LEM5.
Table 2
Sample Size Calculations for Study E2006-G000-303
Alpha=0.05
Difference 
between Active 
and Placebo 
CfB (min)
Power = 80%
Power = 90%
Sample size 
per group
Overall 3 
group sample 
size
Sample size 
per group
Overall 3 
group sample 
size
sSOL (SD=33)
-6.8
371
1113
496
1488
-7.6
300
900
398
1194
-8
269
807
359
1077
-8.7
229
687
300
900
-9
213
639
284
852
-10
172
516
230
690
-11
143
429
191
573
sWASO (SD=43)
-9
360
1080
481
1443
-9.9
300
900
398
1194
-10
292
876
390
1170
-11
241
723
323
969
-11.4
225
675
300
900
-12
203
609
271
813
CfB = change from baseline, sSOL = subjective sleep onset latency, sWASO = subjective wake after sleep 
onset.
The study also had adequate power for the secondary analysis of responders.  A sleep onset 
responder was defined as follows: sSOL at Study Baseline was ≥30 minutes and mean sSOL 
at 6 months was ≤20 minutes, and a sleep maintenance responder was defined as follows: 
sWASO at Study Baseline was ≥60 minutes and mean sWASO at 6 months was ≤60 minutes 
and showed a reduction of >10 minutes compared to Study Baseline.  A total of 900 subjects 
gave >99% power to detect a treatment difference in sleep onset responder rates of 16% and 
sleep maintenance responder rates of 24.4%, both compared with placebo.
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The above sample size also met regulatory safety requirements.  Even with early 
discontinuation rates as high as 50% at Month 6 (ie, 150 subjects remaining) and 60% by 
Month 12 (ie, 120 subjects remaining in each treatment group), the requirement for 
100 subjects in each of the elderly and non-elderly age-groups to complete 12-months of 
treatment on 5 or 10 mg lemborexant would be met.  In addition, a total of 420 subjects 
would complete 6 months of treatment with 5 or 10 mg lemborexant.
3
STATISTICAL METHODS
All statistical analyses will be performed by the sponsor or designee.  When all subjects have 
completed Treatment Period 1 (Period 1), all data will be unblinded to the sponsor. There 
will be 3 database locks.  The first will be of Period 1 data only, where data up to and 
including the visit at Month 6 will be analyzed.  The second will include all data (Period 1 
and ongoing Period 2 data) after all continuing subjects have completed the Month 9 (Period 
2) visit, all available data will be analyzed to support regulatory submissions.  The third will 
include all data where the study has continued to completion.    
For the Period 1 analysis, sponsor staff and certain designees (detailed in the Study Integrity 
Charter) will be unblinded to the treatment allocation; however, subjects, investigators, and 
site personnel will remain blinded.  These are not considered formal interim analyses since 
the primary and key secondary efficacy endpoints are all at Month 6 (Period 1), and there is 
no placebo control group in Period 2. Therefore, no Type I error adjustment is needed for 
efficacy analysis.  
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 group.  sSOL will be log transformed in analyses 
unless otherwise stated.
All statistical tests will be based on the 5% level of significance (two-sided).  
3.1
Study Endpoints
Definitions of baseline, primary, secondary and exploratory endpoints are defined in this 
section.  Where Sleep Diary endpoints are described, the time points refer to the mean of the 
final 7 nights before the visit unless otherwise stated.
3.1.1
Primary Endpoint
The primary endpoint is the mean change from Study Baseline in sSOL at Month 6. 
3.1.2
Secondary Endpoints
The key secondary endpoints are:
•
Mean change from Study Baseline in sSE at Month 6
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•
Mean change from Study Baseline of sWASO at Month 6  
Additional secondary endpoints are:
•
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST, at the 
beginning of treatment (mean of the 7 nights after the 1st dose in Period 1), at Month 1 
and at Month 3
•
Mean change from Study Baseline of sTST at Month 6 
•
Proportion of responders at Month 6 and Month 12, where sleep onset responder is 
defined as follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 months 
is ≤20 minutes, and sleep maintenance responder is defined as follows: sWASO at 
Study Baseline is ≥60 minutes and mean sWASO at 6 months is ≤60 minutes and shows 
a reduction of >10 minutes compared to Study Baseline.
•
Change from Study Baseline in daytime functioning, assessed as the total score from the 
4 items on daytime functioning, on the ISI, at Months 1, 3, and 6
•
Change from Study Baseline on the FSS at Months 1, 3, and 6
•
Ratings on the morning sleepiness item of the Sleep Diary, for:
-
The mean change from Study Baseline of the 1st 7 mornings after the 1st dose in 
Period 1 and Period 2
-
The mean change from Study Baseline at: Month 1, Month 3, and Month 6 
-
The mean change from Study Baseline and from Treatment Period 2 Baseline (as 
appropriate): for subjects with 1, 3, 6, 9 and 12 months exposure  
-
The mean change from Screening for the 1st 7 mornings and 2nd 7 mornings of the 
Follow-up Period
•
Rebound insomnia endpoints as assessed from the Sleep Diary during the Follow-up 
Period
-
Change from Screening of sSOL on each of the 1st 3 nights, mean sSOL of the 1st 
7 nights, and mean sSOL of the 2nd 7 nights of the Follow-up Period
-
Change from Screening of sWASO on each of the 1st 3 nights, mean sWASO of the 
1st 7 nights and mean sWASO of the 2nd 7 nights of the Follow-up Period
-
Proportion of subjects whose sSOL is longer than at Screening for each of the 1st 3 
nights, or whose mean sSOL is longer than at Screening for 1st 7 nights or 2nd 7 
nights of the Follow-up Period
-
Proportion of subjects whose sWASO is higher than at Screening for each of the 1st 
3 nights, or whose mean sWASO is higher than at Study Baseline for the 1st 7 nights 
or 2nd 7 nights of the Follow-up Period
•
Persistence of Effect 
-
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST at 
Months 3, 6, 9, and 12 compared to Month 1
-
Mean change from Treatment Period 2 Baseline (Month 6) of sSOL, of sSE, of 
sWASO and of sTST at Months 9 and 12 compared to Month 7 (the 1st month of 
treatment in Period 2)
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-
Mean change from Study Baseline and Treatment Period 2 Baseline (as appropriate) 
of sSOL, of sSE, of sWASO and of sTST at 3 and 6 months exposure  compared to 1 
month of exposure 
Safety and Tolerability of Lemborexant

During Period 1, compared to PBO

For subjects exposed to lemborexant for 3, 6, 9, and 12
3.1.3
Exploratory Endpoints
The following endpoints will be explored for LEM5 and LEM10.  Except for PK endpoints, 
comparisons to PBO will be made.
•
Change from Study Baseline in the mean value of the item on quality of sleep from the 
Sleep Diary for:
-
The 1st 7 mornings after the 1st dose in Period 1
-
Months 1, 3, and 6
•
Change from Study Baseline and Treatment Period 2 Baseline (as appropriate) in the 
mean value of the item on quality of sleep from the Sleep Diary for:
-
subjects with 1, 3, 6, 9 and 12 months exposure  

Change from Study Baseline in: 
-
EQ-5D-3L at Months 1, 3, and 6
-
WPAI-GH at Months 3 and 6
•
Change from Study Baseline and Treatment Period 2 Baseline (as appropriate) in:
-
EQ-5D-3L for subjects with 3, 6, 9 and 12 months exposure to lemborexant
-
WPAI-GH for subjects with 3, 6, 9 and 12 months exposure  to lemborexant
•
Number and percentage of subjects with a rating of a positive medication effect on each 
PGI-Insomnia item (1) at Months 1, 3, and 6 (placebo-controlled Treatment Period 1) 
and (2) with 3, 6, 9 and 12 months exposure
•
Change from Study Baseline and Treatment Period 2 Baseline (as appropriate) of sSOL, 
sSE, sWASO and sTST with 1, 3, 6, 9 and 12 months exposure, ISI, and FSS with  3, 6, 
9 and 12 months exposure
•
Mean score on the T-BWSQ of LEM5, and LEM10 compared to PBO at End of Study
•
Plasma concentrations of lemborexant and its metabolites M4, M9, and M10
•
PK of lemborexant using population modeling
•
Relationships between lemborexant PK, efficacy, and/or safety variables using PK/PD 
modeling 
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3.1.4
Other Endpoints 
Additional endpoints may be further explored on an exploratory or post-hoc basis to facilitate 
interpretation of study results.  
3.2
Study Subjects
3.2.1
Definitions of Analysis Sets
Safety Analysis Set: The Safety Analysis Set is the group of subjects who received at least 1 
dose of randomized study drug and had at least 1 postdose safety assessment.
On-Treatment Safety Analysis Set: On-Treatment Safety Analysis Set is the group of 
subjects who received at least 1 dose of lemborexant and had at least 1 post dose 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.
