A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the Treatment of Insomnia
Phase: PHASE3
Conditions: Insomnia
Sponsor: Eisai Inc.

Clinical Study Report 
E2006-A001-312 
 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the study protocol and all previous versions are provided on the following 
pages: 
• V4.0 01 Oct 2019 (Amendment 02) 
• V3.0 03 Jun 2019 (Amendment 01) 
• V2.0 12 Apr 2019 (revised original protocol) 
• V1.0 12 Apr 2019 (original protocol) 
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REVISION HISTORY
  Revisions to Version 3.0 
  New version /date: Version 4.0/01 Oct 2019 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Modified the Inclusionary Criteria
to include subjects who meet both 
criteria for intermittent and 
frequent zolpidem (ZOL) use 
during 1 week each of the last 2 
weeks of the 3-week Screening 
Period under Cohort 1
To facilitate the enrollment by 
including all appropriate subjects 
in cohort 1
Section 2 - Inclusion Criteria
Section 2 – Study Design
Section 9.1
Section 9.1.1.1
Section 9.3.1
Section 9.4.3
Simplified the Exclusion Criterion 
No. 12
For clarification
Section 2 - Exclusion Criteria
Section 9.3.2
Provided description of physical 
examination
To clarify procedures for 
performing full physical 
examinations
Section 9.5.1.2.1
Added a word ‘approximately’ 
before the number of subjects
For clarification
Section 2 – Number of Subjects
Section 2 – Sample Size Rationale
Section 2 – Study Design
Section 9.1
Section 9.1.1.1
Section 9.4.3
Section 9.7.2
Corrected the overall number of 
subjects received lemborexant
(LEM)
For correction
Section 7.1.2.1
Modified footnote “i” in Table 3 
and footnote “e” in Table 5 
To clarify procedures for 
performing a physical 
examination
Table 3 footnote
Table 5 footnote
Deleted the text regarding 
study-specific adverse events and 
added as ‘not applicable'
For consistency with other 
Phase 3 protocols
Section 9.5.1.5.3
Section 9.5.4.3.2
Changed the Study Director and 
Medical Monitor to 
Administrative change
Protocol signature Page
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Revisions to Version 2.0 
  New version /date: Version 3.0/03 Jun 2019 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Addition of actigraphy
To provide objective data on the 
effect of LEM and ZOL on sleep 
and wake parameters
Section 2 – Exploratory Objectives
Section 2 – Study Design
Section 2 – Efficacy Assessments 
(Core Study only)
Section 2 – Statistical Methods
Section 2 – Efficacy Analyses 
(Core Study only)
Section 8.3
Section 9.1.1.1
Section 9.1.1.2
Section 9.1.2.1
Section 9.5.1.3.5
Section 9.7.1.1.3
Section 9.7.1.6.3
Table 3
Reorganization of secondary and 
exploratory objectives and 
endpoints
To focus secondary endpoints on 
successful transition due to 
dose-related aspects of LEM
Section 2 – Secondary Objectives
Section 2 – Exploratory Objectives
Section 8.2
Section 8.3
Section 9.7.1.1.2
Section 9.7.1.1.3
Section 9.7.1.6.2
Section 9.7.1.6.3
Clarification of cohort assignment 
based on ZOL use frequency
Clarification 
Section 2 – Study Design
Section 2 - Inclusion Criteria
Section 2 - Exclusion Criteria
Section 9.1
Section 9.1.1.1
Section 9.1.2.1
Section 9.3.1
Section 9.3.2
Section 9.4.3
Clarification of PK sampling in 
the event of an SAE or severe 
unexpected AE and its resolution
Clarification
Table 3
Table 5
Clarification of data collection at 
Visit 2a
Clarification
Table 3
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  Revisions to Version 1.0 
  New version /date: Version 2.0/12 Apr 2019
Change
Rationale
Affected Protocol Sections
Modified the text in Exclusion 
Criterion No. 1 to replace urine 
pregnancy test with serum 
pregnancy test.
Administrative change
Synopsis –Exclusion criteria
Section 9.3.2
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-A001-312
Study Protocol 
Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition from 
Zolpidem to Lemborexant for the Treatment of Insomnia 
Sponsor: 
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Investigational 
Product Name:
E2006/Lemborexant
Indication:
Insomnia 
Phase:
3b
V1.0
12 Apr 2019 (original protocol)
V2.0
12 Apr 2019 (revised original protocol)
V3.0
03 Jun 2019 (Amendment 01)
V4.0
01 Oct 2019 (Amendment 02)
IND Number:
111871
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential. It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the 
Treatment of Insomnia
Investigator(s)
Unknown
Sites
Approximately 15 sites within the United States of America
Study Period and Phase of Development
Phase 3b pilot study
Estimated duration of up to 38 weeks from first subject in to last subject’s last visit.
Objectives
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects with 
insomnia disorder taking zolpidem tartrate immediate release (ZOL-IR) or zolpidem tartrate extended 
release (ZOL-ER), intermittently or frequently, who  transition to lemborexant 5 mg (LEM5) or 10 
mg (LEM10), after 2 weeks of receiving lemborexant (LEM).
Secondary Objectives  (revised per Amendment 01)

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease from 
LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of Insomnia 
(PGI-I) at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking zolpidem (ZOL)
Exploratory Objectives  (revised per Amendment 01)

To evaluate LEM5 or LEM10 scores on the Insomnia Severity Index (ISI) compared with 
Baseline at the end of the 2-week Titration Period

To evaluate LEM5 or LEM10 scores on the Quality of Sleep Rating scale compared with 
Baseline at the end of the 2-week Titration Period

To compare nights on which an evening dose of LEM5 or LEM10 was taken, to nights on which 
an evening dose of ZOL was taken, for the following sleep-related actigraphy variables:
o
Total Sleep Time (TST)
o
Sleep Efficiency (SE)
o
Wake After Sleep Onset (WASO)
o
Wake Bouts

To compare the daytime after an evening dose of LEM5 or LEM10 was taken, to the daytime
after an evening dose of ZOL was taken, for the following wake-related actigraphy variable:
o
Sleep Bouts
Study Design
E2006-A001-312 is a multicenter Phase 3b pilot study evaluating the transition of LEM when 
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administered as a replacement for ZOL-IR or ZOL-ER. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week Screening 
Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week Titration Period), and 
an Extension Phase consisting of the Maintenance Period up to 12 weeks and the Follow-up Period 
4 weeks in duration immediately following the end of the Treatment Phase.  The Pretreatment and 
Treatment Phases will comprise the Core Study.  A Follow-up Period visit occurring 4 weeks after 
the end of the Extension Phase (or Treatment Phase, for subjects not entering the Extension Phase) 
will be conducted.
Core Study
Pretreatment Phase
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day Baseline Period, 
during which subjects will be assessed for eligibility to participate in the study. 
Screening Period
During the Screening Period, subjects will be required to bring the container of their prescribed ZOL 
to the site for verification of prescribed medication and dose. Subjects will be provided with, and 
trained in the use of, a data collection system to record the frequency of ZOL is taken during the 
3-week Screening Period.  Site staff will instruct subjects to complete data entry every morning and 
will emphasize the importance of providing these data.  During the Screening Period, subjects will 
continue to take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5mg or 
10 mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection system for 
at least 14 (preferably contiguous) days out of the allowable 21-day Screening Period in order to be 
eligible for study inclusion.  Eligible subjects will also be provided with an actigraph (for actigraphy) 
to wear continuously throughout the Screening Period.  Subjects will be provided with a daily log 
(sleep log) to note the start and end times of nocturnal sleep periods and to log the approximate times 
that the actigraph was replaced on the subject’s wrist, if inadvertently removed. Subjects will be 
trained to use the actigraph and the log. Site staff will instruct subjects to record (with the current 
date) the following timings in the log: in the evening, record the times when the actigraph was not 
worn; and in the morning, record the bedtimes and morning rise times.  Site staff will emphasize the 
importance of recording these timings in the log.  (revised per Amendment 01)
Subjects will return to clinic at the end of the Screening Period.  Actigraph data will be downloaded 
and transmitted to the central reader, along with the sleep log of bedtimes, morning wake times, and 
the approximate times when the actigraph was replaced on the subject’s wrist. (revised per 
Amendment 01)
Based on ZOL use during the Screening Period (which must match the treatment history ascertained 
at the beginning of the Screening Period), subjects will be assigned to 1 of 2 cohorts as follows:

Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 5 nights 
per week, for the last 2 weeks of the 3-week Screening Period, or (revised per Amendment 
01)

Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for the last 
2 weeks of the 3-week Screening Period (revised per Amendment 01)

The subjects who meet both criteria for intermittent and frequent ZOL use for 1 week each
of the last 2 weeks of the 3-week Screening Period will be assigned to Cohort 1 and referred 
to as Cohort 1-Mixed. (revised per Amendment 02)
All subjects (approximately 20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg 
(LEM5). For Cohort 2, (approximately 40), subjects will be randomized to 1 of 2 Treatment Groups 
(LEM5 or LEM10) in a 1:1 ratio. (revised per Amendment 02)
Baseline Period
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The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment cohort.  
Subjects who are not eligible will conclude their participation, return their actigraphs and sleep logs 
to the study site, and will be considered screen failures.  Upon completion of the Baseline Period, 
subjects who remain eligible will enter the Titration Period.  (revised per Amendment 01)
Treatment Phase
Titration Period
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and LEM10 to 
be taken at home within a few minutes of the time that they intend to sleep at night.  Subjects will 
continue to wear their actigraphs throughout the Titration Period, with the same instructions for use.  
Study restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals will 
be discussed. Subjects will be instructed to not alter (ie, break or cut) their tablets of LEM.  (revised 
per Amendment 01)
Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will decide when to take LEM according to 
their usual pattern, with the requirement that they take LEM at least once per week during the 2-week
Titration Period.  (revised per Amendment 01)
Cohort 2 (Frequent Use, Treatment Groups A and B): Subjects in these cohorts will take LEM at 
least 5 nights per week during the 2-week Titration Period.
For subjects with a starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but not 
mandated) to remain on their assigned dose for 7 days before calling the site should they feel that 
LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  
For subjects with a starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site should they feel that LEM10 should be reduced. 
Subjects will then be instructed to take LEM5 within a few minutes of the time they intend to go to 
sleep.  
At the time of LEM dose change during the Core Study, the reason for the dose change will be 
recorded in the case report form (CRF).  Subjects will be allowed 1 LEM dose adjustment during the 
Titration Period.  Every morning, subjects will enter their insomnia drug use data into the data 
collection system and record their sleep log data, and, provided an insomnia drug was taken the night 
prior, PGI-I and Quality of Sleep Rating will be completed. The ISI will be completed at each study 
visit except Follow-up Visit.  (revised per Amendment 01)
Upon completion of the Titration Period, actigraphs will be returned to the study site, and subjects 
will be considered for eligibility to enter the Extension Phase. (revised per Amendment 01)
Extension Phase
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of LEM that they took at 
the end of the Titration Period.  Subjects will subsequently return to clinic as specified in the 
Schedule of Assessments, and will be instructed to return their supply of LEM at each visit.  Unused 
study drug will be collected, study drug compliance will be assessed.  Subjects will be able to discuss 
changing the dose of LEM at any time during the Maintenance Period, and LEM dose changes may 
be implemented as clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all subjects (eg,
4 weeks after the end of the Treatment Phase for subjects not entering the Extension Phase or after 
the end of the Extension Phase, for subjects entering the Extension Phase).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study. 
Number of Subjects
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Approximately 110 subjects will be screened to provide approximately 60 subjects (approximately 20 
subjects in Cohort 1 and approximately 40 subjects in Cohort 2 [approximately 20 subjects each in 
LEM5 and LEM10]). (revised per Amendment 02)
Inclusion Criteria
1.
Male or female, 18 years or older, at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5) criteria for 
Insomnia Disorder, either currently or prior to ZOL use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep 
and/or awakening earlier in the morning than desired despite adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 but fewer than 5 nights per week), or frequent use 
(at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month
5.
Confirmation of frequent or intermittent use of ZOL (based on review of drug use data). 

Frequent use is defined as taking ZOL at least 5 nights per week for the last 2 weeks of the 
3-week Screening Period (revised per Amendment 02)

Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for the last 
2 weeks of the 3-week Screening Period; or taking ZOL as per the intermittent criteria for 1 week 
of the last 2 weeks of the 3-week Screening Period, and taking ZOL as per the frequent criteria 
for 1 week of the last 2 weeks of the 3-week Screening Period (revised per Amendment 02)
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 
hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia during the 
subject’s participation in the study
Exclusion Criteria
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
serum pregnancy test).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing and throughout the study and for 28 days 
after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
NOTE:  All females will be considered to be of childbearing potential unless they are 
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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).
3.
Any history of moderate or severe obstructive sleep apnea (OSA)
4.
Current evidence of a clinically significant, active respiratory disorder other than mild OSA.  
This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any 
other pulmonary disorder identified by review of medical history or physical examination, and 
which in the opinion of the investigator, could compromise the subject’s safety or interfere with 
study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, circadian 
rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals 
with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator 
indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy
8.
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 sleeping), 
whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Drug use data do not confirm intermittent or frequent use as defined in the Inclusion Criterion
No. 5 (revised per Amendment 02)
13. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
14. Used any prohibited prescription or over-the-counter concomitant medications within 1-week or 
5 half-lives, whichever is longer, before the first dose of study medication (A list of prohibited 
concomitant medications is presented in the protocol).  
15. Used any pharmacologic modality of treatment for insomnia other than zolpidem, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening Period
16. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
17. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
Columbia-Suicide Severity Rating Scale [C-SSRS])
18. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
19. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal 
disease) 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.
20. Hypersensitivity to lemborexant or any of the excipients.
21. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study.
22. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
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the study. Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the investigator this operation does not interfere with the study procedures and patient safety.
23. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics 
or prior suicide attempt(s) within approximately the last 2 years
24. History of drug or alcohol dependency or abuse within approximately the last 2 years
25. Currently enrolled in another clinical study or used any investigational drug or device within 28 
days or 5× the half-life, whichever is longer, preceding informed consent
26. Previously participated in any clinical trial of lemborexant
Study Treatment(s)
Core Study
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night within a few minutes of the time the subject 
intends to sleep, according to the subject’s predetermined intermittent or frequent use schedule.
Comparator Drug:  Not applicable 
Extension Phase
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night a few minutes before the time the subject 
intends to try to sleep.
Duration of Treatment
A maximum of 14 weeks: 
2 weeks of LEM5 or LEM10 during the Treatment Phase of the Core Study,
12 weeks during the Extension Phase
Concomitant Drug/Therapy
Prohibited medications should not be used during the study.  A subject must not have used any 
prohibited prescription or over-the-counter medications within 1-week or 5 half-lives, whichever is 
longer, before the Treatment Phase.
Prohibited medications include moderate and strong cytochrome P450 (CYP)3A inhibitors and all 
CYP3A inducers, and medications that have known sedating effects.  The prohibition applies even if 
the entire class to which that medication belongs is not prohibited (eg, anticonvulsants).  
If a medication is not on the list of prohibited medications but in the opinion of the investigator 
causes or exacerbates the subject’s insomnia, it must not be used throughout the study.  If a 
medication is not specified as prohibited but is in the same class as a medication that is listed in the 
protocol, and if the investigator is uncertain whether the medication has known sedating or alerting 
effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue 
from the study, with the exception that certain prohibited medications may be used for a short 
duration (not to exceed 2 weeks) to treat an acute condition if this is agreed with the Medical 
Monitor.  Note that strong and moderate CYP3A inhibitors and all CYP3A inducers will not be 
permitted at any time for any duration during the study.  Subjects must forgo alcohol consumption 
within 3 hours of bedtime for the duration of participation in the study.  
Assessments
Screening Assessments (Core Study only)
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Sleep Disorders Screening Battery (SDSB):
The SDSB will include:

STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects for OSA 

IRLS:  a subjective scale comprising 10 questions, which measures severity of symptoms of 
restless legs syndrome
Sleep Drug History Questionnaire
Subjects will be asked questions about their history and response to prior sleep medications.
Sleep Drug Experience Interview – Zolpidem
Subjects will be asked questions about their subjective experiences while taking ZOL at the end of 
the Screening Period.
Efficacy Assessments (Core Study only)
Patient Global Impression – Insomnia
The PGI-I is a self-report assessment of subject perception of the effects of a medication on their 
sleep.  The PGI-I has 3 items related to study medication effects (a) helped/worsened sleep, (b) 
decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to 
perceived appropriateness of study medication strength.  The first 3 items are answered on a 3-point 
scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and 
the last item on a different 3-point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior evening.
Insomnia Severity Index
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia.  
The dimensions evaluated are severity of: sleep onset, sleep maintenance, early-morning awakening
problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning, 
noticeability of the sleep problems by others, and distress caused by the sleep difficulties.  A 5-point 
Likert scale is used to rate each item (from 0=no problem, to 4=very severe problem), yielding a total 
score from 0 to 28.  The ISI will be completed at each study visit except Follow-up Visit.  
Quality of Sleep Rating
The Quality of Sleep Rating is a self-reported scale in which subjects are asked, “How would you rate 
the quality of your sleep last night, with 1 being extremely poor, 5 being not good or poor, and 9 
being extremely good?” For Quality of Sleep, higher values are better.  The Quality of Sleep Rating 
will be completed each morning following a dose of ZOL or LEM taken the prior evening during the 
Screening, Baseline, and Titration Periods.
Sleep Drug Experience Interview – Lemborexant
Subjects will be asked questions about their subjective experiences while taking LEM at the end of 
the Titration Period.
Actigraphy  (revised per Amendment 01)
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity monitor that
looks like a wrist watch. This device incorporates a multidirectional accelerometer to monitor degree 
and intensity of motion. Data from an actigraph are collected at a sampling rate of every 30 seconds
and are scored as sleep or wake with a validated algorithm. Sleep/wake parameters are calculated
from the scored data. A central actigraphy reader will score daily actigraphy records using a 
customized algorithm. The in-bed intervals will be provided to the central reader based on the sleep 
logs completed by the subject. Actigraphy data will be used to evaluate the following sleep and wake 
parameters for subjects during the Screening and Titration Periods:

TST: The total time spent in sleep according to the epoch-by-epoch wake/sleep categorization 
during time in bed (TIB)

SE:  100% × the total duration of sleep epochs during the defined nocturnal sleep period/TIB

WASO: The total time spent awake according to the epoch-by-epoch wake/sleep categorization 
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between sleep start (based on 'lights out') and 'got up'

Wake Bouts: Wake of  ≥ 5 minutes that occur during TIB

Sleep Bouts: Continuous sleep ≥ 10 minutes that occur during Time Out of Bed (TOB)
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable.
Safety Assessments (Core Study and Extension Phase)
Safety assessments will consist of monitoring and recording all adverse events (AEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of 
vital signs, weight and ECGs; and the performance of physical examinations.  Subjects will be asked 
about falls at every visit.
Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure.  A set of preferred terms (PTs)
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 that meet serious criteria.  
Columbia – Suicide Severity Rating Scale
Suicidality will be assessed using a site-administered version of the C-SSRS.  The C-SSRS assesses 
an individual’s degree of suicidality, including both suicidal ideation and suicidal behavior. 
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 consecutive months as 
designated in the Schedule of Procedures/Assessments.
Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the Schedule of 
Procedures/Assessments.  This sample will be tested for common drugs of use/abuse:  eg, 
propoxyphene, cocaine metabolites, cannabinoids, methadone, PCP, opiates, benzodiazepines, 
barbiturates, and amphetamines.
Bioanalytical Methods
Not applicable.
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Statistical Methods
The study endpoints for efficacy and safety will be presented by treatment group (LEM5 and 
LEM10) and by pooling across treatments within each cohort and overall.  Missing data will not be 
imputed.
Primary Endpoint
The primary endpoint is the proportion of overall subjects who transition to LEM at the end of the 
Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week Titration 
Period and either 1) enters the Extension Phase, or 2) chooses to not enter the Extension Phase for 
reasons not related to LEM (including, but not limited to, time commitment related to the study, 
study-related travel expenses, or preference to continue insomnia management with another health 
care provider).  
Secondary Endpoints (revised per Amendment 01)
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration Period
within each Cohort.

The proportion of subjects in the LEM5 treatment groups with dose increasing to LEM10 at 
the end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at the 
end of the Titration Period in Cohort 2.

The proportion of subjects with positive medication effect rating on each PGI-I item at the 
end of the 2-week Titration Period by Cohort and overall using end of the Titration Period
treatment. 
Exploratory Endpoints  (revised per Amendment 01)
The exploratory endpoints are as follows:

The change from Baseline in mean ISI score at the end of the Titration Period by Cohort and 
overall using end of the Titration Period treatment.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration Period 
by cohort and overall using end of the Titration Period treatment.

To compare nights on which an evening dose of LEM5 or LEM10 was taken, to nights on 
which an evening dose of ZOL was taken, for the following sleep-related actigraphy 
variables:
o
Mean TST
o
Mean SE
o
Mean WASO
o
Number of Wake Bouts

To compare the daytime after an evening dose of LEM5 or LEM10 was taken, to the daytime
after an evening dose of ZOL was taken, for the following wake-related actigraphy variable:
o
Mean Duration of Sleep Bouts
Analysis Sets
Safety Analysis Set (SAS) –The Safety Analysis Set is the group of subjects who received at least 1 
dose of study drug and had at least 1 postdose safety assessment.
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Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included in the 
Full Analysis Set.
Efficacy Analyses (Core Study only)
All efficacy analyses will be conducted on the FAS. 

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed.

The proportion of subjects who transition to LEM after 2 weeks of treatment in the Titration 
Period will be displayed within each cohort.  

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall, 

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented.

Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately 
within each scale over time by Cohort and overall using end of the Titration Period dose 
groups.

The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these items 
at the end of the Titration Period, and the proportion of subjects who rated the drug as being 
too strong or too weak at Baseline, but whose rating was “just right” at the end of the 
Titration Period (as data allow) will be reported.

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the ISI 
will be summarized at the end of the Titration Period by Cohort and overall using end of the 
Titration Period dose groups

The change from baseline in mean Quality of Sleep Rating score for subjects at the end of the 
Titration Period will be summarized by cohort and overall using end of the Titration Period
dose groups.

Average value of following sleep-related actigraphy variables will be summarized by 
treatment over the nights on which an evening dose of LEM5, LEM10, and ZOL was taken.  
(revised per Amendment 01)
o
Mean TST
o
Mean SE
o
Mean WASO
o
Number of Wake Bouts

Average value of wake-related actigraphy variable, mean duration of Sleep Bouts will be 
summarized by treatment over the daytime after an evening dose of LEM5, LEM10, and 
ZOL was taken.  (revised per Amendment 01)
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable.
Safety Analyses (Core Study and Extension Phase)
Evaluations of safety data will be performed on the SAS. 
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG findings, out-of-
range vital signs, and suicidality (C-SSRS) findings, along with changes from baseline in clinical 
laboratory variables, and vital signs will be summarized for Cohort 1 (Intermittent ZOL use) and 
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Cohort 2 (Frequent ZOL use) using descriptive statistics using end of titration dose group. AEs
summaries, and abnormal findings will also be displayed based on the dose that the subjects were 
taking at the time of the findings.
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered cataplexy or 
seizure, somnolence, and related events, and PTs related to drug abuse liability, will be summarized
separately.  The results of the deliberation of the Adjudication Committee will be reported separately.  
In addition, 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, as per the
Adjudication Committee description.
Other Analyses (Core Study)
Efficacy endpoints may be analyzed by modeling methods if warranted.  Details of all of the analyses 
will be specified in the Statistical Analysis Plan.  (revised per Amendment 01)
Interim Analyses
No interim analyses are planned for this study.
Sample Size Rationale
As a pilot study, sample size estimates are not based on statistical calculations.
This study will enroll approximately 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and 
Cohort 2B) to evaluate the proportion of subjects who transition to LEM as a substitute for zolpidem.  
Approximately 20 subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and approximately 
40 subjects will be assigned to Cohort 2 (Frequent ZOL Use).  This sample size is deemed sufficient 
to inform whether the proposed strategies are sufficient to evaluate whether alternative strategies 
would be required to help understand how best to recommend safe and effective methods for 
transitioning from ZOL to LEM. (revised per Amendment 02)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................4
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................5
3
TABLE OF CONTENTS.................................................................................................16
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................21
5
ETHICS............................................................................................................................23
5.1
Institutional Review Boards/Independent Ethics Committees ..............................23
5.2
Ethical Conduct of the Study.................................................................................23
5.3
Subject Information and Informed Consent...........................................................24
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................24
7
INTRODUCTION ...........................................................................................................25
7.1
Indication ...............................................................................................................25
7.1.1
Current Therapeutic Options........................................................................25
7.1.2
Lemborexant ................................................................................................26
7.1.2.1
Clinical Experience With Lemborexant...............................................26
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................27
7.2
Study Rationale......................................................................................................27
7.2.1
Entry Criteria Rationale...............................................................................28
7.2.2
Rationale for Titration Schedule and Duration............................................28
8
STUDY OBJECTIVES....................................................................................................29
8.1
Primary Objective..................................................................................................29
8.2
Secondary Objectives  (revised per Amendment 01) ............................................29
8.3
Exploratory Objectives  (revised per Amendment 01) ..........................................29
9
INVESTIGATIONAL PLAN..........................................................................................29
9.1
Overall Study Design and Plan..............................................................................29
9.1.1
Pretreatment Phase (Core Study).................................................................31
9.1.1.1
Screening Period (Core Study) ............................................................31
9.1.1.2
Baseline Period (Core Study)...............................................................32
9.1.2
Treatment Phase (Core Study).....................................................................33
9.1.2.1
Titration Period (Core Study) ..............................................................33
9.1.2.2
Follow-Up Period.................................................................................34
9.1.3
Extension Phase ...........................................................................................34
9.2
Discussion of Study Design, Including Choice of Control Groups.......................34
9.3
Selection of Study Population................................................................................34
9.3.1
Inclusion Criteria .........................................................................................34
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9.3.2
Exclusion Criteria ........................................................................................35
9.3.3
Removal of Subjects from Therapy or Assessment.....................................37
9.4
Treatments..............................................................................................................37
9.4.1
Treatment(s) Administered..........................................................................37
9.4.2
Identity of Investigational Product...............................................................38
9.4.2.1
Chemical Name, Structural Formula of Lemborexant.........................38
9.4.2.2
Comparator Drug .................................................................................39
9.4.2.3
Labeling for Study Drug......................................................................39
9.4.2.4
Storage Conditions...............................................................................39
9.4.3
Method of Assigning Subjects to Treatment Groups...................................39
9.4.4
Selection of Doses in the Study...................................................................39
9.4.5
Selection and Timing of Dose for Each Subject..........................................40
9.4.6
Blinding........................................................................................................40
9.4.7
Prior and Concomitant Therapy...................................................................40
9.4.7.1
Drug-Drug Interactions........................................................................40
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................41
9.4.8
Treatment Compliance.................................................................................41
9.4.9
Drug Supplies and Accountability...............................................................41
9.5
Study Assessments.................................................................................................43
9.5.1
Assessments.................................................................................................43
9.5.1.1
Demography.........................................................................................43
9.5.1.2
Screening and Baseline Assessments...................................................43
9.5.1.2.1
Medical History and Physical Examinations.................................43
9.5.1.2.2
Sleep Drug History Questionnaire.................................................43
9.5.1.2.3
Sleep Disorder Screening Battery..................................................44
9.5.1.2.4
Sleep Drug Experience Interview – Zolpidem...............................44
9.5.1.3
Efficacy Assessments...........................................................................44
9.5.1.3.1
Insomnia Severity Index ................................................................44
9.5.1.3.2
Patient’s Global Impression – Insomnia........................................44
9.5.1.3.3
Quality of Sleep Rating..................................................................45
9.5.1.3.4
Sleep Drug Experience Interview – Lemborexant.........................45
9.5.1.3.5
Actigraphy  (revised per Amendment 01) .....................................45
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................46
9.5.1.5
Safety Assessments..............................................................................46
9.5.1.5.1
Adverse Events ..............................................................................46
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9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................49
9.5.1.5.3
Study-Specific Adverse Events......................................................50
9.5.1.5.4
Laboratory Measurements .............................................................50
9.5.1.5.5
Vital Signs, Height, and Weight Measurements............................51
9.5.1.5.6
Physical Examinations...................................................................51
9.5.1.5.7
Electrocardiograms ........................................................................51
9.5.1.5.8
Other Safety Assessments..............................................................51
9.5.2
Schedule of Procedures/Assessments – Core Study....................................52
9.5.2.1
Schedule of Procedures/Assessments ..................................................52
9.5.2.2
Description of Procedures/Assessments Schedule...............................57
9.5.3
Appropriateness of Measurements...............................................................57
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................57
9.5.4.1
Reporting of Serious Adverse Events..................................................57
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................58
9.5.4.3
Reporting of Events Associated with Special Situations.....................59
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59
9.5.4.3.2
Reporting of Study-Specific Events...............................................59
9.5.4.4
Expedited Reporting ............................................................................59
9.5.4.5
Breaking the Blind...............................................................................59
9.5.4.6
Regulatory Reporting of Adverse Events ............................................60
9.5.5
Completion/Discontinuation of Subjects.....................................................60
9.5.6
Abuse or Diversion of Study Drug ..............................................................60
9.6
Data Quality Assurance .........................................................................................61
9.6.1
Data Collection ............................................................................................61
9.6.2
Clinical Data Management ..........................................................................61
9.7
Statistical Methods.................................................................................................61
9.7.1
Statistical and Analytical Plans....................................................................61
9.7.1.1
Study Endpoints...................................................................................62
9.7.1.1.1
Primary Endpoint...........................................................................62
9.7.1.1.2
Secondary Endpoints  (revised per Amendment 01) .....................62
9.7.1.1.3
Exploratory Endpoints  (revised per Amendment 01)...................62
9.7.1.2
Definitions of Analysis Sets.................................................................63
9.7.1.3
Subject Disposition..............................................................................63
9.7.1.4
Demographic and Other Baseline Characteristics ...............................63
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9.7.1.5
Prior and Concomitant Therapy...........................................................64
9.7.1.6
Efficacy Analyses ................................................................................64
9.7.1.6.1
Primary Efficacy Analysis.............................................................64
9.7.1.6.2
Secondary Efficacy Analyses  (revised per Amendment 01) ........64
9.7.1.6.3
Exploratory Efficacy Analyses  (revised per Amendment 01)......64
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................65
9.7.1.8
Safety Analyses....................................................................................65
9.7.1.8.1
Extent of Exposure.........................................................................65
9.7.1.8.2
Adverse Events ..............................................................................66
9.7.1.8.3
Laboratory Values..........................................................................67
9.7.1.8.4
Vital Signs......................................................................................67
9.7.1.8.5
Electrocardiograms ........................................................................68
9.7.1.8.6
Other Safety Analyses....................................................................68
9.7.2
Determination of Sample Size .....................................................................68
9.7.3
Interim Analysis...........................................................................................69
9.7.4
Other Statistical/Analytical Issues ...............................................................69
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................69
10
REFERENCE LIST .........................................................................................................70
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......72
11.1
Changes to the Protocol .........................................................................................72
11.2
Adherence to the Protocol......................................................................................72
11.3
Monitoring Procedures...........................................................................................72
11.4
Recording of Data..................................................................................................73
11.5
Identification of Source Data.................................................................................73
11.6
Retention of Records..............................................................................................74
11.7
Auditing Procedures and Inspection......................................................................74
11.8
Handling of Study Drug.........................................................................................74
11.9
Publication of Results ............................................................................................75
11.10 Disclosure and Confidentiality ..............................................................................75
11.11 Discontinuation of Study .......................................................................................75
12
APPENDICES .................................................................................................................76
LIST OF IN-TEXT TABLES
Table 1
Treatments Administered...........................................................................38
Table 2 
Clinical Laboratory Tests...........................................................................50
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core 
Study (revised per Amendment 01)...........................................................53
Table 4
Clinically Notable Vital Sign Criteria........................................................68
Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 –
Extension (revised per Amendment 01) ....................................................82
LIST OF IN-TEXT FIGURES
Figure 1
Study E2006-A001-312 – Study Design....................................................31
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................76
Appendix 2
Prohibited Concomitant Medications ........................................................78
Appendix 3
Extension Phase .........................................................................................81
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
BMI
Body mass index
BP
blood pressure
CBT-I
Cognitive Behavioral Therapy for Insomnia
CFR
Code of Federal Regulations
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th ed
FAS
full analysis set
GABA
gamma-aminobutyric acid
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ISI
Insomnia Severity Index
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
LEM
lemborexant
LEM5
Lemborexant 5 mg
LEM10
Lemborexant 10 mg
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
OSA
obstructive sleep apnea
PBO
placebo
PGI-I
Patient Global Impression of Insomnia
PT
preferred term
QTcF
Difference between QTc corrected by Fridericia's formulas
SAE
Serious adverse events
SAS
safety analysis set
SDSB
Sleep Disorders Screening Battery
SE
sleep efficiency
SOC
system organ class
TEAE
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory values
TIB
time in bed
TST
total sleep time
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Abbreviation
Term
WASO
wake after sleep onset
ZOL
zolpidem
ZOL-ER
zolpidem tartrate extended release
ZOL-IR
zolpidem tartrate immediate release
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with ICH E6 (Good Clinical Practice), Section 3, and any local regulations (eg, 
Title 21 of the United States Code of Federal Regulations [CFRs], Part 56). Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, 
change in Clinical Research Associate CRA[s], change of telephone number[s]).  
Documentation of IRB compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension 
or termination by the IRB to the sponsor.
Study progress is to be reported to IRBs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports,
and inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB within 90 days.  The end of the 
study will be the date of the last study visit for the last subject in the study.  The sponsor 
should also provide the IRB with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB 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 (2013)

ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
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Committee for Proprietary Medicinal Products, International Council for Harmonisation 
of Pharmaceuticals for Human Use

Title 21 of the US CFR regarding clinical studies, including Part 50 and Part 56 
concerning informed subject consent and IRB regulations and applicable sections of US 
21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (eg, Title 21 CFR Part 50).  Each subject must 
sign an approved ICF before study participation.  The form must be signed and dated by the 
appropriate parties.  The original, signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site.  
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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 investigational sites in the United States of America.
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The name, telephone and fax numbers of the Medical Monitor and other contact personnel at 
the contract research organization(s) (CROs) are listed in the Investigator Study File
provided to each site.
7
INTRODUCTION
7.1
Indication
Lemborexant (LEM) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide), also known as E2006, is 
an orally-administered, novel competitive dual orexin receptor antagonist (DORA) that has 
been developed for the treatment of insomnia and Irregular Sleep-Wake Rhythm Disorder 
(ISWRD).  
7.1.1
Current Therapeutic Options
Treatments for insomnia include both non-pharmacological (Schutte-Rodin, et al., 2008; 
Morgenthaler, et al., 2006) and pharmacological treatments (Sateia, et al., 2017).  Patients 
who undergo thorough diagnostic evaluations for insomnia symptoms are asked about their 
sleep and wake habits, since some cases of insomnia can be addressed by improving sleep 
hygiene.  Principles of good sleep hygiene include regular bedtimes and waketimes, limiting 
alerting activities before bedtime, and limiting caffeine and alcohol intake, among others 
(Schutte-Rodin, et al., 2008).  These techniques are often not adequate to address insomnia 
symptoms (Stepanski and Wyatt, 2003; Irish, et al., 2015).
Another commonly recommended non-pharmacological approach is the use of cognitive 
behavioral therapy for insomnia (CBT-I; Schutte-Rodin, et al., 2008).  CBT-I includes 
techniques to minimize wakefulness at the time the patient intends to sleep.  However, while 
there are data to support the effectiveness of CBT-I, sleep restriction is commonly a major 
component, and this may lead to daytime sleepiness, an unintended consequence of short 
sleep (Kyle, et al., 2014).  In contrast, lemborexant’s mechanism of action would avoid the 
daytime sleepiness caused by sleep restriction, while reducing wakefulness and facilitating 
sleep, which is an important underlying goal of CBT-I.  
There are numerous drugs available for the treatment of insomnia, some available by 
prescription and many available over-the-counter.  Many of the over-the-counter medicines 
lack empirical data from adequate, well-designed and controlled clinical trials to support 
their use (Rosen, et al., 2005); these include melatonin and antihistamines.  Pharmacological 
treatments available by prescription and used clinically for insomnia include sedative 
hypnotics (benzodiazepines, nonbenzodiazepine gamma-aminobutyric acid 
(GABA)-releasing [GABAergics] agents), sedating antidepressants, melatonin agonists, and 
a DORA.  
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7.1.2
Lemborexant
Lemborexant belongs to the pharmacologic class of orexin receptor antagonists, a class of 
chemical compounds developed for the treatment of insomnia.  To date, clinical proof of 
concept has been achieved by 6 orexin receptor antagonists (lemborexant, almorexant 
[ACT-078573], suvorexant [MK-4305], filorexant [MK-6096]), seltorexant [MIN-202], and 
nemorexant [ACT-541468]), demonstrating validity of the mechanism of action (Herring, 
et al., 2012; Hoever, et al., 2012; Connor, et al., 2016; Murphy, et al., 2017; De Boer, et al., 
2018).
Nonclinical data show that lemborexant binds to and competitively antagonizes human 
orexin-1 receptor (OX1R) and orexin-1 receptor (OX2R) in vitro, with rapid association and 
dissociation kinetics at both receptors.  In vitro data show that lemborexant does not 
substantially interact with other sleep-related receptors and channels (Beuckmann, et al, 
2017).  Lemborexant prevents [Ala11, D-Leu15]-orexin-B-induced plasma adrenocorticotropic 
hormone increase in rats, and promotes physiological sleep in mice and rats.  In mice, 
lemborexant does not promote sleep when the orexin pathway has been functionally 
impaired.  In rats, daily treatment for 3 consecutive weeks with lemborexant did not result in 
tolerance or wakefulness rebound upon treatment cessation, and did not elicit direct 
transitions from wakefulness to rapid eye movement (REM) sleep, a narcolepsy-like 
symptom.  However, in strong emotional contexts, lemborexant induced cataplexy-like 
events in mice (Study W-20140712).  Cataplexy has been noted in dogs dosed with another 
orexin antagonist, suvorexant, when presented with food enrichment (Belsomra, 2018), but 
the relationship to cataplexy symptoms in humans has not been established.  At doses up to 
300 mg/kg (300-fold higher than necessary for sleep promotion), lemborexant did not have 
any negative influence on motor coordination in mice, nor did it show any significant 
interaction with ethanol.
7.1.2.1
Clinical Experience With Lemborexant
The safety and efficacy of lemborexant for the treatment of insomnia disorder was confirmed 
in 2 pivotal Phase 3 studies, E2006-G000-303 (Study 303) and E2006-G000-304 (Study 
304).  In Study 304, lemborexant also demonstrated superior improvement on objective and 
subjective measures of sleep onset and maintenance compared to zolpidem tartrate extended 
release (ZOL-ER).  Additional safety assessments pertinent to insomnia drugs, specifically 
regarding postural stability, were also conducted in study E2006-A001-108 and Study 304.  
In these studies, the safety of lemborexant on postural stability was superior compared to 
zolpidem (ZOL).  Based on these data, a New Drug Application for lemborexant was 
submitted to the US Food and Drug Administration for the treatment of insomnia disorder in 
December 2018 and accepted for review in February 2019.
The safety and tolerability of lemborexant has been comprehensively evaluated in a broad 
patient population that includes subjects with insomnia disorder per Diagnostic and 
Statistical Manual of Mental Disorders, 5th ed (DSM-5) (with or without medical or 
psychiatric comorbidities), subjects with Alzheimer's disease and ISWRD, subjects with mild 
obstructive sleep apnea (OSA), and subjects with severe renal impairment or mild to 
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moderate hepatic impairment.  Exposures included dosing of ≥12 months.  Approximately 
40% of subjects in the development program were elderly (≥65 years), providing extensive 
safety and tolerability profile for this important subpopulation at risk for insomnia.  
Overall, of 2835 subjects with sleep disorders, 1847 received lemborexant, 714 received 
placebo (PBO), and 263 received ZOL (extended release) and 11 received ZOL (immediate 
release).  (revised per Amendment 02)
No deaths were reported in subjects treated with lemborexant.
The overall incidence of treatment-emergent serious adverse events (SAEs) for subjects 
treated with lemborexant 5 mg (LEM5) and lemborexant 10 mg (LEM10) in the Phase 3 Pool
was low (2.8% and 2.3%, respectively) but greater than for PBO (0.9%).  However, when 
adjusted by duration of exposure, the overall incidence (subjects per patient-year) was similar 
to PBO (<0.1 for PBO, 0.1 for LEM5, and 0.1 for LEM10).  The overall rate (events per 
patient-year) of treatment-emergent SAEs when adjusted by duration of exposure was <0.1 
for PBO, <0.1 for LEM5, and <0.1 for LEM10.
There were no differences in the types of treatment-emergent SAEs reported during 
long-term treatment with lemborexant. There were no differences in treatment-emergent 
SAEs based on intrinsic factors, including age, sex, and body mass index (BMI) of subjects.  
Notably, the incidence of treatment-emergent SAEs in the elderly was consistent with that in 
younger subjects.
Across the Phase 3 studies of 303 and 304 (total subjects=1945), the majority of 
treatment-emergent SAEs occurred as singular events in 1 subject only.  The SAEs of 
osteoarthritis (0% for PBO, 0.1% for LEM5, 0.4% for LEM10), rib fracture (0.2% for PBO, 
0% for LEM5, 0.1% for LEM10), and diabetic neuropathy (0% for PBO, 0.3% for LEM5, 
0% for LEM10) occurred in more than 1 subject across the PBO, LEM5, and LEM10 groups.  
One (0.1%) serious event of fall was reported in the LEM5 group.
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure
None.
7.2
Study Rationale
Switching of medications for insomnia occurs often in clinical practice based on clinical 
response, AEs, reimbursement patterns, or physician and patient preference.  However, there 
is no clinical trial experience or dosing guidance for transitioning from currently approved 
treatments for insomnia to lemborexant.  Study E2006-A001-312 (Study 312) is designed as 
a pilot study to assess the dosing approach of directly transitioning from ZOL, the most 
commonly prescribed sleep aid (Bertisch, et al., 2014), to lemborexant, without tapering the 
ZOL dose, and with the opportunity for lemborexant dose titration.  This study will provide 
initial information on patient satisfaction after switching to lemborexant, with secondary 
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objectives assessing subjective quality of sleep and tolerability.  If issues are identified 
regarding patient satisfaction, tolerability, or quality of sleep, other dosing paradigms can be 
assessed in future studies to mitigate these issues.  
7.2.1
Entry Criteria Rationale
Subjects with insomnia disorder per DSM-5 criteria (with or without medical or psychiatric 
comorbidities) will be eligible for study entry, which is representative of the typical target 
outpatient population.  All subjects who are willing to substitute ZOL with LEM, regardless 
of the reason(s), will be eligible, and the reason(s) will be captured during screening.  While 
it is anticipated that most eligible subjects would substitute ZOL with LEM due to 
dissatisfaction with ZOL, other reasons, as determined by input from Key Opinion Leaders 
(KOLs) in Sleep Medicine, may include, but are not limited to, concerns regarding ZOL side 
effects, eg, parasomnias.  Including subjects with these various reasons is representative of 
the real-world outpatient setting.
While the approved dosing instructions for women and patients ≥65 stipulate that the lower 
dose of ZOL is to be prescribed, many women and elderly patients may be taking the higher 
dose.  Therefore, for generalizability of the results of the study to the patient population, any 
stable dosing regimen will be eligible, including those subjects taking higher than approved 
doses up to the maximum approved (10 mg IR or 12.5 mg ER).
7.2.2
Rationale for Titration Schedule and Duration 
Since this study is designed to reflect common clinical practice, flexibility to titrate the dose 
up or down is built into the dosing regimen.  In the outpatient setting, clinicians typically 
advise patients to allow themselves one week to adjust to a new medication; therefore, 
subjects assigned to LEM5 will be encouraged to remain on their dose of LEM for 1-week 
prior to titrating up to LEM10, and those assigned to LEM10 will be encouraged to remain 
on their dose of LEM prior to titrating down to LEM5 after one week.
Subjects who intermittently use ZOL are expected to be more likely to be started on LEM5 in 
the outpatient setting, as they are not chronically exposed to, or reliant upon, pharmacologic 
insomnia treatments.  Therefore, all subjects in Cohort 1 will be started on LEM5 during the 
Titration Period of the Treatment Phase.  
The duration of the Treatment Phase of the Core Study is set at 2 weeks, since that amount of 
time is deemed reasonable by expert opinion from consultation with KOLs in Sleep Medicine 
for subjects to decide if they wish to continue on lemborexant.  
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects 
with insomnia disorder taking ZOL immediate release (ZOL-IR) or extended release (ZOL-
ER), intermittently or frequently, who transition to lemborexant 5 mg (LEM5) or 10 mg 
(LEM10), after 2 weeks of receiving lemborexant (LEM).
8.2
Secondary Objectives  (revised per Amendment 01)

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease 
from LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of 
Insomnia (PGI-I) at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking ZOL
8.3
Exploratory Objectives  (revised per Amendment 01)

To evaluate LEM5 or LEM10 scores on the Insomnia Severity Index (ISI) compared 
with Baseline at the end of the 2-week Titration Period

To evaluate LEM5 or LEM10 scores on the Quality of Sleep Rating scale compared with 
Baseline at the end of the 2-week Titration Period

To compare nights on which an evening dose of LEM5 or LEM10 was taken, to nights 
on which an evening dose of ZOL was taken, for the following sleep-related actigraphy 
variables:
o
Total Sleep Time (TST)
o
Sleep Efficiency (SE)
o
Wake After Sleep Onset (WASO)
o
Wake Bouts

To compare the daytime after an evening dose of LEM5 or LEM10 was taken, to the 
daytime after an evening dose of ZOL was taken, for the following wake-related 
actigraphy variable:
o
Sleep Bouts
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER.  Adult (≥18 years) subjects are 
eligible for participation if they have been diagnosed with insomnia disorder per the 
DSM-5th Ed (American Psychiatric Association, 2014), are currently receiving ZOL as 
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monotherapy for insomnia, and who agree to substitute zolpidem tartrate immediate release 
(ZOL-IR) or ZOL-ER with LEM, regardless of the reason. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week
Screening Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week
Titration Period), and an Extension Phase consisting of the Maintenance Period up to 
12 weeks and the Follow-up Period 4 weeks in duration immediately following the end of the 
Treatment Phase.  A Follow-up Period visit occurring 4 weeks after the end of the Extension 
Phase (or Treatment Phase, for subjects not entering the Extension Phase) will be conducted.  
The Pretreatment and Treatment Phases will comprise the Core Study.  The Extension Phase 
is described in detail in Appendix 3.
During the Screening Period, eligible subjects will continuously wear an actigraph and 
prospectively record the number of days ZOL is taken during the 3-week screening period
using a Data Collection System.  Based on ZOL use, subjects will be assigned to 1 of 2 
cohorts of ZOL use frequency:  (revised per Amendment 01)
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 
5 nights per week, for the last 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for the 
last 2 weeks of the 3-week Screening Period  
The subjects who meet both criteria for intermittent and frequent ZOL use for 1 week
each of the last 2 weeks of the 3-week Screening Period will be assigned to Cohort 1 and 
referred to as Cohort 1-Mixed. (revised per Amendment 02)
All subjects in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). Within 
Cohort 2, subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio.  
Subjects who remain eligible for the study will enter the Baseline Period, and continuously 
wear an actigraph during the Titration Period.  (revised per Amendment 01)
Approximately 110 subjects will be screened to provide approximately 60 subjects for 
randomization (approximately 20 subjects in Cohort 1 and approximately 40 subjects in 
Cohort 2 [approximately 20 subjects each in LEM5 and LEM10]).  (revised per Amendment 
02)
The end of the study will be the date of the last study visit for the last subject.
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An overview of the study design is presented in Figure 1.
Figure 1
Study E2006-A001-312 – Study Design
LEM5 = lemborexant 5 mg, LEM5 = lemborexant 5 mg, R = Randomization
9.1.1
Pretreatment Phase (Core Study)
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day 
Baseline Period, during which subjects will be assessed for eligibility to participate in the 
study.
9.1.1.1
Screening Period (Core Study)
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  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.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a diagnosis of insomnia per the DSM-5 (American Psychiatric 
Association, 2014), be currently receiving ZOL as monotherapy for insomnia, and agree to 
substitute zolpidem tartrate immediate release (ZOL-IR) or extended release (ZOL-ER) with 
LEM, regardless of the reason.
During the Screening Period, subjects will be required to bring the container of their 
currently prescribed ZOL to the site for verification of prescribed medication and dose.  
Subjects will be provided with, and trained in the use of, a data collection system to record 
Period:
R
Drug 
3 weeks
Day 1
Titration
2 weeks
Phase:
Screening
12 weeks
Pretreatment
Extension
Cohort 2 (LEM5)
Cohort 2 (LEM10)
Cohort 1 (LEM5)
Maintenance
Drug
Treatment
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the dose and frequency of ZOL which is taken during the 3-week Screening Period.  Site 
staff will instruct subjects to complete data entry every morning and will emphasize the 
importance of providing this data.  During the Screening Period, subjects will continue to 
take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5 mg or 10 
mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection 
system for at least 14 (preferably contiguous) days of the 21-day Screening Period in order to 
be eligible for study inclusion.  Eligible subjects will also be provided with an actigraph (for 
actigraphy) to wear continuously throughout the Screening Period.  Subjects will be provided 
with a daily log (sleep log) to note the start and end times of nocturnal sleep periods and to 
log the approximate times that the actigraph was replaced on the subject’s wrist, if 
inadvertently removed.  Subjects will be trained to use the actigraph and the log.  Site staff 
will instruct subjects to record (with the current date) the following timings in the log: in the 
evening, record the times when the actigraph was not worn; and in the morning, record the 
bedtimes and morning rise times.  Site staff will emphasize the importance of recording these 
timings in the log.  (revised per Amendment 01)
Subjects will return to clinic at the end of the Screening Period. Actigraph data will be 
downloaded and transmitted to the central reader, along with the sleep log of bedtimes, 
morning wake times, and the approximate times when the actigraph was replaced on the 
subject’s wrist.  (revised per Amendment 01)
For subjects who remain eligible for study enrollment, the second Screening Period visit will 
serve as that subject’s Baseline Period, and will occur on the same day. Based on ZOL use 
during the Screening Period (which must match the treatment history ascertained at the 
beginning of the Screening Period), subjects will be assigned to 1 of 2 cohorts as follows:  
(revised per Amendment 01)

Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 
5 nights per week, for the last 2 weeks of the 3-week Screening Period, or 

Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for the 
last 2 weeks of the 3-week Screening Period

The subjects who meet both criteria for intermittent and frequent ZOL use for 1 week 
each of the last 2 weeks of the 3-week Screening Period will be assigned to Cohort 1 and 
referred to as Cohort 1-Mixed. (revised per Amendment 02)
All subjects (approximately 20) in Cohort 1 will begin the Titration Period on lemborexant 5 
mg (LEM5). For Cohort 2, (approximately 40), subjects will be randomized to 1 of 2 
Treatment Groups (LEM5 or LEM10) in a 1:1 ratio. (revised per Amendment 02)
9.1.1.2
Baseline Period (Core Study)
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment 
cohort.  Subjects who are not eligible will conclude their participation, return their actigraphs 
and sleep logs to the study site, and will be considered screen failures.  Upon completion of 
the Baseline Period, subjects who remain eligible by meeting the criteria for 
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inclusion/exclusion (Sections 9.3.1 and Section 9.3.2) will enter the Titration Period.  
(revised per Amendment 01)
9.1.2
Treatment Phase (Core Study)
The Treatment Phase will consist of a 2-week Titration Period and 1-day Follow-up Visit to 
occur 4 weeks after completion of the Titration Period (or as soon as possible following early 
discontinuation) for subjects not entering the Extension Phase.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria at the Baseline Visit, and who have 
entered ZOL medication use data into the Data Collection System for at least 14 of the 21-
day Screening Period as specified in the Inclusion Criteria, are eligible to enter the Treatment 
Phase of the study. 
9.1.2.1
Titration Period (Core Study)
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and 
LEM10 to be taken at home within a few minutes of the time that they intend to sleep.  
Subjects will continue to wear their actigraphs throughout the Titration Period, with the same 
instructions for use.  Study restrictions pertaining to duration of time spent in bed, use of 
alcohol, and timing of meals will be discussed with the subject at each visit during the 
Treatment and Extension Phases.  Subjects will be instructed to not alter (ie break or cut) 
their tablets of LEM.  (revised per Amendment 01)
Subjects assigned to Cohorts 1 and 2 will self-administer the study medication according to 
the following regimens:

Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will decide when to take LEM
according to their usual pattern, with the requirement that they take LEM at least once per 
week during the 2-week Titration Period.  (revised per Amendment 01)

Cohort 2 (Frequent ZOL Use, Treatment Groups A and B): Subjects in these cohorts will 
take LEM at least 5 nights per week during the 2-week Titration Period.
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For subjects starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but 
not mandated) to remain on their assigned dose for 7 days before calling the site to report 
that LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the 
site will then be instructed by phone to take LEM10 within a few minutes of the time 
they intend to sleep.  

For subjects starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain 
on their assigned dose for 7 days before calling the site to report that the dose of LEM10 
should be reduced. Subjects will then be instructed to take LEM5 within a few minutes 
of the time they intend to go to sleep.  
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At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the case report form (CRF).  
Every morning, subjects will enter their insomnia drug use data into the data collection 
system and record their sleep log data, and, provided an insomnia drug was taken the night 
prior, PGI-I and Quality of Sleep Rating will be completed.  The ISI will be completed at 
each clinic visit except Follow-up Visit. (revised per Amendment 01)
Upon completion of the Titration Period, actigraphs will be returned to the study site, and
subjects will be considered for eligibility to enter the Extension Phase (Appendix 3).  
(revised per Amendment 01)
9.1.2.2
Follow-Up Period
For subjects not entering the Extension Phase, the Follow-up Period will start immediately 
after the end of the Treatment Phase and last for 4 weeks.  The purpose of the Follow-up 
Period is to assess adverse events and other safety parameters.  Subjects will be instructed to 
continue insomnia management with the health-care provider who had been treating them 
prior to study entry, if they so desire.
9.1.3
Extension Phase
Subjects who complete the Core Study and wish to continue taking LEM will enter the 
12-week Extension Phase.  Subjects will continue the LEM dose and regimen established 
during the Titration Period; however, the dose may be titrated up or down depending on 
response and tolerability, per subject input and investigator judgement.  For subjects who are 
eligible for the Extension Phase but who do not wish to continue study participation, the 
reason for discontinuation from the study will be recorded.  At the end of the Extension 
Phase, the Follow-up Period will begin, and last for 4 weeks.  
Details of the Extension Phase are provided in Appendix 3.
9.2
Discussion of Study Design, Including Choice of Control Groups
See Section 7.2, Study Rationale.
9.3
Selection of Study Population
Approximately 60 subjects will be enrolled at approximately 15 sites in the United States of 
America.  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, 18 years or older, at the time of informed consent
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2.
Meets the DSM-5 criteria for Insomnia Disorder, either currently or prior to zolpidem 
use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying 
asleep and/or awakening earlier in the morning than desired despite adequate 
opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 but fewer than 5 nights per week), or 
frequent use (at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month  (revised 
per Amendment 01)
5.
Confirmation of frequent or intermittent use of ZOL (based on review of drug use data). 
(revised per Amendment 02)

Frequent use is defined as taking ZOL at least 5 nights per week for the last 2 weeks of 
the 3-week Screening Period (revised per Amendment 02)

Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for 
the last 2 weeks of the 3-week Screening Period; or taking ZOL as per the intermittent 
criteria for 1 week of the last 2 weeks of the 3-week Screening Period, and taking ZOL as 
per the frequent criteria for 1 week of the last 2 weeks of the 3-week Screening Period
(revised per Amendment 02)
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia 
during the subject’s participation in the study
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive serum pregnancy test).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study 
drug.
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
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o
an oral contraceptive (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 28 days after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
3.
Any history of moderate or severe OSA
4.
Current evidence of a clinically significant, active respiratory disorder other than mild 
OSA.  This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary 
disease or any other pulmonary disorder identified by review of medical history or 
physical examination, and which in the opinion of the investigator, could compromise the 
subject’s safety or interfere with study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, 
circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule 
out individuals with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not 
excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week 
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
8.
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 
sleeping), whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Drug use data do not confirm intermittent or frequent use as defined in the Inclusion 
Criterion No. 5 (revised per Amendment 02)
13. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
14. Used any prohibited prescription or over-the-counter concomitant medications within 
1-week or 5 half-lives, whichever is longer, before the first dose of study medication (A 
list of prohibited concomitant medications is presented in the protocol).  
15. Used any pharmacologic modality of treatment for insomnia other than ZOL, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening 
Period
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16. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
17. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS])
18. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
19. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and 
renal disease) 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.
20. Hypersensitivity to lemborexant or any of the excipients.
21. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study.
22. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study. Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the investigator this operation does not interfere with the 
study procedures and patient safety.
23. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
24. History of drug or alcohol dependency or abuse within approximately the last 2 years
25. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days or 5× the half-life, whichever is longer, preceding informed consent.
26. 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.
9.4
Treatments
9.4.1
Treatment(s) Administered
The following treatments will be administered to subjects in the Core Study (Table 1).
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Table 1
Treatments Administered
Drug Name
Strength
Oral Dose Form
Number Dispensed and Frequency
Duration
Lemborexant
5 mg
Tablet
1×5 mg tablets, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Lemborexant
10 mg
Tablet
1×10 mg tablet, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For Cohorts 1 and 2A (starting dose of LEM5), subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site to report that LEM5 is not fully 
effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  

For Cohort 2B (starting dose of LEM10), subjects will be encouraged to remain on their 
assigned dose for 7 days before calling the site to report that the dose of LEM10 should 
be reduced.  Subjects will then be instructed to take LEM5 within a few minutes of the 
time they intend to go to sleep.  
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the CRF.  
9.4.2
Identity of Investigational Product
Lemborexant will be supplied by the sponsor in labeled containers.  
Study drug must be stored as instructed on the study drug label.  Study drug must be kept in a 
secure location and carefully stored at the study site within its original container.  The 
sponsor will provide the study drug packaged as open-label supplies.  Each subject’s study 
drug will consist of lemborexant tablets supplied in bottles.
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-fluoropyridin-2-yl)cyclopropanecarboxamide)

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
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9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Based on ZOL use during the Screening Period, subjects will be assigned to 1 of 2 cohorts as 
shown below:  (revised per Amendment 01)
Cohort 1 (Intermittent ZOL Use):  taking ZOL at least 3 but fewer than 5 nights per week, 
for the last 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  taking ZOL at least 5 nights per week for the last 2 weeks
of the 3-week Screening Period  
The subjects who meet both criteria for intermittent and frequent ZOL use for 1 week
each of the last 2 weeks of the 3-week Screening Period will be assigned to Cohort 1 and 
referred to as Cohort 1-Mixed. (revised per Amendment 02)
All subjects (approximately 20) in Cohort 1 will receive LEM5. Subjects in Cohort 2 will be 
randomized to 1 of 2 Treatment Groups: Cohort 2A (approximately 20 subjects) will start on 
LEM5, and Cohort 2B (approximately 20 subjects) will start on LEM10. (revised per 
Amendment 02)
9.4.4
Selection of Doses in the Study
The doses to be administered are LEM5 and LEM10.  In December 2018, these doses were 
submitted for approval in the US for the indication of insomnia.  These doses were originally 
selected after conducting a dose-finding study (E2006-G000-201) after which their safety 
and efficacy were confirmed in 2 Phase 3 studies, Studies 303 and 304.
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9.4.5
Selection and Timing of Dose for Each Subject
Subjects will be provided a supply of LEM5 and LEM10 to be taken at home within a few 
minutes of the time they intend to sleep.  Subjects will be instructed on study restrictions 
pertaining to duration of time spent in bed, use of alcohol, and timing of meals.  Subjects will 
be instructed not to alter (ie, break or cut) their tablets of LEM.
9.4.6
Blinding
This is an open-label study with randomization to treatment for subjects assigned to 
Cohort 2.
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 or 30 days before first 
dose/administration of study drug, if appropriate) will be recorded.  The adverse event or 
medical condition for which the concomitant medication or therapy was administered will be 
recorded.
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 Treatment Period.
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 the protocol, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that strong and moderate cytochrome P450 (CYP)3A 
inhibitors and all CYP3A inducers will not be permitted at any time for any duration during 
the study.
9.4.7.1
Drug-Drug Interactions
Coadministration with moderate and strong 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 2.  
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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
Prohibited Concomitant Therapies and Drugs
Prohibited medications (Appendix 2) 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 Treatment Period.
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A 
inducers.  Prohibited therapies also include: any pharmacologic treatment for insomnia 
disorder (with the exception of ZOL use during the Screening Period only); medications that 
are used for the purpose of inducing sleep (hypnotics) and medications that have known 
sedating effects.  This prohibition applies even if the entire class to which that medication 
belongs is not prohibited (eg, anticonvulsants).
If a medication is not on the list of prohibited medications (Appendix 2) 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 2, 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.  
If a subject starts any prohibited medication or a new treatment/modality for insomnia 
disorder, he/she must discontinue from the study.
Subjects must forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study.  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 bottles returned to the investigator at the end 
of the Titration Period.
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
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
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB for the institution where the study is to be conducted

A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study

The IRB membership list and statutes or Health and Human Services Assurance number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV

A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study
drugs (dispensing, inventory, and record keeping) following the sponsor’s 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, (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, Medicine and Healthcare products Regulatory Agency [MHRA]).  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 
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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, sealed, and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  Where study drugs are approved for destruction at the site, 
destruction will occur following the site’s standard procedures and certificates of destruction 
will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic 
information will include birth year, sex, and race/ethnicity.  
9.5.1.2
Screening and Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical, sleep, and psychiatric history will be recorded as designated in the Schedule of 
Procedures/Assessments (Table 3).  All medical and surgical history within 5 years must be 
noted in the Medical History and Current Medical Conditions CRF.
Physical examinations will be performed, as designated in the Schedule of 
Procedures/Assessments (Table 3).  A full physical examination will include evaluation of 
the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, 
skin, and a brief neurological examination to assess possible impairment in major functions 
(ie, motor, cerebellar, sensory, major pathological reflexes) (revised per Amendment 02).
The urogenital examination will be excluded (revised per Amendment 02), unless there are 
special circumstances and at the discretion of the investigator.  Documentation of the 
physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.  Changes from screening physical examination findings that meet the 
definition of an AE will be recorded on the Adverse Events CRF.
9.5.1.2.2
SLEEP DRUG HISTORY QUESTIONNAIRE
At Screening, subjects will complete a questionnaire reporting their history and response to 
prior sleep medications, as well as their motivation for participating in the study.
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9.5.1.2.3
SLEEP DISORDER 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 Sleep Disorders Screening Battery (SDSB) will 
be administered (see below).  
The SDSB will include the following, to be self-administered by subjects: 

The STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects 
for OSA (Chung et al., 2008)

The IRLS:  a subjective scale comprising 10 questions, which measures disease severity 
of restless legs syndrome (Abetz et al., 2006).
9.5.1.2.4
SLEEP DRUG EXPERIENCE INTERVIEW – ZOLPIDEM
At the end of the Screening Period, subjects will be asked questions about their subjective 
experiences while taking ZOL.  The responses will be compared to the Sleep Drug 
Experience Interview – Lemborexant, which is done at the end of the Treatment Phase, in 
order to provide qualitative information regarding an individual’s subjective experience with 
LEM compared to ZOL.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
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. The ISI 
will be completed at each study visit except Follow-up Visit.  
9.5.1.3.2
PATIENT’S GLOBAL IMPRESSION – INSOMNIA
The PGI-I is a self-report assessment of subject perception of the effects of a medication on 
their sleep (Herring, et al., 2018).  The PGI-I has 3 items related to study medication effects 
(a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) 
increased/decreased total sleep time, and 1 item related to perceived appropriateness of study 
medication strength.  The first 3 items are answered on a 3-point scale (1=positive 
medication effect, 2=neutral medication effect, 3=negative medication effect) and the last 
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item on a different 3 point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior 
evening during the Screening, Baseline, and Titration Periods.
9.5.1.3.3
QUALITY OF SLEEP RATING
The Quality of Sleep Rating (Krystal and Edinger, 2008) is a self-reported scale in which 
subjects are asked, “How would you rate the quality of your sleep last night, with 1 being 
extremely poor, 5 being not good or poor, and 9 being extremely good?” For Quality of 
Sleep, higher values are better.  The Quality of Sleep Rating will be completed each morning 
following a dose of ZOL or LEM taken the prior evening during the Screening, Baseline, and 
Titration Periods.
9.5.1.3.4
SLEEP DRUG EXPERIENCE INTERVIEW – LEMBOREXANT
At the end of the Titration Period, subjects will be asked questions about their subjective 
experiences while taking LEM.  The responses will be compared to the Sleep Drug 
Experience Interview – ZOL, which is done at the end of the Screening Period, in order to 
provide qualitative information regarding an individual’s subjective experience with LEM 
compared to ZOL.
9.5.1.3.5
ACTIGRAPHY  (REVISED PER AMENDMENT 01)
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity 
monitor that looks like a wrist watch.  This device incorporates a multidirectional 
accelerometer to monitor degree and intensity of motion.  Data from an actigraph are 
collected at a sampling rate of every 30 seconds and are scored as sleep or wake with a 
validated algorithm.  Sleep/wake parameters are calculated from the scored data. 
Eligible subjects will be provided with an actigraph (for actigraphy) to wear continuously
throughout the Screening Period, and, for those who qualify at the end of the Screening 
Period for study enrollment, during the Treatment Phase. Subjects will be provided with a 
daily log (sleep log) for noting the start and end times of nocturnal sleep periods and to log 
the approximate times that the actigraph was replaced on the subject’s wrist, if inadvertently 
removed. Subjects will be trained to use the actigraph and the log.  Site staff will instruct 
subjects to record (with the current date) the following timings in the log: in the evening, 
record the times when the actigraph was not worn; and in the morning, record the bedtimes 
and morning rise times.  Site staff will emphasize the importance of recording these timings 
in the log.
A central actigraphy reader will score daily actigraphy records using a customized algorithm.  
The in-bed intervals will be provided to the central reader based on the sleep logs completed 
by the subject.  
Actigraphy data will be used to evaluate the following sleep and wake parameters for 
subjects during the Screening and Titration Periods:
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
TST: The total time spent in sleep according to the epoch-by-epoch wake/sleep 
categorization during time in bed (TIB)