On-Treatment Full Analysis Set (FAS):  On-Treatment FAS is the group of subjects who 
received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy 
measurement.
6-Month Completer Analysis Set: The 6-Month Completer Analysis Set is the group of 
subjects in the FAS who had all efficacy assessments up to and including Month 6 (ie, Week 
1 and Months 1 to 6 visits) without missing primary or key secondary efficacy assessments at 
any of these visits.
PK Analysis Set: The PK Analysis Set is the group of subjects who have at least 
1 quantifiable lemborexant plasma concentration or its metabolites, with adequately 
documented dosing history.
PK/PD Analysis Set: The PK/PD Analysis Set is the group of subjects receiving either 
lemborexant or PBO who have efficacy or safety data with documented dosing history.  In 
addition, subjects receiving lemborexant should have at least 1 quantifiable lemborexant 
concentration data point as per the PK Analysis Set.
Per Protocol Analysis Set (PP): The PP is the group of subjects who sufficiently complied 
with the protocol. This analysis set will include all subjects in the Full Analysis Set who 
sufficiently complied with the protocol during Period 1. The criteria for exclusion in this 
analysis set are listed below:
•
Violated inclusion/exclusion criteria
•
Duplicate randomization
•
Missing primary efficacy assessment
•
Prohibited concomitant medication
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•
Study drug not administered
•
Incorrect study drug kit dispensed
•
Non compliance of study medication 
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
The number of subjects screened, the number and percentage of screen failures, and their 
primary reason for screen failure will be summarized. 
Subject disposition will be summarized by treatment groups for all randomized subjects. The 
number and percentage of subjects who completed or prematurely terminated from the 
treatment phase and from the study will be summarized separately by their primary reason 
for termination for each treatment group.  
In addition, the number and percentage of randomized subjects who continued into Period 1 
and Period 2 will be summarized by treatment group. The number and percentage of 
randomized subjects will be summarized by region, country, and sites for each treatment 
group.  The number and percentage of randomized subjects in each of the study populations 
will also be presented.
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 randomized study drug and dosage
•
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, Safety Analysis Set and On-
Treatment Safety Analysis Set will be summarized for each treatment group using descriptive 
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statistics.  Continuous demographic and baseline variables include age, height, weight, and 
BMI; categorical variables include sex, age group (< 65, 65 to < 75, ≥75), BMI group (<18.5, 
18.5 to <25, 25 to 30, >30), region (North America, Europe and New Zealand, Asia), race,
and ethnicity.  
The selected baseline assessments of Sleep Diary variables including sSOL, sWASO, sSE, 
sTST, sTIB, number of awakenings, quality of sleep, morning sleepiness; ISI total score and 
its individual question score; FSS will be summarized by treatment group. The BDI-II and 
BAI scores measured at screening will also be summarized.
3.2.4.1
Medical History
All medical histories as documented by the Medical History and Current Medical Conditions 
eCRF 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.  A 
subject data listing of medical history and current medical conditions will be provided.
3.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD; Mar 2017 or latest 
version). If the Safety Analysis Set and FAS differ, then the prior and concomitant 
medication summaries will be repeated on the FAS. 
Prior medications are defined as medications that stopped before the first dose of study drug, 
where study drug includes placebo during the Run-In Period.
Concomitant medications are defined as medications that (1) started before the first dose of 
study drug (including placebo 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 
placebo Run-In Period) to the last dose day plus 14 days. 
For the Run-In Period, a concomitant medication is defined as a medication that started on or 
before the 1st dose of study medication of the Run-In Period and continued during the Run-
In Period, or started during the Run-In Period. For Period 1, a concomitant medication is 
defined as a medication that started on or before the 1st dose of study medication of Period 1 
and continued during Period 1, or started during Period 1. For Period 2, a concomitant 
medication is defined as a medication that started on or before the 1st dose of study 
medication in Period 2 and continued during Period 2, or started during Period 2.
The number (percentage) of subjects who take prior and concomitant medications will be 
summarized on the Safety Analysis Set by treatment group, Anatomical Therapeutic 
Chemical class (ATC) and World Health Organization Drug Dictionary-preferred term (PT). 
If the Safety Analysis Set and FAS differ, then the prior and concomitant medication 
summaries will be repeated on the FAS.
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If the subject has taken the same concomitant medication (as coded to preferred WHO-drug 
term) more than once, the subject will be counted only once in the tabulation.
Separate summaries of concomitant medications will be provided for Run-in Period (using 
Safety Analysis Set), Period 1 (using Safety Analysis Set), Period 2 (using On-Treatment 
Safety Analysis Set) and Period 1 plus Period 2 (using On-Treatment Safety Analysis Set).
3.2.6
Treatment Compliance
Treatment compliance (in %) for each study drug will be calculated on the basis of number of 
tablets dispensed, lost and returned, separately for each type of tablet, for all randomized 
subjects 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 will be summarized using descriptive summary statistics and number 
(percentage) of subjects using the categories <80%, ≥80% to ≤100%, >100% to ≤120%, and 
> 120% for each treatment group. Separate summaries will be provided for Run-in Period 
(using Safety Analysis Set), Treatment Period 1 (using Safety Analysis Set), and Treatment 
Period 2 (using On-Treatment Safety Analysis Set).
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 120 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, Europe and New Zealand, Asia) will be examined as 
specified in the respective sections in this document.
3.3.2
Adjustments for Covariates
Baseline assessment, region, and age groups 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 primary endpoint and secondary 
endpoint comparisons to control for the overall type 1 error at the 0.05 significance level.  
The first endpoint comparison will be tested at the 0.05 significance level.  If the testing is 
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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 Study Baseline at Month 6 in sSOL, LEM10 compared to PBO 
•Change from Study Baseline at Month 6 in sSOL, 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:
•Change from Study Baseline at Month 6 in sSE, LEM10 compared to PBO 
•Change from Study Baseline at Month 6 in sSE, LEM5 compared to PBO 
•Change from Study Baseline at Month 6 in sWASO, LEM10 compared to PBO
•Change from Study Baseline at Month 6 in sWASO, LEM5 compared to PBO
No multiplicity testing will be performed for other secondary or exploratory endpoints.
3.3.4
Examination of Subgroups
Subgroup analysis of primary and key-secondary efficacy endpoints will be performed using 
age group (< 65, 65 to < 75, ≥75), sex (male and female), race (white, black, Asian, and 
other), region, and BMI group (< 18.5, ≥18.5 to <25, ≥25 to 30, and >30) as detailed in
Section 3.4 and Section 3.6.  
3.3.5
Handling of Missing Data, Dropouts, and Outliers
This study collected sleep diary data directly from subjects via a vendor-provided hand-held 
device; it is possible that some values entered by subjects may have resulted from input 
errors. For example, it is not possible for a total waketime to be longer than the time the 
subject spends in bed for the night.  In such cases, erroneous data will be considered as 
missing values in data analyses. Efficacy data handling will be mentioned in the Section 6.1.
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 
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:
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Table 3
Multiple Imputation Methods
MI Methods
Assumption
Analysis Type
Complete Case 
Missing Value 
(CCMV)
Subjects with missing data at any day 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-7
CCMV(k=7)
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.
Timepoints 
where results 
are available
Wk1
M1
M2
M3
M4
M5
M6
Pattern 1
x
x
x
x
x
x
x
Pattern 2
x
x
x
x
x
x
.
Pattern 3
x
x
x
x
x
.
.
Pattern 4
x
x
x
x
.
.
.
Pattern 5
x
x
x
.
.
.
.
Pattern 6
x
x
.
.
.
.
.
Pattern 7
x
.
.
.
.
.
.
Wk1=week1; M1=month1; M2=month2; M3=month3; M4=month4; 
M5=month5; M6=month6; x=observed data; .=missing data
Sensitivity
Tipping Point
Imputation towards the null hypotheses: A range of shifts 
starting from the primary analysis (CCMV) 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
Imputation towards the null hypotheses: A range of shifts will be 
used in the multiple imputation of missing data assuming MAR
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.
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3.3.6
Other Considerations
The following estimands are evaluated for the primary efficacy endpoint (change from 
baseline in mean sSOL on Month 6) 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.
Table 4
Estimands
Estimand
Description
Population
Intervention Effect of Interest
Analysis 
Type
Difference in outcome 
improvement for all 
randomized subjects
- all randomized subjects 
regardless of the 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 
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-7
missing value pattern (all available up to 7
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 7 monotone 
missing patterns will be used in the 
imputation – see Section 3.4.1.3for 
details.  Thus this method relaxes the 
assumption of the primary analysis of 
using only completers to impute the 
missing data.
Sensitivity 
(CCMV-7)
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 starting from the primary 
analysis (CCMV) 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 the treatment 
subjects actually received 
- include data after dropout
FAS
missing values imputed using MMRM 
model 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.))