SE: 100% × the total duration of sleep epochs during the defined nocturnal sleep 
period/TIB

WASO: The total time spent awake according to the epoch-by-epoch wake/sleep 
categorization between sleep start (based on 'lights out') and 'got up'

Wake Bouts: Wake of  ≥ 5 minutes that occur during TIB

Sleep Bouts: Continuous sleep ≥ 10 minutes that occur during Time Out of Bed (TOB)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
Not applicable.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades (for both increasing and 
decreasing severity), regular monitoring of hematology, blood chemistry, and urine values; 
periodic measurement of vital signs and ECGs; and performance of physical examinations.  
Subjects will be asked about falls at every visit.
Sponsor’s grading for laboratory values are presented in Appendix 1. 
Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure.  A set of 
preferred terms (PTs) 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 [ standard 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 SAE form for any of the 
above events that meet serious criteria.
9.5.1.5.1
ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
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relationship with the medicinal product.  For this study, the study drug is lemborexant (in 
doses of 5 mg and 10 mg). 
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, x-ray) that results in symptoms, a change in treatment, or discontinuation 
of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase
and for 7 days or 5× the half-life after the last dose, whichever is longer.  SAEs will be 
collected for 28 days after the last dose or for 5× the half-life, whichever is longer.  
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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 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.
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 9.5.1.5.8 for a description of the C-SSRS). 
The number (percentage) of subjects with treatment emergent adverse events (TEAEs) of 
cataplexy or other events that are characterized according to the customized MedDRA query 
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PT as cataplexy related events will be summarized separately.  The number of adjudicated 
events based on the report of the Adjudication Committee will also reported separately.
Customized MedDRA Queries for AEs that could potentially be considered cataplexy will be 
summarized.  The results of the deliberation of the Adjudication Committee will be reported 
separately.  All AEs must be followed for 28 days, or 5× the half-life, whichever is longer
after the subject’s last dose, or until resolution, whichever comes first.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
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?
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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 adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed 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
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If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
STUDY-SPECIFIC ADVERSE EVENTS
Not applicable. (revised per Amendment 02)
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 3) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study (Core Study).
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the Screening, Baseline, and Titration Periods 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.  Local laboratories will perform tests to qualify 
subjects for entry into the study.  Laboratory certification as available will be included in the 
final clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.5
VITAL SIGNS, HEIGHT, AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3) 
by a validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  Height is measured once at Screening.
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in 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) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
Columbia-Suicide Severity Rating Scale
The C-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  Suicidality will be assessed as designated in the Schedule of 
Procedures and Assessments (Table 3), using a site-administered version of the C-SSRS 
(Posner, et al., 2011).  
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women 
and postmenopausal women who have been amenorrheic for less than 12 consecutive months
as designated in the Schedule of Procedures/Assessments (Table 3).
Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 3).  This sample will be tested for common 
drugs of use/abuse: eg, propoxyphene, cocaine metabolites, cannabinoids, methadone, 
phencyclidine (PCP), opiates, benzodiazepines, barbiturates, and amphetamines.
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9.5.2
Schedule of Procedures/Assessments – Core Study
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments for the Core Study.
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study (revised per 
Amendment 01)
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Sleep Drug History Questionnaire
X
Sleep Disorder Screening Batteryg
X
Insomnia Severity Index
X
Xh
X
X
X
X
C-SSRS
X
Xh
X
X
X
X
X
Medical, sleep, psychiatric history
X
Prior and concomitant medications
X
Xh
X
X
X
X
X
Dispense study drug
X
X
Retrieve unused study drug
X
X
Study drug compliance
X
X
X
Physical examinationi
X
Xh
X
X
X
X
X
Vital signs and weight
X
Xh
X
X
X
X
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study (revised per 
Amendment 01)
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
Height
X
Clinical laboratory testsj
X
X
X
X
X
Urine drug screenk
X
Xh
X
X
X
X
Urine pregnancy testl
X
Xh
X
X
X
X
Serum pregnancy testl,m
X
X
12-lead ECGn
X
Xh
X
X
X
X
PGI-Io
X
Xh
X
X
X
X
Quality of Sleep Ratingo
X
Xh
X
X
X
X
Sleep Drug Experience Interview -
zolpidem
X
X
X
Sleep Drug Experience Interview -
lemborexant
X
Dispense actigraph
X
Retrieve actigraph
Xp
X
X
Review data from data collection 
Xh
X
X
X
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study (revised per 
Amendment 01)
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
system and sleep log
Adverse eventsq,r
X
Xh
X
X
X
X
X
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C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram, PGI-I = Patient Global Impression – Insomnia, T = Termination Visit, UNS = Unscheduled Visits
All visits to be done within ±7 days of the schedule, except for Visits 2, 3 and 4, which must be done within ±3 days.
a:
The Follow-up Visit will be conducted 4 weeks after the End of Study Visit for subjects who completed the Titration Period but do not enter the Extension Phase.
b:
Subjects will return to clinic at the end of the Screening Period.  The Baseline Period will occur on the same day for subjects who remain eligible for study enrollment. 
Assessments conducted at the end of the Screening Period (Visit 2a) will serve as the assessments for the Baseline Period (Visit 2b) if a subject is enrolled into the Treatment 
Phase. Assessments will be performed once across Visit 2a and Visit 2b.  Assessments to be conducted at Baseline (but which are not done at Visit 2a) will include clinical 
laboratory tests and dispensing of study drug.
c:
This visit will represent the End of Study Visit for subjects who completed the Titration Period but are not entering the Extension Phase.  Subjects should otherwise enter the 
Extension Phase immediately after completion of the Titration Period of the Core Study, in which case this visit will also serve as the first visit of the Extension Phase.
d:
Subjects who discontinue study drug prematurely at any time after entering the Treatment Phase will be encouraged to return to the site as soon as practicable (preferably 
within 7 days) to complete the Early Termination Visit.
e:
ECG will only be done during Early Termination and Unscheduled Visits if the results from the previous visit were deemed to be clinically significant by the investigator.
f:
Assessments during Unscheduled Visits will be conducted at the discretion of the investigator.
g:
Sleep Disorders Screening Battery comprises: STOP Bang and International Restless Legs Scale.
h:
Data for Visit 2a will represent the Baseline Period (Visit 2b) assessment if the subject is enrolled.  Assessments will be performed once across Visit 2a and Visit 2b.
i:
A full physical examination will be conducted at Visit 1. A brief physical examination will be conducted (including head, eyes, ears, nose, throat, heart, lungs, abdomen, and 
extremities, and at the discretion of the investigator, other physical conditions of note) at Visit 2a, Visit 3, and at the Follow-up Visit. For Early Termination and Unscheduled 
Visits, a physical examination will be conducted at the discretion of the investigator.  (revised per Amendment 02)
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
k:
Urine drug test at Unscheduled Visits will be conducted at the discretion of the investigator and at Early Termination only for subjects who withdraw because of an AE
l:
Female subjects of child-bearing potential only.
m:
To be conducted at Visit 1, and if urine pregnancy testing is positive.
n:
The ECG should be repeated if a clinically significant (as determined by the investigator) abnormality is observed.
o:
From the beginning of the Pretreatment Phase to the end of the Treatment Phase, and provided an insomnia drug was taken the night prior, PGI-I and Sleep Quality Rating 
data will be entered into the electronic data capture system by the subject. 
p:
Actigraphs will be collected from subjects who do not meet Screening criteria after data review at Visit 2a.  (revised per Amendment 01)
q:
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a narrative for the 
event, per Section 9.5.1.5, Adjudication Committee.
r:
If possible, a blood sample for the measurement of study drug plasma concentration should be drawn at the first report of an SAE or a severe unexpected AE and its 
resolution. (revised per Amendment 01)
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Table 5 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 3.
9.5.3
Appropriateness of Measurements
The clinical assessments are standard measurements commonly used in studies of drugs for 
the treatment of subjects with insomnia.
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. Because the objectives of this study include assessing the 
response to lemborexant of nighttime sleep and daytime impairment complaints, the ISI will 
be evaluated for changes from baseline.
The PGI-I has been used in studies evaluating the impact of treatment for insomnia on the 
patients’ global perceptions of sleep quality and quality of life.
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.  
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 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase, after the subject’s last dose.  All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator 
to be related to the study treatment or any protocol-required procedure should be reported to 
the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
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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 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the 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 a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, 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 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
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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 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
Not applicable.
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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 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early termination procedures indicated in 
the Schedule of Procedures/Assessments (Table 3).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic response, 
withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In addition to the 
primary reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event CRF.
Sites will be assessed for the appropriateness of study drug storage and retrieval at the time 
of site selection.  Required policies and procedures will be clearly communicated to the site 
to assess the site’s capabilities and adherence to storage, dispensing, reconciliation, and 
retention of study drug.
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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.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and a snapshot of the database is obtained and released) and randomization codes 
have been released.  Statistical analyses will be performed using SAS software or other 
validated statistical software as required.  The study endpoints for efficacy and safety will 
presented by treatment group (LEM5 and LEM10) and by pooling across treatments within 
each cohort and overall.  Missing data will not be imputed. Further details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of the Core Study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database lock.
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9.7.1.1
Study Endpoints
This study is designed to reflect clinical practice, in which patient satisfaction of the 
treatment after switching is an important consideration for maintaining a patient on that 
treatment.  This was the basis for defining the outcome of transition to lemborexant.  While 
sleep quality assessments are included as secondary outcomes in this pilot study to 
supplement the Phase 3 clinical trial data, it is not necessary to establish the absolute amount 
of improvement in sleep parameters, but rather whether the subject is satisfied enough to 
continue treatment with lemborexant.   
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of overall subjects who transition to LEM at the end 
of the Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week 
Titration Period and either 1) enters the Extension Phase, or 2) chooses to not enter the 
Extension Phase for reasons not related to LEM (including, but not limited to, time 
commitment related to the study, study-related travel expenses or preference to continue 
insomnia management with another health care provider).
9.7.1.1.2
SECONDARY ENDPOINTS  (REVISED PER AMENDMENT 01)
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration 
Period within each Cohort.

The proportion of subjects in the LEM5 treatment groups with dose increasing to 
LEM10 at the end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at 
the end of the Titration Period in Cohort 2.

The proportion of subjects with positive medication effect rating on each PGI-I item at 
the end of the 2-week Titration Period by Cohort and overall using end of the Titration 
Period treatment. 
9.7.1.1.3
EXPLORATORY ENDPOINTS  (REVISED PER AMENDMENT 01)
The exploratory endpoints are as follows:  

The change from Baseline in mean ISI score at the end of the Titration Period by Cohort 
and overall using end of the Titration Period treatment.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration 
Period by cohort and overall using end of the Titration Period treatment
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
To compare nights on which an evening dose of LEM5 or LEM10 was taken, to nights 
on which an evening dose of ZOL was taken, for the following sleep-related actigraphy 
variables:
o
Mean TST
o
Mean SE
o
Mean WASO
o
Number of Wake Bouts

To compare the daytime after an evening dose of LEM5 or LEM10 was taken, to the 
daytime after an evening dose of ZOL was taken, for the following wake-related 
actigraphy variable:
o
Mean Duration of Sleep Bouts
9.7.1.2
Definitions of Analysis Sets
Safety Analysis Set (SAS) – The SAS is the group of subjects who received at least 1 dose of 
study drug and had at least 1 postdose safety assessment.
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included
in the FAS.
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 and treatment discontinuation.  Other reasons for study treatment and study 
terminations will also be summarized.  These tabulations will be produced for all randomized 
subjects by randomized treatment groups.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each randomized and end of the Titration Period treatment groups 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 
(<18.5, 18.5 to <25, 25 to ≥30), race, and ethnicity.
Characteristics of insomnia at Study Baseline will be summarized using ISI, PGI-I, and 
Quality of Sleep Rating. 
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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 WHO Drug Global March 2019 or later. The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by randomized treatment group, Anatomical Therapeutic Chemical 
(ATC) class, and WHO-DD PT.  
9.7.1.6
Efficacy Analyses
All efficacy analyses will be conducted on the FAS.  Efficacy endpoints may be analyzed by 
modeling methods if warranted.  Details of all of the analyses will be specified in the 
Statistical Analysis Plan.  (revised per Amendment 01)
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in 
the Titration Period will be displayed.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES  (REVISED PER AMENDMENT 01)
The secondary analyses are as follows:

The proportion of subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed within each cohort.  

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall.

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented.

The proportion of subjects in each of the 4 items of the PGI-I will be summarized 
separately within each scale over time by Cohort and overall using end of the Titration 
Period dose groups.  

The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these 
items at the end of the Titration Period, and the proportion of subjects who rated the drug 
as being too strong or too weak at Baseline, but whose rating was “just right” at the end 
of the Titration Period (as data allow) will be reported.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES  (REVISED PER AMENDMENT 01)

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on 
the ISI will be summarized at the end of the Titration Period by Cohort and overall 
using end of the Titration Period dose groups.
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
The change from baseline in mean Quality of Sleep Rating score for subjects at the 
end of the Titration Period will be summarized by cohort and overall using end of 
Titration Period dose groups.

Average value of following sleep-related actigraphy variables will be summarized by 
treatment over the nights on which an evening dose of LEM5, LEM10, and ZOL was 
taken.  
o
Mean TST
o
Mean SE
o
Mean WASO
o
Number of Wake Bouts