Supplement
ary
(MMRM 
analysis 
assuming 
MAR)
Difference in outcome 
improvement for all 
randomized subjects
- all randomized subjects 
regardless of the treatment 
subjects actually received 
6-Months 
Completer 
Analysis Set
subjects who completed all primary and 
secondary efficacy assessments without 
missing visits 
Supplement
ary
(completer 
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Estimand
Description
Population
Intervention Effect of Interest
Analysis 
Type
- subjects who complete the 
study without missing efficacy 
assessments
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.)
Supplement
ary (PP 
analysis)
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; 
3.4
Efficacy Analyses
Efficacy analyses for Treatment Period 1 will be performed on the FAS unless otherwise 
specified. Different baseline values will be used for endpoints defined during Treatment 
Period 1 (ie, Day 1 to Month 6) and during Treatment Period 2 (ie Month 7 to Month 12).  
Baseline values for each efficacy parameter are specified in Section 6.1.1.  The On-
Treatment FAS will be used for the on treatment summaries produced by time on treatment.
Unless specified otherwise, all efficacy endpoints will be derived by calculating the average 
of weekly (7 days) diary parameter values (Section 6.1).
12-month LEM exposure data will be summarized by treatment (LEM5, LEM10) and 
duration of exposure (1 month [30 days], 3 months [90 days], 6 months [180 days], 9 months 
[270 days] and 12 months [365 days]). Treatment groups are LEM5 and LEM10, and include 
both (a) LEM Period 1 subjects on the On-Treatment Full Analysis Set using the change 
from Study Baseline and (b) LEM Period 2 subjects previously receiving PBO on the On-
Treatment Full Analysis Set using the change from Period 2 Baseline. No hypothesis test will 
be performed for efficacy endpoints beyond the Month 6 visit. 
The primary and key secondary endpoints comparisons are tested following the gate-keeping 
testing procedure described in Section 3.3.3 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 testings will only proceed if the previous test is 
statistically significant at the 0.05 level.
3.4.1
Primary Efficacy Analyses
The primary efficacy endpoint is the change from Study Baseline of sSOL at Month 6 of 
LEM10 and LEM5 compared to PBO.
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Null Hypothesis: No difference exists in the mean change from Study Baseline to Month 6 of 
treatment with LEM10 (or LEM5) as compared with PBO.
Alternative Hypothesis: For sSOL, a difference exists in the mean change from Study 
Baseline to Month 6 for LEM10 (or LEM5) as compared with PBO. 
The sSOL change from Study Baseline to Month 6 will be analyzed using the mixed effect
model repeated measurement (MMRM) analysis on the FAS.  The model will be adjusted for 
the corresponding Study Baseline value, region (North America, Europe and New Zealand, 
Asia), age group (<65 years old, ≥65 years old), treatment, time (1st 7 nights, Month 1, 
Month 2, Month 3, Month 4, Month 5 and Month 6) and the interaction of treatment by time.  
Since the sSOL 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 toeplitz covariance matrix (TOEP) will be used.  In the case of non-
convergence with TOEP, the autoregressive covariance matrix [AR (1)] will be used in the 
model.
Before the implementation of the MMRM model, the missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are 
missing not at random (MNAR) utilizing the complete case missing value pattern (CCMV -
subjects who completed all 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.
3.4.1.1
Multiple Imputation
Step 1 (imputing missing data): Thirty multiple imputed complete datasets were to be 
constructed using imputation regression model of baseline sSOL, baseline ISI, age, sex, race
(white, black, and other), and region (North America, Europe and New Zealand, Asia), 
baseline BMI. baseline log(sSOL), baseline ISI with a predefined arbitrary seed number 
(seed=2006).  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 (<65 years old, ≥65 years old), region (North America, Europe and New Zealand, 
Asia), treatment, visit (1st 7 nights, Month 1, Month 2, Month 3, Month 4, month 5 and 
Month 6), and treatment-by-visit interaction as fixed effect, and the baseline log(sSOL) 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.
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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 endpoints described in Section 3.4.1 will be summarized using descriptive 
statistics by each subgroup listed below.  No hypothesis testing will be performed in the 
subgroup analyses.
•
Age group 1 (< 65, 65 to < 75, ≥75 years old)
•
Age group 2 (<65, ≥65 years old)
•
Sex (male and female)
•
Race (white, black, Asian and other)
•
Region (North America, Europe and New Zealand, Asia)
•
BMI group (kg/m2) (<18.5, 18.5 to <25, ≥25 to 30, >30 kg/m2)
3.4.1.3
Sensitivity Analyses
The following analyses will be considered as sensitivity analyses:
•
MI Imputation assuming MNAR utilizing CCMV-7: The same MMRM method used in 
the primary analysis will be applied utilizing CCMV-7 (ie, up to 7 monotone missing 
patterns will be used for missing value imputation as follows):
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Table 5
Monotone Missing Patterns for Primary Efficacy Analysis
Timepoints where results are 
available
Wk1
M1
M2
M3
M4
M5
M6
Pattern 1
x
x
x
x
x
x
x
Pattern 2
x
x
x
x
x
x
.
Pattern 3
x
x
x
x
x
.
.
Pattern 4
x
x
x
x
.
.
.
Pattern 5
x
x
x
.
.
.
.
Pattern 6
x
x
.
.
.
.
.
Pattern 7
x
.
.
.
.
.
.
Wk1=week1; M1=month1; M2=month2; M3=month3; M4=month4; M5=month5; M6=month6; 
x=observed data; .=missing data
Tipping point analysis: A range of shifts starting from the primary analysis (CCMV) 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.
The same primary efficacy analyses described in Section 3.4.1 (MMRM analysis with 
MI for missing value imputation) will be repeated based on non-Log transformed data.
A MI Imputation assuming MNAR utilizing CCMV-7: The same MMRM method used 
in the primary analysis will be applied utilizing CCMV-7 based on non-Log transformed 
data.
Tipping point analysis based on non-Log transformed data: A range of shifts starting 
from the primary analysis (CCMV) 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.
3.4.1.4
Supplementary Analyses
The following analyses will be considered as supplementary analyses:
•
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 6-Months 
Completer Analysis Set. 
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•
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).
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) based on non-Log 
transformed data.
3.4.2
Secondary Efficacy Analyses
3.4.2.1
Key Secondary Efficacy Analyses
The change from Study Baseline of key secondary endpoints sSE and sWASO at Month 6 
comparing LEM10/LEM5 to PBO will be analyzed as follows.  
CHANGE FROM STUDY BASELINE OF SSE AT MONTH 6
The change from Study Baseline of sSE at Month 6 will be analyzed using the mixed effect
model repeated measurement (MMRM) analysis on the FAS.  The model will be adjusted for 
the corresponding Study Baseline value, region (North America, Europe and New Zealand, 
Asia), age group (<65 years old, ≥65 years old), treatment, time (1st 7 nights, Month 1, 
Month 2, Month 3, Month 4, Month 5 and Month 6) and the interaction of treatment by time.  
The unstructured covariance matrix (UN) will be used in the analysis.  In the case of non-
convergence of UN, the toeplitz covariance matrix (TOEP) will be used.  In the case of non-
convergence with TOEP, the autoregressive covariance matrix [AR(1)] will be used in the 
model.  
Before the implementation of the MMRM model, the missing values will be imputed using a
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are 
missing not at random (MNAR).  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.
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 (North America, Europe and New Zealand, Asia), baseline BMI, baseline mean sSE, 
baseline ISI, and mean sSE at first 7 nights, mean sSE at Month 1, mean sSE at Month 2,
mean sSE at Month 3, mean sSE at Month 4, mean sSE at Month 5 and mean sSE at Month 
6.  50 multiple imputed datasets will be used for sSE, where data are truncated to 0 (where 
imputations <0) and 100 (where imputations >100).
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CHANGE FROM STUDY BASELINE OF SWASO ON MONTH 6
The change from Study Baseline of sWASO on Month 6 will be analyzed using the mixed 
effect model repeated measurement (MMRM) analysis on the FAS.  The model will be 
adjusted for the corresponding Study Baseline value, region (North America, Europe and 
New Zealand, Asia), age group (<65 years old, ≥65 years old), treatment, time (1st 7 nights, 
Month 1, Month 2, Month 3, Month 4, Month 5 and Month 6) and the interaction of 
treatment by time.  The unstructured covariance matrix (UN) will be used in the analysis.  In 
the case of non-convergence of UN, the toeplitz covariance matrix (TOEP) will be used.  In 
the case of non-convergence with TOEP, the autoregressive covariance matrix [AR(1)] will 
be used in the model.  
Before the implementation of the MMRM model, the missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are 
missing not at random (MNAR).  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.
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 (North America, Europe and New Zealand, Asia), baseline BMI, baseline mean 
sWASO, baseline ISI, and mean sWASO at first 7 nights, mean sWASO at Month 1, mean 
sWASO at Month 2, mean sWASO at Month 3, mean sWASO at Month 4, mean sWASO at 
Month 5 and mean sWASO at Month 6.  
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3.4.2.2
Sensitivity Analyses for Key Secondary Efficacy Analyses
The following analyses will be considered as sensitivity analyses:
•
MI Imputation utilizing CCMV-7: The same MMRM method used in the primary 
analysis will be applied utilizing CCMV-7 (ie, up to 7 monotone missing patterns will 
be used for missing value imputation as follows):
Table 6
Monotone Missing Patterns for Secondary Efficacy Analysis
Timepoints where results are 
available
Wk1
M1
M2
M3
M4
M5
M6
Pattern 1
x
x
x
x
x
x
x
Pattern 2
x
x
x
x
x
x
.
Pattern 3
x
x
x
x
x
.
.
Pattern 4
x
x
x
x
.
.
.
Pattern 5
x
x
x
.
.
.
.
Pattern 6
x
x
.
.
.
.
.
Pattern 7
x
.
.
.
.
.
.
Wk1=week1; M1=month1; M2=month2; M3=month3; M4=month4; M5=month5; M6=month6; 
x=observed data; .=missing data
•
Tipping point analysis: A range of shifts starting from the primary analysis (CCMV)
will be used in the multiple imputation of missing data to identify the specific shift and 
treatment effect that will tip the results from statistically significant to non-significant.
3.4.2.3
Supplementary Analyses for Key Secondary Efficacy Analyses
The following analyses will be considered as supplementary analyses:
•
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 6-Months 
Completer Analysis Set.
•
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).
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3.4.2.4
Other Secondary Efficacy Analyses
For all other secondary endpoints described below, the continuous variable will be 
summarized by using descriptive statistics by time point and the categorical variable will be 
summarized as the number and percentage of subjects by time point.
Unless is covered from the same model from the primary and secondary efficacy endpoints, 
or specified otherwise, 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 region and age group.  Missing 
values will be considered as non-responders in all responder analyses.  No multiplicity 
adjustment will be made for all analyses.
The following endpoints will be analyzed.
EFFICACY MEASURES DERIVED FROM THE SLEEP DIARY
•
Change from Study Baseline of mean sSOL, mean sSE, mean sWASO and mean sTST 
for the 1st 7 nights, Months 1, 2, 3, 4 and 5; and mean sTST at Month 6; for LEM5 and 
LEM10 compared to PBO
•
Change from Study Baseline/ Treatment Period 2 Baseline of mean sSOL, mean sSE, 
mean sWASO and mean sTST for 1, 3, 6, 9 and 12 months exposure to LEM5 and 
LEM10. . Data from subjects randomized to LEM5 or LEM10 at the start of the study 
will use Study Baseline, data from subjects who were re-randomized to LEM5 or 
LEM10 in Period 2 will use Treatment Period 2 Baseline.  
•
The proportion of responders, separately for sSOL and sWASO, will be analyzed, for 
the first 7 nights, Months 1, 2, 3, 4, 5 and 6 for LEM5 and LEM10 compared to PBO:
-
The sleep onset responder is defined as: sSOL at Study Baseline is >30 minutes and 
mean sSOL at each month (first 7 nights, Months 1, 2, 3, 4, 5, 6) is ≤20 minutes, 
-
The sleep maintenance responder is defined as: sWASO at Study Baseline 
is>60 minutes and mean sWASO at each month (first 7 nights, Months 1, 2, 3, 4, 5, 6)
is ≤60 minutes and shows a reduction of >10 minutes compared to Study Baseline.
The proportion of responders will be analyzed based on the subjects with sSOL > 30 
minutes at the baseline for sSOL and separately the subjects with sWASO > 60 minutes 
at the baseline for sWASO.
•
The proportion of responders, separately for sSOL and sWASO, at Months 7, 8, 9, 10, 
11 and 12 will also be summarized by using two types of baseline (ie., Study Baseline, 
Period 2 Baseline).  The definition of the responder at Month 7, 8, 9, 10, 11 and 12 will 
be as follows:
-
The sleep onset responder is defined as: sSOL at Study Baseline (or Period 2 
Baseline) is >30 minutes and mean sSOL at each month (Months 7, 8, 9, 10, 11 and
12) is ≤20 minutes, 
-
The sleep maintenance responder is defined as: sWASO at Study Baseline (or Period 
2 Baseline) is >60 minutes and mean sWASO at each month (Months 7, 8, 9, 10, 11 
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and 12) is ≤60 minutes and shows a reduction of >10 minutes compared to Study 
Baseline (or Period 2 Baseline).
The proportion of responders will be analyzed based on the subjects with sSOL > 30 
minutes at the baseline for sSOL and separately the subjects with sWASO > 60 minutes 
at the baseline for sWASO.
•
Morning sleepiness item of the Sleep Diary:
-
Change from Study Baseline of mean rating on morning sleepiness at the 1st 
7 mornings after the 1st dose in Treatment Period 1, Month 1, Month 2, Month 3,
Month 4, Month 5 and Month 6.
-
Change of mean rating on morning sleepiness from Study Baseline / Treatment 
Period 2 Baseline for 1st 7 mornings after the 1st LEM dose, 1, 3, 6, 9 and 12 months
of exposure to LEM5 and LEM10. Data from subjects randomized to LEM5 or 
LEM10 at the start of the study will use Study Baseline, data from subjects who were 
re-randomized to LEM5 or LEM10 in Period 2 will use Treatment Period 2 Baseline.  
Change from Screening of mean rating on morning sleepiness of 1st 7 mornings and 
2nd 7 mornings in Follow-Up Period.
•
Rebound insomnia endpoints during the Follow-up Period as follows:
-
Change from Screening of sSOL on each of the 1st 3 nights, mean sSOL of the 1st 3
nights, mean sSOL of the 1st 7 nights, and mean sSOL of the 2nd 7 nights of the 
Follow-up Period
-
Change from Screening of sWASO on each of the 1st 3 nights, mean sWASO of the 
1st 3 nights, mean sWASO of the 1st 7 nights and mean sWASO of the 2nd 7 nights 
of the Follow-up Period
-
Proportion of subjects whose sSOL is longer than at Screening by at least 5 minutes 
for each of the 1st 3 nights, mean sSOL of the 1st 3 nights, mean of the 1st 7 nights, 
and mean of the 2nd 7 nights of the Follow-up Period
-
Proportion of subjects whose sWASO is higher than at Screening by at least 5 
minutes for each of the 1st 3 nights, mean sWASO of the 1st 3 nights, mean of the 1st 
7 nights, and mean of the 2nd 7 nights of the Follow-up Period.
The actual value of sSOL and sWASO will be analyzed separately using analysis of 
covariance model (ANCOVA) with factors of age group (<65, and ≥65 years older), 
region (North America, Europe and New Zealand, Asia), and treatment for each time 
point (baseline, each of the first 3 nights, mean of the first 3 nights, mean of the first 7 
nights, and mean of the last 7 nights of the Follow-up Period).  The 95% CI of the 
treatment difference will be constructed for each time point.  It will be considered as 
strong evidence of rebound insomnia if the lower bound of the 95% CI of sSOL or 
sWASO for each of the 3 nights, the mean of the first 3 nights, mean of the first 7 nights, 
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.  In this analysis, the treatment 
groups will be defined as the last randomized study treatment just before the Follow-up 
period.
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• Analyses for persistence versus loss of effect will be conducted for sSOL, sSE, sWASO 
and sTST at Months 2 through Month 12 compared to Month 1.  
The 95% CI for the change from Study Baseline of sSOL, sSE, sWASO and sTST at 
each visit will be calculated using the MMRM model assuming MAR (no missing 
value imputation) with factors of age group (<65, and ≥65 years older), region (North 
America, Europe and New Zealand, Asia), treatment, visit and treatment-by-visit 
interaction as fixed effect, and baseline value as covariate based on FAS.  At each 
month beyond Month 1, the change from Study Baseline will be compared to either the 
lower bound of the 95% CI (for sSE and sTST) or the upper bound of the 95% CI (for 
sSOL and sWASO) at Month 1.  Persistence of effect will be defined as present if the 
mean change from Study Baseline at Month 6 is above the lower bound of the 95% CI 
at Month 1 for sSE or sTST and below the upper bound of the 95% CI at Month 1 for 
sSOL and sWASO.