Average value of wake-related actigraphy variable, mean duration of Sleep Bouts will 
be summarized by treatment over the daytime after an evening dose of LEM5,
LEM10, and ZOL was taken.  
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
Not applicable.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
end of Titration Period dose groups, will be summarized on an “as treated” basis using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include TEAEs,
physical examination, clinical laboratory parameters, vital signs, 12-lead ECG results, and 
the C-SSRS.  Study Day 1 for all safety analyses will be defined as the date of the first dose 
of study drug.  
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
AEs summaries, and abnormal findings will also be displayed based on the dose that the 
subjects were taking at the time of the findings.
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.  
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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 22.0 or higher) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA PT and primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
Adverse events will be summarized using the Safety Analysis Set.  The incidence of AEs will 
be summarized by end of Titration Period dose for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics.  To obtain the incidence (%), the 
number of subjects with at least 1 event and the percentage of subjects with AEs by SOC and 
by PT will be calculated.  Incidence (%) by causal relationship with study drug and by 
severity will also be calculated.  For clinically significant events, time of onset, and recovery 
will be reported.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data 
listing of all SAEs will be provided.
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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 a Customized MedDRA Query (CMQ) PT as cataplexy-related 
events, as well drug abuse liability will be summarized separately.  The number of 
adjudicated events based on the report of the Adjudication Committee will also reported 
separately.  In addition, 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, as per the Adjudication Committee description.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.4, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and end of Titration Period dose using 
descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.4 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs). Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Mean changes from baseline in vital signs (ie, systolic and diastolic BP, pulse, respiratory 
rate, body temperature, weight) and out-of-range vital signs will be summarized by end of 
Titration Period dose groups for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent
ZOL use) using descriptive statistics.
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Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 4).  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 
end of Titration Period dose and time point.
Table 4
Clinically Notable Vital Sign Criteria
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
ECG assessments will be performed at Screening and at the end of the Titration Period.  The 
incidence of abnormal ECG findings will be summarized by end of Titration Period dose for 
Cohort 1 (Intermittent ZOL Use) and Cohort 2 (Frequent ZOL Use) using descriptive 
statistics.  Shift tables will present changes from baseline in ECG interpretation (categorized 
as normal and abnormal) by time point.
9.7.1.8.6
OTHER SAFETY ANALYSES
The results of C-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.
9.7.2
Determination of Sample Size
As a pilot study, sample size estimates are not based on statistical calculations. 
This study will enroll approximately 60 subjects across 3 treatment arms (Cohort 1, Cohort 
2A, and Cohort 2B) to evaluate the proportion of subjects who transition to LEM as a 
substitute for ZOL.  Approximately 20 subjects will be assigned to Cohort 1 (Intermittent 
ZOL Use), and 40 subjects will be assigned to Cohort 2 (Frequent ZOL Use), with 
approximately 20 subjects randomized to receive LEM5 or LEM10 within Cohort 2.  This 
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sample size is deemed sufficient to inform whether the proposed strategies are sufficient to 
determine whether alternative strategies would be required to help understand how best to 
recommend safe and effective methods for transitioning from ZOL to LEM.  (revised per 
Amendment 02)
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
Abetz L, Arbuckle R, Allen RP, Diego GB, Hening W, Walters SA, et al. The Reliability, 
Validity and Responsiveness of the International Resless Legs Syndrome Study Group 
Rating Scale and Subscales in a Clinical-Trail setting. Sleep Med. 2006;7: 340-49.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders, 
5th ed. American Psychiatric Publishing, 2014.
Bastien CH, Vallieres A, Morin CM.  Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med. 2001;2:297-7.
Belsomra (suvorexant) tablets, for oral use, Prescribing Information [updated 12 Jul 2018; 
cited 09 Sept 2018]. Available from:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5b72731-1acb-45b7-9c13-
290ad12d3951
Bertisch SM, Herzig SJ, Winkelman JW, Buettner C.  National use of prescription 
medications for insomnia: NHANES 1999-2010.  Sleep.  2014;37(2):343-9.
Beuckmann CT, Suzuki M, Ueno T, Nagaoka K, Arai T, Higashiyama H.  In vitro and in 
silico characterization of lemborexant (E2006), a novel dual orexin receptor antagonist. 
J Pharmacol Exp Ther. 2017;362(2):287–95.
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(5):812-21.
Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Snyder E, et al. A Phase II 
dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist 
filorexant (MK-6096) in patients with primary insomnia. Int J Neuropsychopharmacol. 
2016;19:1–10.
De Boer P, Drevets WC, Roael H, van der Ark P, Kent JM, Kezic I, et al. A randomized 
Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with 
insomnia without psychiatric comorbidity. J Psychopharmacol. 2018;32:668–77.
Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. Orexin receptor 
antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 
2012;79:2265–74.
Herring WJ, Snyder E, Tao P, Svetnik V, Lines C.  Performance of the Patient Global 
Impressions – Severity Scale as a self-reported patient assessment of insomnia severity. 
Neurology.  2018;90(15 Suppl):1-107.
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Hoever P, Dorffner G, Beneš H, Penzel T, Danker-Hopfe H, Barbanoj MJ, et al. Orexin 
receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin 
Pharmacol Ther. 2012;91(6):975–85.
Irish LA, Kline CE, Gunn HE, Buysse DJ, Hall MH.  The role of sleep hygiene in promoting 
public health: A review of empirical evidence. Sleep Med Rev.  2015(22):23–36.
Krystal AD, Edinger JD. Sleep Med. Measuring sleep quality.  2008;9(Suppl 1):S10-7.
Kyle SD, Miller CB, Rogers Z, Siriwardena AN, MacMahon KM, Espie CA.  Sleep 
restriction therapy for insomnia is associated with reduced objective total sleep time, 
increased daytime somnolence, and objectively impaired vigilance: implications for the 
clinical management of insomnia disorder. Sleep.  2014;37(2):229–37.
Morgenthaler T, Kramer M; Alessi C, Friedman L, Boehlecke B, Brown T, et al.  Practice 
parameters for the psychological and behavioral treatment of insomnia: an update.  An 
American Academy of Sleep Medicine report. Sleep.  2006;29(11):1415–19.
Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a 
dual orexin receptor antagonist (DORA) for the treatment of insomnia disorder:  results from 
a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin Sleep Med. 
2017;13:1289–99.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The 
Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77.
Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, et al.  Oral 
nonprescription treatment for insomnia: an evaluation of products with limited evidence.  J 
Clin Sleep Med. 2005 Apr 15;1(02):173–87.
Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M.  Clinical guideline for the 
evaluation and management of chronic insomnia in adults.  J Clin Sleep Med.
2008;4(5):487–504.
Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL.  Clinical practice guideline for 
the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep 
Medicine clinical practice guideline, J Clin Sleep Med, 2017;13(2): 307-49.
Stepanski EJ, Wyatt JK.  Use of sleep hygiene in the treatment of insomnia.  Sleep Med Rev.
2003 Jun 1;7(3):215–25.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB 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 detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts
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
Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as Interactive Voice/Web Response 
System (IxRS), x-rays, and other imaging reports (eg, sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation)

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

Electronic Patient-Reported Outcome by self-reported measures
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
The efficacy assessments are evaluated based on the data entered into electronic Patient-
Reported Outcome.  The applicable data are input directly by each subject from the 
viewpoint of his/her health condition without the interpretation of the investigator. 
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
The data collected by electronic Patient-Reported Outcome are also considered source data.  
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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or designated contractor, or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
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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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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 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
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
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 

gamma-aminobutyric acid (GABA)
analogues 

Hydantoins 

Phenyltriazines
Antihistamines (centrally-acting H1, including 
over-the-counter [OTC]) 

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

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
Moderate CYP3A inhibitors 

Amprenavir

Aprepitant

Atazanavir

Casopitant

Cimetidine

Ciprofloxacin

Clotrimazole

Crizotinib

Cyclosporin

Darunavir

Dronadarone

Erythromycin

Faldaprevir

Fluconazole

Fluvoxamine

Imatinib

Netupitant

Tofisopam

Verapamil
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Category
Medication
Cytochrome P450 (CYP)3A inducers

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

-
Monoamine oxidase inhibitors (MAOIs)

-
Opioid Analgesics

-
Muscle relaxants (centrally-acting) with known sedating 
effects

GABA analogues 

Hydantoins 

Phenyltriazines
Other

Warfarin, heparin, ticlopidine

Systemic isoretinoin

Systemic glucocorticoids
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Appendix 3
Extension Phase
Study Design and Plan
The Extension Phase comprises a Maintenance Period of up to 12 weeks in duration, and a 
Follow-up Period visit that is to occur 4 weeks after the end of the Maintenance Period.
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of Lemborexant 
(LEM) that they took at the end of the Titration Period.  Subjects will subsequently return to 
clinic at the visit as specified in the Schedule of Assessments, and will be instructed to return 
their supply of LEM at each visit.  Unused study drug will be collected, and study drug 
compliance will be assessed. Subjects will be able to discuss changing the dose of LEM at 
any time during the Maintenance Period, and LEM dose changes may be implemented as 
clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all 
subjects (eg, 4 weeks after the end of the Maintenance Period).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study.  
Study Drug Supplies
Subjects will enter the Extension Phase from the Titration Phase of the Core Study, taking 
the same dose of LEM that was their final dose of the Titration Phase, ie, LEM5 or LEM10 
taken orally in tablet form at night a few minutes before the time the subject intends to try to 
sleep.
Schedule of Procedures/Assessments
Table 5 presents the Schedule of Procedures and Assessments for the 12-week Extension 
Phase.
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 – Extension (revised per 
Amendment 01)
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS
X
X
X
X
Prior and concomitant medications
X
X
X
X
Study drug compliance
X
X
X
Dispense study drug
Retrieve unused study drug
X
X
X
Physical examinatione
X
X
X
X
Vital signs and weight
X
X
X
X
Clinical laboratory testsf
X
X
X
Urine drug screeng
X
X
X
Urine pregnancy testh
X
X
X
Serum pregnancy testh,i
X
12-Lead ECGj
X
X
X
Adverse eventsk,l
X
X
X
X
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 – Extension (revised per 
Amendment 01)
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram.
All visits to be done within ±7 days of the schedule.
a:
The Follow-up Visit will be conducted 4 weeks after the end of the Extension Phase.
b:
Subjects who discontinue study drug prematurely at any time after entering the Extension will be encouraged to return to the site as soon as practicable 
(preferably within 7 days).
c:
During Early Termination and unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the 
investigator.
d:
Assessments during an Unscheduled Visit to be conducted at the discretion of the investigator.
e:
A full physical examination will be conducted at Visit 4 and 5. For Early Termination and Unscheduled Visits, a full physical examination will be conducted
at the discretion of the investigator. (revised per Amendment 02)
f:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
g:
Urine drug test to be conducted at Unscheduled Visits at the discretion of the investigator and at Early Termination only for subjects who withdraw because of 
an adverse event. 
h:
Female subjects of child-bearing potential only. 
i:
To be conducted if urine pregnancy testing is positive
j:
The ECG should be repeated if a clinically significant abnormality (as determined by the investigator) is observed.
k:
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 9.5.1.5, Adjudication Committee
l:
If possible, a blood sample for the measurement of study drug plasma concentration should be drawn at the first report of an SAE or severe unexpected AE and 
at its resolution.  (revised per Amendment 01)
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Statistical Analyses
All statistical analyses will be the responsibility of the Biostatistics Department of Eisai.  
Statistical programming and analyses will be performed using SAS or other validated 
software. 
Safety Analyses
The primary focus of data summarization for the Extension Phase will be on safety and 
tolerability.  Evaluations of safety data will be performed on the Safety Analysis Set.
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product 
Name:
E2006\Lemborexant
IND Number:
111871
SIGNATURES
Authors:
Eisai, Inc
Date
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product
Name:
E2006\Lemborexant
IND Number:
111871
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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Clinical Study Protocol  
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Confidential 
Page 1 of 85  
 
REVISION HISTORY 
 Revisions to Version 2.0  
 New version /date:  Version 3.0/03 Jun 2019 (per Amendment 01) 
Change 
Rationale 
Affected Protocol Sections 
Addition of actigraphy 
To provide objective data on the 
effect of LEM and ZOL on sleep 
and wake parameters 
Section 2 – Exploratory Objectives 
Section 2 – Study Design 
Section 2 – Efficacy Assessments 
(Core Study only) 
Section 2 – Statistical Methods 
Section 2 – Efficacy Analyses 
(Core Study only) 
Section 8.3 
Section 9.1.1.1 
Section 9.1.1.2 
Section 9.1.2.1 
Section 9.5.1.3.5 
Section 9.7.1.1.3 
Section 9.7.1.6.3 
Table 3 
Reorganization of secondary and 
exploratory objectives and 
endpoints 
To focus secondary endpoints on 
successful transition due to 
dose-related aspects of LEM 
Section 2 – Secondary Objectives 
Section 2 – Exploratory Objectives 
Section 8.2 
Section 8.3 
Section 9.7.1.1.2 
Section 9.7.1.1.3 
Section 9.7.1.6.2 
Section 9.7.1.6.3 
Clarification of cohort assignment 
based on ZOL use frequency 
Clarification  
Section 2 – Study Design 
Section 2 - Inclusion Criteria 
Section 2 - Exclusion Criteria 
Section 9.1 
Section 9.1.1.1 
Section 9.1.2.1 
Section 9.3.1 
Section 9.3.2 
Section 9.4.3 
Clarification of PK sampling in 
the event of an SAE or severe 
unexpected AE and its resolution 
Clarification 
Table 3 
Table 5 
Clarification of data collection at 
Visit 2a 
Clarification 
Table 3 
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 Revisions to Version 1.0  
 New version /date: Version 2.0/12 Apr 2019 
Change 
Rationale 
Affected Protocol Sections 
Modified the text in Exclusion 
Criterion No. 1 to replace urine 
pregnancy test with serum 
pregnancy test. 
Administrative change 
• 
Synopsis –Exclusion criteria 
• 
Section 9.3.2 
 
 
 
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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E2006-A001-312 
Study Protocol 
Title: 
A Multicenter, Pilot Study to Evaluate Next-Dose Transition from 
Zolpidem to Lemborexant for the Treatment of Insomnia  
Sponsor:  
Eisai Inc. 
100 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
US 
 
 
Investigational 
Product Name: 
E2006/Lemborexant  
 
Indication: 
Insomnia  
Phase: 
3b 
 
V1.0 
12 Apr 2019 (original protocol) 
 
V2.0 
12 Apr 2019 (revised original protocol) 
 
V3.0 
03 Jun 2019 (Amendment 01) 
IND Number: 
111871 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E2006 
Name of Active Ingredient:  Lemborexant 
Study Protocol Title 
A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the 
Treatment of Insomnia 
Investigator(s) 
Unknown 
Sites 
Approximately 15 sites within the United States of America 
Study Period and Phase of Development 
Phase 3b pilot study 
Estimated duration of up to 38 weeks from first subject in to last subject’s last visit. 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects with 
insomnia disorder taking zolpidem tartrate immediate release (ZOL-IR) or zolpidem tartrate extended 
release (ZOL-ER), intermittently or frequently, who  transition to lemborexant 5 mg (LEM5) or 10 
mg (LEM10), after 2 weeks of receiving lemborexant (LEM). 
Secondary Objectives  (revised per Amendment 01) 
• 
To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease from 
LEM10 to LEM5 during the 2-week Titration Period 
• 
To evaluate the subject impression of treatment using the Patient Global Impression of Insomnia 
(PGI-I) at the end of the 2-week Titration Period 
• 
To evaluate the safety and tolerability of LEM in subjects previously taking zolpidem (ZOL) 
Exploratory Objectives  (revised per Amendment 01) 
• 
To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared with 
Baseline at the end of the 2-week Titration Period 
• 
To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared with 
Baseline at the end of the 2-week Titration Period 
• 
To compare nights on which an evening dose of LEM, LEM5, and LEM10 was taken, to nights 
on which an evening dose of ZOL was taken, for the following sleep-related actigraphy variables: 
o Total Sleep Time (TST) 
o Sleep Efficiency (SE) 
o Wake After Sleep Onset (WASO) 
o Wake Bouts 
• 
To compare the daytime after an evening dose of LEM, LEM5, and LEM10 was taken, to the 
daytime after an evening dose of ZOL was taken, for the following wake-related actigraphy 
variable:  
o Sleep Bouts 
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Study Design 
E2006-A001-312 is a multicenter Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER.  
The study will consist of 3 phases:  a Pretreatment Phase (consisting of up to a 3-week Screening 
Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week Titration Period), and 
an Extension Phase consisting of the Maintenance Period up to 12 weeks and the Follow-up Period 
4 weeks in duration immediately following the end of the Treatment Phase.  The Pretreatment 
and Treatment Phases will comprise the Core Study.  A Follow-up Period visit occurring 4 weeks 
after the end of the Extension Phase (or Treatment Phase, for subjects not entering the Extension 
Phase) will be conducted. 
Core Study 
Pretreatment Phase 
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day Baseline Period, 
during which subjects will be assessed for eligibility to participate in the study.  
Screening Period 
During the Screening Period, subjects will be required to bring the container of their prescribed ZOL 
to the site for verification of prescribed medication and dose.  Subjects will be provided with, and 
trained in the use of, a data collection system to record the frequency of ZOL is taken during the 
3-week Screening Period.  Site staff will instruct subjects to complete data entry every morning and 
will emphasize the importance of providing these data.  During the Screening Period, subjects will 
continue to take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5mg or 
10 mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection system for 
at least 14 (preferably contiguous) days out of the allowable 21-day Screening Period in order to be 
eligible for study inclusion.  Eligible subjects will also be provided with an actigraph (for actigraphy) 
to wear continuously throughout the Screening Period.  Subjects will be provided with a daily log 
(sleep log) to note the start and end times of nocturnal sleep periods and to log the approximate times 
that the actigraph was replaced on the subject’s wrist, if inadvertently removed.  Subjects will be 
trained to use the actigraph and the log.  Site staff will instruct subjects to record (with the current 
date) the following timings in the log: in the evening, record the times when the actigraph was not 
worn; and in the morning, record the bedtimes and morning rise times.  Site staff will emphasize the 
importance of recording these timings in the log.  (revised per Amendment 01) 
Subjects will return to clinic at the end of the Screening Period.  Actigraph data will be downloaded 
and transmitted to the central reader, along with the sleep log of bedtimes, morning wake times, and 
the approximate times when the actigraph was replaced on the subject’s wrist.  (revised per 
Amendment 01) 
Based on ZOL use during the Screening Period (which must match the treatment history ascertained 
at the beginning of the Screening Period), subjects will be assigned to 1 of 2 cohorts as follows: 
• Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 5 nights per 
week, for  at least the last 2 weeks of the 3-week Screening Period, or (revised per Amendment 
01) 
• Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for at least the 
last 2 weeks of the 3-week Screening Period (revised per Amendment 01) 
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5).  For 
Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio.  
Baseline Period 
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The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment cohort.  
Subjects who are not eligible will conclude their participation, return their actigraphs and sleep logs 
to the study site, and will be considered screen failures.  Upon completion of the Baseline Period, 
subjects who remain eligible will enter the Titration Period.  (revised per Amendment 01) 
Treatment Phase 
Titration Period 
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and LEM10 to 
be taken at home within a few minutes of the time that they intend to sleep at night.  Subjects will 
continue to wear their actigraphs throughout the Titration Period, with the same instructions for use.  
Study restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals will 
be discussed.  Subjects will be instructed to not alter (ie, break or cut) their tablets of LEM.  (revised 
per Amendment 01) 
Cohort 1 (Intermittent ZOL Use):  Subjects in this cohort will decide when to take LEM according to 
their usual pattern, with the requirement that they take LEM at least once per week during the 2-week 
Titration Period.  (revised per Amendment 01) 
Cohort 2 (Frequent Use, Treatment Groups A and B):  Subjects in these cohorts will take LEM at 
least 5 nights per week during the 2-week Titration Period. 
For subjects with a starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but not 
mandated) to remain on their assigned dose for 7 days before calling the site should they feel that 
LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.   
For subjects with a starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site should they feel that LEM10 should be reduced.  
Subjects will then be instructed to take LEM5 within a few minutes of the time they intend to go to 
sleep.   
At the time of LEM dose change during the Core Study, the reason for the dose change will be 
recorded in the case report form (CRF).  Subjects will be allowed 1 LEM dose adjustment during 
the Titration Period.  Every morning, subjects will enter their insomnia drug use data into the data 
collection system and record their sleep log data, and, provided an insomnia drug was taken the night 
prior, PGI-I and Quality of Sleep Rating will be completed.  The ISI will be completed at each study 
visit except Follow-up Visit.  (revised per Amendment 01) 
Upon completion of the Titration Period, actigraphs will be returned to the study site, and subjects 
will be considered for eligibility to enter the Extension Phase.  (revised per Amendment 01) 
Extension Phase 
Maintenance Period 
During the 12-week Maintenance Period, subjects will continue on the dose of LEM that they took at 
the end of the Titration Period.  Subjects will subsequently return to clinic as specified in the 
Schedule of Assessments, and will be instructed to return their supply of LEM at each visit.  Unused 
study drug will be collected, study drug compliance will be assessed.  Subjects will be able to discuss 
changing the dose of LEM at any time during the Maintenance Period, and LEM dose changes may 
be implemented as clinically determined by the investigator with input from the subject. 
Follow-Up Period 
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all subjects (eg, 
4 weeks after the end of the Treatment Phase for subjects not entering the Extension Phase or after 
the end of the Extension Phase, for subjects entering the Extension Phase). 
End of Study 
The end of the study will be the date of the last study visit for the last subject in the study.  
 
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Number of Subjects 
Approximately 110 subjects will be screened to provide approximately 60 subjects (20 subjects in 
Cohort 1 and 40 subjects in Cohort 2 [20 in LEM5, 20 in LEM10]). 
Inclusion Criteria 
1. Male or female, 18 years or older, at the time of informed consent 
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5) criteria for 
Insomnia Disorder, either currently or prior to ZOL use, as follows: 
• 
Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep 
and/or awakening earlier in the morning than desired despite adequate opportunity for sleep 
• 
Frequency of complaint ≥3 times per week 
• 
Duration of complaint ≥3 months 
• 
Associated with complaint of daytime impairment 
3. Reports spending at least 7 hours in bed per night 
4. History of intermittent (taking ZOL at least 3 but fewer than 5 nights per week), or frequent use 
(at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month 
5. Confirmation of intermittent or frequent use of ZOL (based on review of drug use data).  
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for at least 
the last 2 weeks of the 3-week Screening Period.  Frequent use is defined as taking ZOL at least 5 
nights per week for at least the last 2 weeks of the 3-week Screening Period  (revised per 
Amendment 01) 
6. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 
hours each night 
7. Willing not to start another pharmacologic treatment for the management of insomnia during the 
subject’s participation in the study 
Exclusion Criteria 
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
serum pregnancy test).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug 
2. Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device or intrauterine hormone-releasing system (IUS) 
o a contraceptive implant 
o an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing and throughout the study and for 28 days 
after study drug discontinuation) 
o have a vasectomized partner with confirmed azoospermia. 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation 
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
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ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing). 
3. Any history of moderate or severe obstructive sleep apnea (OSA) 
4. Current evidence of a clinically significant, active respiratory disorder other than mild OSA.  
This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any 
other pulmonary disorder identified by review of medical history or physical examination, and 
which in the opinion of the investigator, could compromise the subject’s safety or interfere with 
study assessments 
5. A current diagnosis of periodic limb movement disorder, restless legs syndrome, circadian 
rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals 
with symptoms of certain sleep disorders other than insomnia as follows: 
• 
STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not excluded) 
• 
International Restless Legs Scale (IRLS) score ≥16 
6. Habitually naps during the day more than 3 times per week  
7. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator  
indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy 
8. 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 sleeping), 
whether spontaneous or associated with a pharmacological sleep agent. 
9. Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night 
10. Takes a dose of ZOL that is lower than what is prescribed 
11. Reports having altered ZOL tablets 
12. Reports intermittent or frequent use of ZOL at Visit 1 which is not confirmed, based on review of 
drug use data, at Visit 2a.  Intermittent use is defined as taking ZOL at least 3 but fewer than 5 
nights per week, for at least the last 2 weeks each of the 3-week Screening Period.  Frequent use 
is defined as taking ZOL at least 5 nights per week for at least the last 2 weeks of the 3-week 
Screening Period  (revised per Amendment 01) 
13. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study  
14. Used any prohibited prescription or over-the-counter concomitant medications within 1-week or 
5 half-lives, whichever is longer, before the first dose of study medication (A list of prohibited 
concomitant medications is presented in the protocol).   
15. Used any pharmacologic modality of treatment for insomnia other than zolpidem, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening Period 
16. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG 
17. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
Columbia-Suicide Severity Rating Scale [C-SSRS]) 
18. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS) 
19. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal 
disease) 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. 
20. Hypersensitivity to lemborexant or any of the excipients. 
21. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study. 
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22. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study. Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the investigator this operation does not interfere with the study procedures and patient safety. 
23. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics 
or prior suicide attempt(s) within approximately the last 2 years 
24. History of drug or alcohol dependency or abuse within approximately the last 2 years 
25. Currently enrolled in another clinical study or used any investigational drug or device within 28 
days or 5× the half-life, whichever is longer, preceding informed consent 
26. Previously participated in any clinical trial of lemborexant 
Study Treatment(s) 
Core Study 
Test drug:   
LEM5 or LEM10 taken orally in tablet form at night within a few minutes of the time the subject 
intends to sleep, according to the subject’s predetermined intermittent or frequent use schedule. 
Comparator Drug:  Not applicable  
Extension Phase 
Test drug:   
LEM5 or LEM10 taken orally in tablet form at night a few minutes before the time the subject 
intends to try to sleep. 
Duration of Treatment 
A maximum of 14 weeks:  
2 weeks of LEM5 and/or LEM10 during the Treatment Phase of the Core Study, 
12 weeks during the Extension Phase 
Concomitant Drug/Therapy 
Prohibited medications should not be used during the study.  A subject must not have used any 
prohibited prescription or over-the-counter medications within 1-week or 5 half-lives, whichever is 
longer, before the Treatment Phase. 
Prohibited medications include moderate and strong cytochrome P450 (CYP)3A inhibitors and all 
CYP3A inducers, and medications that have known sedating effects.  The prohibition applies even if 
the entire class to which that medication belongs is not prohibited (eg, anticonvulsants).   
If a medication is not on the list of prohibited medications but in the opinion of the investigator 
causes or exacerbates the subject’s insomnia, it must not be used throughout the study.  If a 
medication is not specified as prohibited but is in the same class as a medication that is listed in the 
protocol, and if the investigator is uncertain whether the medication has known sedating or alerting 
effects, the Medical Monitor must be consulted. 
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue 
from the study, with the exception that certain prohibited medications may be used for a short 
duration (not to exceed 2 weeks) to treat an acute condition if this is agreed with the Medical 
Monitor.  Note that strong and moderate CYP3A inhibitors and all CYP3A inducers will not be 
permitted at any time for any duration during the study.  Subjects must forgo alcohol consumption 
within 3 hours of bedtime for the duration of participation in the study.   
 
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Assessments 
Screening Assessments (Core Study only) 
Sleep Disorders Screening Battery (SDSB):  
The SDSB will include: 
• 
STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects for OSA  
• 
IRLS:  a subjective scale comprising 10 questions, which measures severity of symptoms of 
restless legs syndrome 
Sleep Drug History Questionnaire 
Subjects will be asked questions about their history and response to prior sleep medications. 
Sleep Drug Experience Interview – Zolpidem 
Subjects will be asked questions about their subjective experiences while taking ZOL at the end of 
the Screening Period. 
Efficacy Assessments (Core Study only) 
Patient Global Impression – Insomnia 
The PGI-I is a self-report assessment of subject perception of the effects of a medication on their 
sleep.  The PGI-I has 3 items related to study medication effects (a) helped/worsened sleep, (b) 
decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to 
perceived appropriateness of study medication strength.  The first 3 items are answered on a 3-point 
scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and 
the last item on a different 3-point scale (medication:  1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior evening. 
Insomnia Severity Index 
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia.  
The dimensions evaluated are severity of:  sleep onset, sleep maintenance, early-morning awakening 
problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning, 
noticeability of the sleep problems by others, and distress caused by the sleep difficulties.  A 5-point 
Likert scale is used to rate each item (from 0=no problem, to 4=very severe problem), yielding a total 
score from 0 to 28.  The ISI will be completed at each study visit except Follow-up Visit.   
Quality of Sleep Rating 
The Quality of Sleep Rating is a self-reported scale in which subjects are asked, “How would you rate 
the quality of your sleep last night, with 1 being extremely poor, 5 being not good or poor, and 9 
being extremely good?” For Quality of Sleep, higher values are better.  The Quality of Sleep Rating 
will be completed each morning following a dose of ZOL or LEM taken the prior evening during the 
Screening, Baseline, and Titration Periods. 
Sleep Drug Experience Interview – Lemborexant 
Subjects will be asked questions about their subjective experiences while taking LEM at the end of 
the Titration Period. 
Actigraphy  (revised per Amendment 01) 
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity monitor that 
looks like a wrist watch.  This device incorporates a multidirectional accelerometer to monitor degree 
and intensity of motion.  Data from an actigraph are collected at a sampling rate of every 30 seconds 
and are scored as sleep or wake with a validated algorithm.  Sleep/wake parameters are calculated 
from the scored data.  A central actigraphy reader will score daily actigraphy records using a 
customized algorithm.  The in-bed intervals will be provided to the central reader based on the sleep 
logs completed by the subject.  Actigraphy data will be used to evaluate the following sleep and wake 
parameters for subjects during the Screening and Titration Periods: 
• 
TST: The total time spent in sleep according to the epoch-by-epoch wake/sleep categorization 
during time in bed (TIB) 
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• 
SE:  100% × the total duration of sleep epochs during the defined nocturnal sleep period/TIB 
• 
WASO:  The total time spent awake according to the epoch-by-epoch wake/sleep categorization 
between sleep start (based on 'lights out') and 'got up' 
• 
Wake Bouts:  Wake of  ≥ 5 minutes that occur during TIB 
• 
Sleep Bouts:  Continuous sleep ≥ 10 minutes that occur during Time Out of Bed (TOB) 
Pharmacokinetic Assessments 
Not applicable. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable.  
Safety Assessments (Core Study and Extension Phase) 
Safety assessments will consist of monitoring and recording all adverse events (AEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of 
vital signs, weight and ECGs; and the performance of physical examinations.  Subjects will be asked 
about falls at every visit. 
 
Adjudication Committee 
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure.  A set of preferred terms (PTs) 
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.   
Columbia – Suicide Severity Rating Scale 
Suicidality will be assessed using a site-administered version of the C-SSRS.  The C-SSRS assesses 
an individual’s degree of suicidality, including both suicidal ideation and suicidal behavior.  
Pregnancy Test 
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months as designated in the 
Schedule of Procedures/Assessments. 
Urine Drug Test 
A 30-mL urine sample will be collected at designated time points as specified in the Schedule of 
Procedures/Assessments.  This sample will be tested for common drugs of use/abuse:  eg, 
propoxyphene, cocaine metabolites, cannabinoids, methadone, PCP, opiates, benzodiazepines, 
barbiturates, and amphetamines. 
Bioanalytical Methods 
Not applicable. 
Statistical Methods 
The study endpoints for efficacy and safety will be presented by treatment group (LEM5 and 
LEM10) and by pooling across treatments within each cohort and overall.  Missing data will not be 
imputed. 
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Primary Endpoint 
The primary endpoint is the proportion of overall subjects who transition to LEM at the end of the 
Titration Period. 
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week Titration 
Period and either 1) enters the Extension Phase, or 2) chooses to not enter the Extension Phase for 
reasons not related to LEM (including, but not limited to, time commitment related to the study, 
study-related travel expenses, or preference to continue insomnia management with another health 
care provider).   
Secondary Endpoints (revised per Amendment 01) 
The secondary endpoints are as follows: 
• 
The proportion of subjects who transition to LEM at the end of the 2-week Titration Period 
within each Cohort. 
• 
The proportion of subjects in the LEM5 treatment groups with dose increasing to LEM10 at 
the end of the Titration Period by Cohort and overall. 
• 
The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at the 
end of the Titration Period in Cohort 2. 
• 
The proportion of subjects with positive medication effect rating on each PGI-I item at the 
end of the 2-week Titration Period by Cohort and overall using end of the Titration Period 
treatment.  
Exploratory Endpoints  (revised per Amendment 01) 
The exploratory endpoints are as follows: 
• 
The change from Baseline in mean ISI score at the end of the Titration Period by Cohort and 
overall using end of the Titration Period treatment. 
• 
The change from baseline in mean Quality of Sleep Rating at the end of the Titration Period 
by cohort and overall using end of the Titration Period treatment. 
• 
To compare nights on which an evening dose of LEM, LEM5, and LEM10 was taken, to 
nights on which an evening dose of ZOL was taken, for the following sleep-related 
actigraphy variables: 
o Mean TST 
o Mean SE 
o Mean WASO 
o Number of Wake Bouts 
• 
To compare the daytime after an evening dose of LEM, LEM5, and LEM10 was taken, to the 
daytime after an evening dose of ZOL was taken, for the following wake-related actigraphy 
variable: 
o Mean Duration of Sleep Bouts 
Analysis Sets 
Safety Analysis Set (SAS) –The Safety Analysis Set is the group of subjects who received at least 1 
dose of study drug and had at least 1 postdose safety assessment. 
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included in the 
Full Analysis Set. 
 