The same analyses for persistence versus loss of effect over Period 2 will compare 
sSOL, sSE, sWASO, and sTST at Months 7 through 12 to these measures at Month 7 
for only the subjects who were randomized to PBO in Period 1 and who continued into 
Period 2. At each month beyond Month 7, the change from Treatment Period 2 
Baseline will be compared to either the lower bound of the 95% CI (for sSE and sTST) 
or the upper bound of the 95% CI (for sSOL and sWASO) at Month 7.  Persistence of 
effect will be defined as present if the mean change from Treatment Period 2 Baseline 
at Month 12 is above the lower bound of the 95% CI at Month 7 for sSE or sTST and 
below the upper bound of the 95% CI at Month 7 for sSOL and sWASO.
Analyses for persistence versus loss of effect over duration of exposure will be 
conducted for On-Treatment Full Analysis Set subjects.  These analyses will compare 1 
month of duration of exposure of sSOL, sSE, sWASO and sTST at 3 and 6 months 
duration of exposure, for a) LEM Period 1 subjects using the change from Study 
Baseline and (b) LEM Period 2 subjects previously receiving PBO using the change 
from Period 2 Baseline.  At 3 and 6 months duration of exposure, the change from 
Study Baseline/Treatment Period 2 Baseline will be compared to either the lower 
bound of the 95% CI (for sSE and sTST) or the upper bound of the 95% CI (for sSOL 
and sWASO) at 1 month duration of exposure.  Persistence of effect will be defined as 
present if the mean change from Study Baseline/Treatment Period 2 Baseline at 6
months of exposure is above the lower bound of the 95% CI at 1 month of exposure for 
sSE or sTST and below the upper bound of the 95% CI at 1 month of exposure for 
sSOL and sWASO.
INSOMNIA SEVERITY INDEX AND FATIGUE SEVERITY SCALE
The following endpoints will be analyzed for the ISI and FSS:
•
Change from Study Baseline of the total score from items 1-7, and items 4-7, separately,
on the ISI at Months 1, 3, 6 of LEM5 and LEM10 compared to PBO.  
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•
Change from Study Baseline and Treatment Period 2 Baseline (as appropriate) of the 
total score from items 1-7, and items 4-7, separately, on the ISI for subjects with 3, 6, 9 
and 12 months of exposure.
•
Change from Study Baseline on the FSS score at Months 1, 3, 6 of LEM5 and LEM10 
compared to PBO
•
Change from Study Baseline and Treatment Period 2 Baseline (as appropriate) on the 
FSS score for subjects with 3, 6, 9 and 12 months of exposure.
The FSS will be further analyzed to evaluate whether lemborexant treatment affected fatigue 
severity in those who entered the study with clinically significant levels of fatigue.  These 
subgroup analyses will include only those whose total FSS score was ≥18 at Study Baseline, 
which can be considered the lower threshold on the FSS for the presence of clinically 
significant fatigue.  Analyses using the FSS analysis model will then be applied.  In addition, 
S-plot figures will show the proportion of subjects with varying rates of response on the FSS 
as follows: 
•
Cumulative proportion of subjects with varying absolute decreases from Study Baseline 
in total FSS score: the x-axis will show decrease from baseline in 5-unit increments up 
to a ≥40-unit decrease from baseline at Months 1, 3 and 6. Responder rates of -10 
and -30 units will be marked on the S-Plot.
•
Cumulative proportion of subjects with varying relative decreases from Study Baseline 
in total FSS score: the x-axis will show decrease from baseline in 10% increments up to 
a 100% decrease from baseline at Months 1, 3 and 6. Responder rates of -10% 
and -30% will be marked on the S-Plot.
3.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
3.5.1
Pharmacokinetic Analyses
The plasma concentrations of lemborexant and its metabolites M4, M9, and M10 will be 
summarized using descriptive statistics by dose, time and day based on Safety Analysis Set.
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 
(eg, demographics, concomitant medications) on the PK of lemborexant will be evaluated.  
The PK model will be parameterized for oral clearance (CL/F) and volumes of distribution.  
Derived exposure parameters such as AUC and Cmax of lemborexant and any other relevant 
parameters will be calculated from the model using the individual estimates parameterized 
for oral clearance and dosing history. A separate analysis plan for the population PK 
analyses will be developed and finalized before the database lock.
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3.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
The PK/PD relationship between exposure to lemborexant and the efficacy variables 
including but not limited to sSOL, sSE, and sWASO, and the safety variables including but 
not limited to morning sleepiness and frequently occurring 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.
3.6
Safety Analyses
Evaluations of safety will be performed on the relevant Safety Analysis Set and On-
Treatment Safety Analysis Set, as appropriate. All safety analyses will be performed based 
on observed data using tabulation or descriptive statistics only.
No hypothesis testing will be performed for safety analyses
3.6.1
Treatment Definitions
For visit-based Safety data (ie, laboratory values, vital signs, ECGs, etc) data will be 
summarized by treatment (LEM5, LEM10) and duration of exposure to treatment (3, 6, 9 and 
12 months). Treatment groups are LEM5 and LEM10, and include both (a) LEM Period 1 
subjects on the On-Treatment Safety Analysis Set using the change from Study Baseline and 
(b) LEM Period 2 subjects previously receiving PBO on the On-Treatment Safety Analysis 
Set using the change from Period 2 Baseline. Summaries of exposure, AEs, TEMAV, 
clinically abnormal vital sign and ECG values will be summarized for:
•
Period 1 data, where treatment groups are PBO, LEM5 and LEM10 in the Safety 
Analysis Set (ie, subjects who received at least 1 dose of study drug in Treatment Period 
1)
•
12-month LEM exposure, where treatment groups are LEM5 and LEM10 in the On-
Treatment Safety Analysis Set (ie., subjects who received at least 1 dose of 
lemborexant), where data will be summarized by exposure to treatment (3, 6, 9 and 12 
months)
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3.6.2
Extent of Exposure
The extent of exposure (mean daily dose, cumulative dose, duration of exposure) to study 
drug will be summarized descriptively.  Period 1 data with LEM5 or LEM10 will be 
summarized for: the number (percent) of subjects who completed 1 month (30 or more days), 
3 months (90 or more days), and 6 months (180 or more days). 12-month exposure with 
LEM5 or LEM10 will be summarized for: the number (percent) of subjects who completed 3 
months (90 or more days), 6 months (180 or more days), 9 months (270 or more days) and 12 
months (365 or more days) of dosing.
The duration of exposure to study drug is defined as the date of last dose – the date of first 
dose date +1.
The exposure to Run-In Period placebo will be presented in the subject data listings only.  
3.6.3
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.
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 (see below).
A 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 first dose of study drug), having been 
absent before the randomized study medication is started or 
•
Reemerges during active treatment, having been present at pretreatment (before the 
randomized study medication is started) but stopped before treatment, or 
•
Worsens in severity during active treatment (after randomized study medication starts) 
relative to the pretreatment state, when the AE is continuous.
Separately, a TEAE during each Period (ie, Run-In, Treatment Period 1 or Treatment Period 
2) is defined as: 
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1. TEAE during the Run-In:  AE that emerges prior to the date of first dose in Treatment 
Period 1 or the date of last dose in Run-In + 14 days, whichever comes earlier.
2. TEAE during Period 1:  AE that emerges after the date of first dose in Treatment Period 1
but prior to (a) the date of first dose in Period 2 or (b) the date of last dose in Treatment 
Period 1 + 14 days, whichever comes earlier.
3. TEAE during Period 2:  AE that emerges after the date of first dose in Treatment Period 2 
but prior to the date of last dose in Treatment Period 2 + 14 days, whichever comes 
earlier.
Adverse events will be summarized using the Safety Analysis Set and On-Treatment Safety 
Analysis Set by treatment groups.  
The number (percentage) of subjects with TEAEs during the Run-In Period will be 
summarized by SOC and PT.
The following summary tables will be produced for the Period 1 (Safety Analysis Set)and 
On-Treatment (On-Treatment Safety Analysis Set) separately. 
An overview table of TEAEs, 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 will be provided for each treatment group.  
In addition, the following summaries will be produced for the TEAEs by treatment group:
•
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 maximum severity
•
Incidence of treatment-related TEAEs by SOC, PT, and maximum severity
•
Incidence of TEAEs by SOC, PT, and relationship to treatment
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 
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:
•
Incidence of treatment-emergent SAEs by SOC and PT 
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•
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 will also be summarized by MedDRA SOC, 
PT for each treatment group.
3.6.3.1
Selected Adverse Events
The following summary tables will be produced for the Period 1 (Safety Analysis Set)and 12-
month LEM exposure (On-Treatment Safety Analysis Set) separately. 
The following significant AEs will be summarized by SOC and PT:
•
Cataplexy
•
Potential cataplexy
•
Falls
•
Seizures
•
Abuse liability events
Cataplexy includes the TEAEs with MedDRA PT of cataplexy, and drop attack.
Cataplexy and potential cataplexy includes the TEAEs with MedDRA PT listed in Appendix 
2 plus all events that have been flagged by investigator as potential event of cataplexy in the 
eCRF.
Falls includes the TEAEs with MedDRA PT of “fall” only.
Seizure includes TEAEs with MedDRA PTs belonging to MedDRA Standardized Queries 
(SMQ) of “Convulsions” (Narrow Terms).
Abuse liability events include TEAEs with MedDRA PT listed in Appendix 3.
3.6.3.2
Subgroup Analysis of TEAE
Subgroup summaries will be presented for the following summary tables.  These summaries 
will be repeated for the Period 1 (Safety Analysis Set)and 12-month LEM exposure (On-
Treatment Safety Analysis Set) separately.
•
Overview table of TEAEs, including number of subjects with TEAEs, treatment-related 
TEAEs, severe TEAEs, treatment-emergent serious AEs (TESAEs), deaths, TEAEs 
leading to study drug withdrawal 
•
Incidence of TEAEs by SOC and PT
•
Incidence of TESAEs by SOC and PT
The following demographic and baseline information will be used in the subgroup summary:
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•
Age group 1 (<65, 65 to <75, and ≥75 years old)
•
Age group 2 (<65 and ≥65 years old)
•
Sex (male and female)
•
Race (white, black, Asian, and other)
•
Region (North America, Europe and New Zealand, Asia)
•
BMI (<25, 25 to 30, >30 kg/m2)
Percentages will be based on the total number of subjects in the relevant treatment group. A 
subject with 2 or more TEAEs with the same PT (or SOC) will be counted only once for that 
PT (or SOC).
3.6.4
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 
9.5.1.5.3 Laboratory Measurements, the actual value and the change from Study Baseline 
will be summarized at each scheduled visit using descriptive statistics by treatment group.  
The change from Study Baseline/Treatment Period 2 Baseline (as appropriate) will also be 
repeated for the 12-month LEM exposure (On-Treatment Safety Analysis Set), summarized 
by treatment group and duration of exposure.
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 Study Baseline (LNH) to each scheduled visit will be provided 
by treatment group for each laboratory parameter based on Safety Analysis Set.  The shift 
tables will also be repeated for the 12-month LEM exposure (On-Treatment Safety Analysis 
Set), summarized by treatment group and duration of exposure.
The Sponsor’s Grading for Laboratory Values (Appendix 1) presents the Eisai criteria that 
will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (TEMAV).  Except for phosphate, a TEMAV is determined if a postbaseline grade
increases from baseline and the postbaseline grade is greater than or equal to a grade of 2.  
For phosphate, a TEMAV was defined as a postbaseline value with an increase from baseline 
to a grade of 3 or higher.
The number (percentage) of subjects with TEMAVs will be summarized by treatment group 
using the Safety Analysis Set.  The number (percentage) of subjects with TEMAVs will be 
produced separately for the Period 1, up to 12-months treatment, up to 6-months treatment 
and On-Treatment. When displaying the incidence of TEMAVs, each subject will be counted 
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once in the laboratory parameter high and in the laboratory parameter low categories, as 
applicable.
3.6.4.1
Subgroup Analysis of Laboratory Values
Subgroup summaries will be presented for the following summary tables.  These summaries 
will be repeated for the Period 1 (Safety Analysis Set) and 12-month LEM exposure (On-
Treatment Safety Analysis Set) separately.
•
Mean and mean change from baseline by visit for selected parameters in Table 7
•
TEMAVs
Table 7
Selected Laboratory Parameters for Subgroup Analysis
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, red blood cell count, and 
white blood cell count 
Chemistry – Liver Function Tests
alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, 
gamma 
glutamyl 
transpeptidase, 
direct 
bilirubin, total bilirubin
Chemistry – Renal Function Tests
blood urea/blood urea nitrogen, creatinine
The following demographic and baseline information will be used in the subgroup summary:
•
Age group 1 (<65, 65 to <75, and ≥75 years old)
•
Age group 2 (<65 and ≥65 years old) 
•
Sex (male and female)
•
Race (white, black, Asian, and other)
•
Region (North America, Europe and New Zealand, Asia)
•
BMI (<25, 25 to 30, >30 kg/m2)
3.6.5
Vital Signs
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiration rate, temperature) and weight, and changes from Study Baseline and Period 2 
Baseline will be presented by visit and treatment group.  Analysis of changes from baseline 
will be based on the number of subjects with both nonmissing baseline and relevant 
postbaseline results.
Clinically notable vital sign values will be identified on the listings as those above (H) or 
below (L) a clinically notable range, as per Table 8.  The clinically notable vital sign values 
will be presented for change from Study Baseline (Safety Analysis Set) by treatment group 
and by time point. This will also be repeated for the 12-month LEM exposure (On-Treatment 
Safety Analysis Set), summarized by treatment group and duration of exposure.
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Table 8
Vital Sign Criteria
Variable
Criterion Valuea
Change Relative to 
Study Baseline/Period 2 
Baselinea
Clinically Notable 
Range
Pulse 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
>30 bpm
Increase of >=10 bpm
H
<8 bpm
Decrease of >=4 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 Study Baseline or Period 2 Baseline, as appropriate.
3.6.6
Electrocardiograms
Descriptive statistics for ECG parameters and changes from Study Baseline (Safety Analysis 
Set) will be presented by treatment group.  This will also be repeated for the 12-month LEM 
exposure (On-Treatment Safety Analysis Set), summarized by treatment group and duration 
of exposure. Shift tables will present changes from Study Baseline in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant) by time point.
In addition, maximum postbaseline measurement will also be tabulated separately for the 
Period 1 and 12-month LEM exposure 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
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3.6.7
Other Safety Analyses
3.6.7.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality is 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 occurrence of suicidal ideation or suicidal behavior at each visit will 
be summarized by treatment group using frequency count.  A subject will be counted once 
for each of these categories if at least one question is answered positive belonging to the 
category.
In addition, self-injurious non-suicidal behavior will also be summarized separately for 
occurrence in a similar fashion to suicidal ideation and behavior.
3.6.7.2
Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (T-BWSQ)
Withdrawal symptoms are assessed using the T-BWSQ at the End of Study (EOS) visit.  
Subjects are 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.  Since this 
questionnaire is completed at the EOS visit only, this analysis will be performed at the EOS 
visit based on Safety Analysis set. The same analysis will be repeated for the subgroup based 
on the duration of exposure.
3.7
Other Analyses
3.7.1
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 
state”).  
Each dimension score will be summarized separately at Study Baseline and each postbaseline 
timepoint (Month 1, Month 3 and Month 6) using frequency count on observed data only 
with no imputation.  The change from Study Baseline of EQ VAS will be summarized by 
treatment group for Month 1, Month 3, and Month 6.  The change from Study Baseline of 
EQ VAS will be analyzed using MMRM assuming MAR for Month 1, Month 3 and Month 6 
on observed data only based on FAS with no imputation for missing values.
The each dimension and EQ-VAS change from Study Baseline/Treatment Period 2 Baseline 
(as appropriate) will be summarized for the 12-month LEM exposure (On-Treatment Safety 
Analysis Set), summarized by treatment group and duration of exposure .
The time point window presented in Section 6.2.3 will be used to determine the analysis visit.
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3.7.2
Patient Global Impression (PGI) - Insomnia
The PGI-Insomnia questionnaire captures the global impression of the study medication’s 
effect at each postbaseline time point.  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 summarized separately as number and percentage of subjects for each time 
point (Month 1, Month 3 and Month 6).  Furthermore, each item will be analyzed using chi-
square test for Month 1, Month 3 and Month 6 on observed data only based on FAS with no 
imputation for missing values, and repeated for age subgroups. For this analysis, each item 
will be categorized as follows: “positive medication effect” versus others for the first 3 item; 
“just right” versus others for the last item). This will also be repeated for the 12-month LEM 
exposure (On-Treatment Safety Analysis Set) will be summarized by treatment group and 
duration of exposure.
The time point window presented in 8.2.3 will be used to determine the analysis visit.
3.7.2.1
WPAI-GH
The WPAI-GH consists of six questions: Q1 = currently employed; Q 2 = hours missed due 
to health problems; Q3 = hours missed other reasons; Q4 = hours actually worked; Q5 = 
degree health affected productivity while working; Q6 = degree health affected productivity 
in regular unpaid activities. 
The four main outcomes derived by the following definition will be summarized by visit. The 
change from Study Baseline for the main outcomes will be summarized by visit. This will 
also be repeated for the 12-month LEM exposure (On-Treatment Safety Analysis Set), 
summarized by treatment group and duration of exposure.
The time point window presented in 8.2.4 will be used to determine the analysis visit.
1. Percent work time missed due to health: Q2 / (Q2+Q4) * 100
2. Percent impairment while working due to health: Q5 / 10 * 100
3. Percent overall work impairment due to health: [{Q2 / (Q2+Q4)} + {1- (Q2 / (Q2+Q4))} 
*(Q5/10)] *100 
4. Percent activity impairment due to health: Q6 /10 *100
The above 1 to 3 will be obtained from the subjects who were employed (ie., Q1 =’Y’).
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3.8
Exploratory and Pharmacodynamic Analyses
The change from Study Baseline for the mean score of the quality of sleep item on the Sleep 
Diary will be analyzed using MMRM assuming MAR (no missing value imputation) for the 
mean of the 1st 7 days of Period 1 and at Months 1, through 6. 
Furthermore, the mean score of the quality of sleep item change from Study 
Baseline/Treatment Period 2 Baseline (as appropriate) for the 12-month LEM exposure (On-
Treatment Safety Analysis Set), summarized by treatment group and duration of exposure.
4
INTERIM ANALYSES
4.1
DSMB (Data Safety Monitoring Board)
The DSMB will serve as an independent safety monitoring committee and will perform the 
safety data reviews.  The interim safety analyses will be conducted by an independent 
statistician, who is working on behalf of Eisai from a CRO that is independent of study 
conduct.
To maintain the credibility and integrity of the trial, procedures will be 
implemented to ensure the DSMB and the independent statistician have sole access to the 
unblinded interim safety data. 
Full details of the DSMB operation procedures are 
documented in the DSMB charter. The sponsor will be kept blinded until the unblinding of 
Period 1. No decision to stop the study based on superior efficacy or futility of lemborexant
to placebo is planned. Data will be cleaned as required prior to the scheduled DSMB data 
reviews.
4.2
Interim Analysis
No formal interim analysis is planned for this study.
5
CHANGES IN THE PLANNED ANALYSES
The following major changes to the statistical methods in this analysis plan were made after
Amendment 03 of the Protocol was approved.
•
Additional time points (ie., Months 2, 4, 5) have been included in MMRM as covariates
for the primary and key secondary analysis.
•
An additional safety analysis set (ie., On-Treatment Safety Analysis Set) has been 
defined and the safety analysis based on the On-Treatment Safety Analysis Set has been 
added.
The full changes to the statistical methods in this analysis plan were made in version 2.0 of 
the SAP from version 1.0 are detailed in Table 1 at the beginning of the SAP.
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6
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
6.1
Efficacy Data Handling
6.1.1
Baseline Efficacy
For the analyses of PBO-controlled endpoints (ie, Day 1 to Month 6), “Study Baseline” is 
defined as the data captured during the Run-In Period (or during the Baseline Period).  For 
the analyses of data that are not placebo-controlled (ie, Month 7 to Month 12), data from the 
Month 6 visit will be used as the “Period 2 Baseline” for some analyses. 
Unless otherwise specified, the Study Baseline measurement is the last observed 
measurement among all available measurements, including from unscheduled assessments, 
prior to the first dose of randomized study medication for a given assessment.  For the 
following endpoints, baseline measurement is defined as follows: 
•
Sleep diary parameters: the mean of diary data entered on the last 7 mornings before 
Visit 3a during the Run-In Period
•
ISI: Last available ISI measurement on or before Visit 3a (excluding Visit 1)
•
FSS: Last available FSS measurement on or before Visit 3a (excluding Visit 1)
•
EQ-5D-3L: Last available EQ-5D-3L measurement on or before Visit 3a (excluding 
Visit 1)
•
WPAI-GH: Last available WPAI-GH measurement on or before Visit 3a (excluding 
Visit 1)
For each Sleep Diary parameter at baseline, if no more than 2 of the final 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 the 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 fewer than 4
values are available, the parameter will be considered missing for the corresponding time 
point. 
For the analysis using the MMRM assuming MAR (no missing value imputation), the above 
handling will be used to obtain the average of weekly (7 days) diary parameter values.
6.1.2
Derivation of Primary and Key Secondary Endpoints for Sleep Diary
Each Sleep Diary parameter will be derived by calculating the average of weekly (7 days) 
diary parameter values.  
Baseline is the mean of diary data entered on the last 7 mornings during the Run-In Period
before randomization; sleep diary parameter of the first 7 nights is the mean of diary data 
entered on the first 7 mornings following the start of treatment; sleep diary parameter for 
each visit is the mean of diary data entered on the last 7 mornings prior to that visit.
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For the follow-up period, if the first 7 nights overlap with the last 7 nights (eg, the follow-up 
period is less than 14 days in total), the last non-overlap nights will be used in calculating the 
average value for the last 7 nights.
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)
6.1.3
Visit Windowing
For the Sleep Diary, the following visit windowing rule in Table 9 will be applied based on 
measurements from unscheduled visits and early termination visits to attain the measurement 
for analysis for the given scheduled visit.  
Table 9
Windowing Rules for Efficacy Endpoints from Sleep Diary
Visit 
Target Visit Day
(in study days)
Visit Window
(in study days)
First 7 nights 
2
2 - 8
Visit 4 (Month 1)
30
24 - 30
Visit 5 (Month 2)
60
54 – 60
Visit 6 (Month 3)
90
84 - 90
Visit 7 (Month 4)
120
114 - 120
Visit 8 (Month 5)
150
144 - 150
Visit 9 (Month 6)
180
174 - 180 (or last 7 days prior to 
subject entering Period  2, 
whichever is earlier) *
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Table 9
Windowing Rules for Efficacy Endpoints from Sleep Diary
Visit 
Target Visit Day
(in study days)
Visit Window
(in study days)
Visit 10 (Month 7)
210
204 - 210
Visit 11 (Month 8)
240
234 - 240
Visit 12 (Month 9)
270
264 - 270
Visit 13  (Month 10)
300
294 - 300
Visit 14 (Month 11)
330
324 - 330
Visit 15 (Month 12)
364
Last 7 days from study days 358 -
371 (or last dose date + 1 for 
subjects who completed 12 months 
treatment, whichever  is earlier)
*: If subjects discontinued the study and did not enter Treatment Period 2, last 7 days from study days 168 -180 
will be used.
6.2
SAFETY DATA HANDLING
6.2.1
Baseline Safety
The baseline value for all safety endpoints will be the last non-missing measurement
occurring prior to the first dose of the study medication.
For visit-based safety summaries there may be two different baseline value as followed:  
•
Study Baseline: defined as the last non-missing measurement occurring prior to the first 
dose of the study medication in Period 1.
•
Treatment Period 2 Baseline: defined as the last non-missing measurement occurring 
prior to the first dose of the study medication in Period 2.
6.2.2
Handling of Missing Safety data, Drop-outs, and Outliers
For the purpose of summarizing maximum severity, if the severity of an AE is missing for a
subject, then, if this subject has another AE with the same preferred term that has “severe”
severity, the maximum severity of the AE will be noted as “severe’; otherwise the maximum
severity will be noted as missing. Similarly, for the purpose of summarizing TEAE treatment 
relationship, if the relationship of an AE to study drug is missing, the AE will be noted to be
related if there is another related AE with the same preferred term, otherwise this relationship 
will be noted as missing.
For determining treatment-emergent markedly abnormal laboratory values, a missing 
baseline laboratory value will be assumed to be of grade 0.
No special handling of missing data is planned for the analysis of any of the other safety
variables.
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Data exceptions or outliers will be determined by inspection of the tables, listings, and graphs 
in consultation with the clinical study team, if applicable. 
All the listings will display the original missing values.
6.2.3
Visit Windowing
For the laboratory values, ECG, vital signs, weight, eC-SSRS, T-BWSQ, PGI-Insomnia, 
WPAI-GH and EQ-5D-3L, the following visit windowing rule in Table 10 will be applied 
based on measurements from unscheduled visits and early termination visits to attain the 
measurement for analysis for the given scheduled visit. 
Table 10
Windowing Rules for Safety Endpoints
Visit 
Target Visit Day (in study days)
Visit Window (in study days)
Visit 4 (Month 1)
30
2 - 45
Visit 5 (Month 2)
60
46 - 75
Visit 6 (Month 3)
90
76 - 135
Visit 9 (Month 6)
180
136 – Prior to the date of first dose 
of Period 2
If subjects discontinue treatment,  
the visit window will be 136 –  187
Visit 12 (Month 9)
270
The date of first dose in Period 2 -
315
If subjects discontinue treatment,  
the visit window will be 188 –  315
Visit 15 (Month 12)
364
316 - 371
End of Study (EOS)
378
Nominal visit 
(ie., the visit captured in eCRF will 
be used)
In case of multiple assessments within the same visit window, the assessment closest to the 
target visit day will be used in data analyses; in the event of two assessments being equally 
close to the scheduled visit day, the latest assessment in time will be used. 
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:
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CONVERT DATASET INTO MONOTONE MISSING DATA PATTERN (IMPUTING ARBITRARY 
MISSING DATA):
PROC MI data=<dataset> nimpute=30 seed=2006 out=<dataset1>;
   VAR age BMI baseline… visit1-visit8;
   MCMC chain=multiple nbiter=500 niter=300 impute=monotone;
   BY treatment;
RUN;
IMPUTE MISSING VALUES:
PROC MI data=<dataset1> nimpute=1 seed=2006 out=<dataset2>;
   CLASS treatment sex race region;
   MONOTONE regression ( /details);
   MNAR model (visit2-visit8/ 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;
   LSMEANS visit*treatment/DIFF 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
•
sSOL: age, baseline BMI, baseline ISI, baseline log(mean sSOL), log(mean sSOL) at 
first 7 nights, log(mean sSOL) at Month 1, log(mean sSOL) at Month 2, log(mean 
sSOL) at Month 3, log(mean sSOL) at Month 4, log(mean sSOL) at Month 5, log(mean 
sSOL) at Month 6
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•
sSE: age, baseline BMI, baseline ISI, baseline mean sSE, mean sSE at first 7 nights, 
mean sSE at Month 1, mean sSE at Month 2, mean sSE at Month 3, mean sSE at Month 
4, mean sSE at Month 5, mean sSE at Month 6
•
sWASO: age, baseline BMI, baseline ISI, baseline mean sWASO, mean sWASO at first 
7 nights, mean sWASO at Month 1, mean sWASO at Month 2, mean sWASO at Month 
3, mean sWASO at Month 4, mean sWASO at Month 5, mean sWASO at Month 6
•
sTST: age, baseline BMI, baseline ISI, baseline mean sTST, mean sTST at first 7 
nights, mean sTST at Month 1, mean sTST at Month 2, mean sTST at Month 3, mean 
sTST at Month 4, mean sTST at Month 5, mean sTST at Month 6
To Impute Missing Values
•
sSOL: treatment, sex, race, region + variables used to create monotone missing data 
pattern
•
sSE: treatment, sex, race, region + variables used to create monotone missing data 
pattern
•
sWASO: treatment, sex, race, region + variables used to create monotone missing data 
pattern
•
sTST: treatment, sex, race, region + variables used to create monotone missing data 
pattern
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 sSOL (Log sSOL), 
sSE and sWASO using the multiple imputation methodology as described in the section 
above but with the following modifications:
1. Convert the dataset into monotone missing data patterns (30 datasets), as above.
2. Generate the dataset so that there is a missing data indicator for data that has been 
imputed (ie, 1= observed, 0= missing).
3. Perform CCMV imputation. Ensure the missing data indicator is kept in this dataset.
4. Using the CCMV dataset, 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 MNAR/CCMV
assumption when the shift is zero. These shifts are to be applied to Month 6 only. 
5. For each shift apply the PROC MIXED model by _imputation_ and combine results 
using PROC MIANALYZE
6. Store results from PROC MIANALYZE for each shift
7. If the MNAR (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.
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8. 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.
9. The values for <shift> in Step 1 will be applied uniformly (same shift) to both LEM5 and 
LEM10 at Month 6.
10. The values for <shift> will correspond to worsening values for the endpoint according to 
the following:
•
Increasing positive shift values (sSOL, sWASO)
•
Increasing negative shift values (sSE)
11. The following specifies which comparisons are of interest when evaluating p-values for 
this procedure:
LEM5 and LEM10 vs. Placebo (sSOL, sSE, sWASO)
For the MAR sensitivity analysis, the following procedure should be applied:
1. Convert the dataset into monotone missing data patterns (30 datasets), as above.
2. 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 Month 6 only. 
PROC MI data=<dataset1> nimpute=1 seed=2006 out=<dataset2>;
   
CLASS treatment sex race region;
   
MONOTONE regression ( /details);
   
MNAR adjust (visit8/ shift=<shift> adjustobs=(treatment=LEM5));
   
MNAR adjust (visit8/ shift=<shift> adjustobs=(treatment= LEM10));
   
VAR treatment age sex race region BMI baseline…visit8;
   
BY _imputation_;
RUN;
3. 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.
4. 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.
5. The values for <shift> in Step 1 will be applied uniformly (same shift) to both LEM5 and 
LEM10 at Month 6.
6. The values for <shift> will correspond to worsening values for the endpoint according to 
the following:
•
Increasing positive shift values (sSOL, sWASO)
•
Increasing negative shift values (sSE)
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7. The following specifies which comparisons are of interest when evaluating p-values for 
this procedure:
•
LEM5 and LEM10 vs. Placebo (sSOL, sSE, sWASO)
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.  
9
MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
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 Imputations 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
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
List of Potential Cataplexy Events
Code
Preferred Term
10007737
Cataplexy
10009346
Clonus
10050093
Consciousness fluctuating
10012373
Depressed level of consciousness
10013036
Diplopia
10076060
Eyelid myoclonus
10078509
Heteronymous diplopia
10078508
Homonymous diplopia
10021118
Hypotonia
10024855
Loss of consciousness
10049565
Muscle fatigue
10072889
Muscle tone disorder
10028372
Muscular weakness
10028622
Myoclonus
10053854
Opsoclonus myoclonus
10036653
Presyncope
10050496
Reversible ischaemic neurological deficit
10071299
Slow speech
10042772
Syncope
10044380
Transient global amnesia
10044390
Transient ischaemic attack
10013887
Dysarthria
10033799
Paralysis
10009192
Circulatory collapse
10015995
Eyelid ptosis
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Appendix 3
List of Abuse Liability Events
Code
Preferred Term
10063746
Accidental death
10000381
Accidental overdose
10000383
Accidental poisoning
10054196
Affect lability
10074080
Autoscopy
10078602
Behavioral addiction
10067494
Confusional arousal
10012218
Delirium
10012335
Dependence
10077805
Depersonalisation/derealisation disorder
10013142
Disinhibition
10013457
Dissociation
10013462
Dissociative disorder
10013654
Drug abuse
10061111
Drug abuser
10080753
Product administered at inappropriate site
10013663
Drug dependence
10052237
Drug detoxification
10066053
Drug diversion
10061822
Drug intolerance
10052804
Drug tolerance
10052805
Drug tolerance decreased
10052806
Drug tolerance increased
10079381
Drug use disorder
10013752
Drug withdrawal convulsions
10013753
Drug withdrawal headache
10013754
Drug withdrawal syndrome
10014551
Emotional disorder
10049119
Emotional distress
10015535
Euphoric mood
10016322
Feeling abnormal
10016330
Feeling drunk
10017062
Formication
10019063
Hallucination
10019070
Hallucination, auditory
10019071
Hallucination, gustatory
10019072
Hallucination, olfactory
10062824
Hallucination, synaesthetic
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10019074
Hallucination, tactile
10019075
Hallucination, visual
10019079
Hallucinations, mixed
10019133
Hangover
10020927
Hypnagogic hallucination
10020928
Hypnopompic hallucination
10049564
Impaired driving ability
10049976
Impatience
10021567
Impulsive behaviour
10021588
Inappropriate affect
10022523
Intentional overdose
10074903
Intentional product misuse
10076308
Intentional product use issue
10022998
Irritability
10023236
Judgement impaired
10026749
Mania
10048294
Mental status changes
10027940
Mood altered
10027951
Mood swings
10028747
Nasal necrosis
10028765
Nasal septum perforation
10028766
Nasal septum ulceration
10028896
Needle track marks
10061862
Neonatal complications of substance abuse
10033295
Overdose
10079763
Performance enhancing product use
10061355
Poisoning
10067669
Prescription form tampering
10069330
Product tampering
10070592
Product used for unknown indication
10037249
Psychotic behaviour
10061920
Psychotic disorder
10038001
Rebound effect
10040026
Sensory disturbance
10062684
Somatic hallucination
10066169
Substance abuse
10067688
Substance abuser
10076595
Substance dependence
10070964
Substance use
10079384
Substance use disorder
10072387
Substance-induced mood disorder
Eisai
Confidential
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Statistical Analysis Plan
E2006-G000-303
Eisai
Final V2
Confidential
Page 58 of 59
10072388
Substance-induced psychotic disorder
10043431
Thinking abnormal
10070863
Toxicity to various agents
10049414
Treatment noncompliance
10048010
Withdrawal syndrome
MedDRA v21.0
Eisai
Confidential
Page 59 of 190


Statistical Analysis Plan
E2006-G000-303
Eisai
Final V2
Confidential
Page 59 of 59
SIGNATURE PAGE
Authors:
[electronic signature in eDMS]
Neuroscience Business Group, Eisai Ltd
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]
 
Neurology Business Group, Eisai Ltd.
Date
Eisai
Confidential
Page 60 of 190
PPD
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PPD
PPD
PPD
PPD
PPD
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