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Efficacy Analyses (Core Study only) 
All efficacy analyses will be conducted on the FAS.  
• 
The proportion of overall subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed. 
• 
The proportion of subjects who transition to LEM after 2 weeks of treatment in the Titration 
Period will be displayed within each cohort.   
• 
The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall,  
• 
The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented. 
• 
Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately 
within each scale over time by Cohort and overall using end of the Titration Period dose 
groups. 
• 
The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these items 
at the end of the Titration Period, and the proportion of subjects who rated the drug as being 
too strong or too weak at Baseline, but whose rating was “just right” at the end of the 
Titration Period (as data allow) will be reported. 
• 
Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the ISI 
will be summarized at the end of the Titration Period by Cohort and overall using end of the 
Titration Period dose groups 
• 
The change from baseline in mean Quality of Sleep Rating score for subjects at the end of the 
Titration Period will be summarized by cohort and overall using end of the Titration Period 
dose groups. 
• 
Average value of following sleep-related actigraphy variables will be summarized by 
treatment over the nights on which an evening dose of LEM, LEM5, LEM10, and ZOL was 
taken.  (revised per Amendment 01) 
o Mean TST 
o Mean SE 
o Mean WASO 
o Number of Wake Bouts 
• 
Average value of wake-related actigraphy variable, mean duration of Sleep Bouts will be 
summarized by treatment over the daytime after an evening dose of LEM, LEM5, LEM10, 
and ZOL was taken.  (revised per Amendment 01) 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses  
Not applicable. 
Safety Analyses (Core Study and Extension Phase) 
Evaluations of safety data will be performed on the SAS.  
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG findings, out-of-
range vital signs, and suicidality (C-SSRS) findings, along with changes from baseline in clinical 
laboratory variables, and vital signs will be summarized for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics using end of titration dose group.  AEs 
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summaries, and abnormal findings will also be displayed based on the dose that the subjects were 
taking at the time of the findings. 
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered cataplexy or 
seizure, somnolence, and related events, and PTs related to drug abuse liability, will be summarized 
seperately.  The results of the deliberation of the Adjudication Committee will be reported separately.  
In addition, 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, as per the 
Adjudication Committee description. 
Other Analyses (Core Study) 
Efficacy endpoints may be analyzed by modeling methods if warranted.  Details of all of the analyses 
will be specified in the Statistical Analysis Plan.  (revised per Amendment 01) 
Interim Analyses 
No interim analyses are planned for this study. 
Sample Size Rationale 
As a pilot study, sample size estimates are not based on statistical calculations.  
This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 2B) to 
evaluate the proportion of subjects who transition to LEM as a substitute for zolpidem.  Twenty 
subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be assigned to 
Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to receive LEM5 or 
LEM10 within Cohort 2.  This sample size is deemed sufficient to inform whether the proposed 
strategies are sufficient to evaluate whether alternative strategies would be required to help 
understand how best to recommend safe and effective methods for transitioning from ZOL to LEM. 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................3 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................4 
3 
TABLE OF CONTENTS .................................................................................................15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................20 
5 
ETHICS............................................................................................................................22 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................22 
5.2 
Ethical Conduct of the Study .................................................................................22 
5.3 
Subject Information and Informed Consent ...........................................................23 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................23 
7 
INTRODUCTION ...........................................................................................................24 
7.1 
Indication ...............................................................................................................24 
7.1.1 
Current Therapeutic Options........................................................................24 
7.1.2 
Lemborexant ................................................................................................25 
7.1.2.1 
Clinical Experience With Lemborexant ...............................................25 
7.1.2.2 
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................26 
7.2 
Study Rationale ......................................................................................................26 
7.2.1 
Entry Criteria Rationale ...............................................................................27 
7.2.2 
Rationale for Titration Schedule and Duration ............................................27 
8 
STUDY OBJECTIVES ....................................................................................................28 
8.1 
Primary Objective ..................................................................................................28 
8.2 
Secondary Objectives  (revised per Amendment 01) ............................................28 
8.3 
Exploratory Objectives  (revised per Amendment 01) ..........................................28 
9 
INVESTIGATIONAL PLAN ..........................................................................................28 
9.1 
Overall Study Design and Plan ..............................................................................28 
9.1.1 
Pretreatment Phase (Core Study) .................................................................30 
9.1.1.1 
Screening Period (Core Study) ............................................................30 
9.1.1.2 
Baseline Period (Core Study)...............................................................31 
9.1.2 
Treatment Phase (Core Study) .....................................................................32 
9.1.2.1 
Titration Period (Core Study) ..............................................................32 
9.1.2.2 
Follow-Up Period.................................................................................33 
9.1.3 
Extension Phase ...........................................................................................33 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................33 
9.3 
Selection of Study Population ................................................................................33 
9.3.1 
Inclusion Criteria .........................................................................................33 
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9.3.2 
Exclusion Criteria ........................................................................................34 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................36 
9.4 
Treatments..............................................................................................................36 
9.4.1 
Treatment(s) Administered ..........................................................................36 
9.4.2 
Identity of Investigational Product...............................................................37 
9.4.2.1 
Chemical Name, Structural Formula of Lemborexant .........................37 
9.4.2.2 
Comparator Drug .................................................................................38 
9.4.2.3 
Labeling for Study Drug ......................................................................38 
9.4.2.4 
Storage Conditions ...............................................................................38 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................38 
9.4.4 
Selection of Doses in the Study ...................................................................38 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................38 
9.4.6 
Blinding........................................................................................................39 
9.4.7 
Prior and Concomitant Therapy ...................................................................39 
9.4.7.1 
Drug-Drug Interactions ........................................................................39 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs .....................................40 
9.4.8 
Treatment Compliance .................................................................................40 
9.4.9 
Drug Supplies and Accountability ...............................................................40 
9.5 
Study Assessments .................................................................................................42 
9.5.1 
Assessments .................................................................................................42 
9.5.1.1 
Demography .........................................................................................42 
9.5.1.2 
Screening and Baseline Assessments...................................................42 
9.5.1.2.1 
Medical History and Physical Examinations .................................42 
9.5.1.2.2 
Sleep Drug History Questionnaire .................................................42 
9.5.1.2.3 
Sleep Disorder Screening Battery ..................................................42 
9.5.1.2.4 
Sleep Drug Experience Interview – Zolpidem...............................43 
9.5.1.3 
Efficacy Assessments...........................................................................43 
9.5.1.3.1 
Insomnia Severity Index ................................................................43 
9.5.1.3.2 
Patient’s Global Impression – Insomnia ........................................43 
9.5.1.3.3 
Quality of Sleep Rating ..................................................................44 
9.5.1.3.4 
Sleep Drug Experience Interview – Lemborexant .........................44 
9.5.1.3.5 
Actigraphy  (revised per Amendment 01) .....................................44 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................45 
9.5.1.5 
Safety Assessments ..............................................................................45 
9.5.1.5.1 
Adverse Events ..............................................................................45 
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9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................48 
9.5.1.5.3 
Study-Specific Adverse Events......................................................49 
9.5.1.5.4 
Laboratory Measurements .............................................................49 
9.5.1.5.5 
Vital Signs, Height, and Weight Measurements ............................50 
9.5.1.5.6 
Physical Examinations ...................................................................50 
9.5.1.5.7 
Electrocardiograms ........................................................................50 
9.5.1.5.8 
Other Safety Assessments ..............................................................50 
9.5.2 
Schedule of Procedures/Assessments – Core Study ....................................51 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................51 
9.5.2.2 
Description of Procedures/Assessments Schedule ...............................56 
9.5.3 
Appropriateness of Measurements ...............................................................56 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................56 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................56 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................57 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................58 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................58 
9.5.4.3.2 
Reporting of Study-Specific Events...............................................58 
9.5.4.4 
Expedited Reporting ............................................................................58 
9.5.4.5 
Breaking the Blind ...............................................................................58 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................59 
9.5.5 
Completion/Discontinuation of Subjects .....................................................59 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................59 
9.6 
Data Quality Assurance .........................................................................................60 
9.6.1 
Data Collection ............................................................................................60 
9.6.2 
Clinical Data Management ..........................................................................60 
9.7 
Statistical Methods .................................................................................................60 
9.7.1 
Statistical and Analytical Plans ....................................................................60 
9.7.1.1 
Study Endpoints ...................................................................................61 
9.7.1.1.1 
Primary Endpoint ...........................................................................61 
9.7.1.1.2 
Secondary Endpoints  (revised per Amendment 01) .....................61 
9.7.1.1.3 
Exploratory Endpoints  (revised per Amendment 01) ...................61 
9.7.1.2 
Definitions of Analysis Sets.................................................................62 
9.7.1.3 
Subject Disposition ..............................................................................62 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................62 
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9.7.1.5 
Prior and Concomitant Therapy ...........................................................63 
9.7.1.6 
Efficacy Analyses ................................................................................63 
9.7.1.6.1 
Primary Efficacy Analysis .............................................................63 
9.7.1.6.2 
Secondary Efficacy Analyses  (revised per Amendment 01) ........63 
9.7.1.6.3 
Exploratory Efficacy Analyses  (revised per Amendment 01) ......63 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................64 
9.7.1.8 
Safety Analyses ....................................................................................64 
9.7.1.8.1 
Extent of Exposure .........................................................................64 
9.7.1.8.2 
Adverse Events ..............................................................................65 
9.7.1.8.3 
Laboratory Values ..........................................................................66 
9.7.1.8.4 
Vital Signs ......................................................................................66 
9.7.1.8.5 
Electrocardiograms ........................................................................67 
9.7.1.8.6 
Other Safety Analyses....................................................................67 
9.7.2 
Determination of Sample Size .....................................................................67 
9.7.3 
Interim Analysis ...........................................................................................68 
9.7.4 
Other Statistical/Analytical Issues ...............................................................68 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................68 
10 REFERENCE LIST .........................................................................................................69 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......71 
11.1 
Changes to the Protocol .........................................................................................71 
11.2 
Adherence to the Protocol ......................................................................................71 
11.3 
Monitoring Procedures...........................................................................................71 
11.4 
Recording of Data ..................................................................................................72 
11.5 
Identification of Source Data .................................................................................72 
11.6 
Retention of Records..............................................................................................73 
11.7 
Auditing Procedures and Inspection ......................................................................73 
11.8 
Handling of Study Drug .........................................................................................73 
11.9 
Publication of Results ............................................................................................74 
11.10 Disclosure and Confidentiality ..............................................................................74 
11.11 Discontinuation of Study .......................................................................................74 
12 APPENDICES .................................................................................................................75 
 
LIST OF IN-TEXT TABLES 
Table 1 
Treatments Administered ...........................................................................37 
Table 2  
Clinical Laboratory Tests ...........................................................................49 
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Table 3 
Schedule of Procedures and Assessments in E2006-A001-312 – Core 
Study  (revised per Amendment 01) ..........................................................52 
Table 4 
Clinically Notable Vital Sign Criteria........................................................67 
Table 5 
Schedule of Procedures and Assessments in Study E2006-A001-312 – 
Extension  (revised per Amendment 01) ...................................................81 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study E2006-A001-312 – Study Design....................................................30 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor’s Grading for Laboratory Values .................................................75 
Appendix 2 
Prohibited Concomitant Medications ........................................................77 
Appendix 3 
Extension Phase .........................................................................................80 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
BMI 
Body mass index 
BP 
blood pressure 
CBT-I 
Cognitive Behavioral Therapy for Insomnia 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP3A 
Cytochrome P450 
DORA 
dual orexin receptor antagonist 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th ed 
FAS 
full analysis set 
GABA 
gamma-aminobutyric acid 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
ISI 
Insomnia Severity Index 
IRB 
Institutional Review Board 
IRLS 
International Restless Legs Scale 
LEM 
lemborexant 
LEM5 
Lemborexant 5 mg 
LEM10 
Lemborexant 10 mg 
LNH 
low/normal/high 
MedDRA 
Medical Dictionary for Regulatory Activities 
OSA 
obstructive sleep apnea 
PBO 
placebo 
PGI-I 
Patient Global Impression of Insomnia 
PT 
preferred term 
QTcF 
Difference between QTc corrected by Fridericia's formulas 
SAE 
Serious adverse events 
SAS 
safety analysis set 
SDSB 
Sleep Disorders Screening Battery 
SE 
sleep efficiency 
SOC 
system organ class 
TEAE 
treatment-emergent adverse events 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TIB 
time in bed 
TST 
total sleep time 
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Abbreviation 
Term 
WASO 
wake after sleep onset 
ZOL 
zolpidem 
ZOL-ER 
zolpidem tartrate extended release 
ZOL-IR 
zolpidem tartrate immediate release 
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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with ICH E6 (Good Clinical Practice), Section 3, and any local regulations (eg, 
Title 21 of the United States Code of Federal Regulations [CFRs], Part 56).  Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, 
change in Clinical Research Associate CRA[s], change of telephone number[s]).  
Documentation of IRB compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension 
or termination by the IRB to the sponsor. 
Study progress is to be reported to IRBs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports, 
and inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRB within 90 days.  The end of the 
study will be the date of the last study visit for the last subject in the study.  The sponsor 
should also provide the IRB with a summary of the study’s outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB 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 (2013)  
• 
ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
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Committee for Proprietary Medicinal Products, International Conference on 
Harmonisation of Pharmaceuticals for Human Use 
• 
Title 21 of the US CFR regarding clinical studies, including Part 50 and Part 56 
concerning informed subject consent and IRB regulations and applicable sections of US 
21 CFR Part 312 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained. 
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (eg, Title 21 CFR Part 50).  Each subject must 
sign an approved ICF before study participation.  The form must be signed and dated by the 
appropriate parties.  The original, signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site.   
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. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 investigational sites in the United States of America. 
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The name, telephone and fax numbers of the Medical Monitor and other contact personnel at 
the contract research organization(s) (CROs) are listed in the Investigator Study File 
provided to each site. 
7 
INTRODUCTION 
7.1 
Indication 
Lemborexant (LEM) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide), also known as E2006, is 
an orally-administered, novel competitive dual orexin receptor antagonist (DORA) that has 
been developed for the treatment of insomnia and Irregular Sleep-Wake Rhythm Disorder 
(ISWRD).   
7.1.1 
Current Therapeutic Options 
Treatments for insomnia include both non-pharmacological (Schutte-Rodin, et al., 2008; 
Morgenthaler, et al., 2006) and pharmacological treatments (Sateia, et al., 2017).  Patients 
who undergo thorough diagnostic evaluations for insomnia symptoms are asked about their 
sleep and wake habits, since some cases of insomnia can be addressed by improving sleep 
hygiene.  Principles of good sleep hygiene include regular bedtimes and waketimes, limiting 
alerting activities before bedtime, and limiting caffeine and alcohol intake, among others 
(Schutte-Rodin, et al., 2008).  These techniques are often not adequate to address insomnia 
symptoms (Stepanski and Wyatt, 2003; Irish, et al., 2015). 
Another commonly recommended non-pharmacological approach is the use of cognitive 
behavioral therapy for insomnia (CBT-I; Schutte-Rodin, et al., 2008).  CBT-I includes 
techniques to minimize wakefulness at the time the patient intends to sleep.  However, while 
there are data to support the effectiveness of CBT-I, sleep restriction is commonly a major 
component, and this may lead to daytime sleepiness, an unintended consequence of short 
sleep (Kyle, et al., 2014).  In contrast, lemborexant’s mechanism of action would avoid the 
daytime sleepiness caused by sleep restriction, while reducing wakefulness and facilitating 
sleep, which is an important underlying goal of CBT-I.   
There are numerous drugs available for the treatment of insomnia, some available by 
prescription and many available over-the-counter.  Many of the over-the-counter medicines 
lack empirical data from adequate, well-designed and controlled clinical trials to support 
their use (Rosen, et al., 2005); these include melatonin and antihistamines.  Pharmacological 
treatments available by prescription and used clinically for insomnia include sedative 
hypnotics (benzodiazepines, nonbenzodiazepine gamma-aminobutyric acid 
(GABA)-releasing [GABAergics] agents), sedating antidepressants, melatonin agonists, and 
a DORA.   
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7.1.2 
Lemborexant 
Lemborexant belongs to the pharmacologic class of orexin receptor antagonists, a class of 
chemical compounds developed for the treatment for insomnia.  To date, clinical proof of 
concept has been achieved by 6 orexin receptor antagonists (lemborexant, almorexant 
[ACT-078573], suvorexant [MK-4305], filorexant [MK-6096]), seltorexant [MIN-202], and 
nemorexant [ACT-541468]), demonstrating validity of the mechanism of action (Herring, 
et al., 2012; Hoever, et al., 2012; Connor, et al., 2016; Murphy, et al., 2017; De Boer, et al., 
2018). 
Nonclinical data show that lemborexant binds to and competitively antagonizes human 
orexin-1 receptor (OX1R) and orexin-1 receptor (OX2R) in vitro, with rapid association and 
dissociation kinetics at both receptors.  In vitro data show that lemborexant does not 
substantially interact with other sleep-related receptors and channels (Beuckmann, et al, 
2017).  Lemborexant prevents [Ala11, D-Leu15]-orexin-B-induced plasma adrenocorticotropic 
hormone increase in rats, and promotes physiological sleep in mice and rats.  In mice, 
lemborexant does not promote sleep when the orexin pathway has been functionally 
impaired.  In rats, daily treatment for 3 consecutive weeks with lemborexant did not result in 
tolerance or wakefulness rebound upon treatment cessation, and did not elicit direct 
transitions from wakefulness to rapid eye movement (REM) sleep, a narcolepsy-like 
symptom.  However, in strong emotional contexts, lemborexant induced cataplexy-like 
events in mice (Study W-20140712).  Cataplexy has been noted in dogs dosed with another 
orexin antagonist, suvorexant, when presented with food enrichment (Belsomra, 2018), but 
the relationship to cataplexy symptoms in humans has not been established.  At doses up to 
300 mg/kg (300-fold higher than necessary for sleep promotion), lemborexant did not have 
any negative influence on motor coordination in mice, nor did it show any significant 
interaction with ethanol. 
7.1.2.1 
Clinical Experience With Lemborexant 
The safety and efficacy of lemborexant for the treatment of insomnia disorder was confirmed 
in 2 pivotal Phase 3 studies, E2006-G000-303 (Study 303) and E2006-G000-304 (Study 
304).  In Study 304, lemborexant also demonstrated superior improvement on objective and 
subjective measures of sleep onset and maintenance compared to zolpidem tartrate extended 
release (ZOL-ER).  Additional safety assessments pertinent to insomnia drugs, specifically 
regarding postural stability, were also conducted in study E2006-A001-108 and Study 304.  
In these studies, the safety of lemborexant on postural stability was superior compared to 
zolpidem (ZOL).  Based on these data, a New Drug Application for lemborexant was 
submitted to the US Food and Drug Administration for the treatment of insomnia disorder in 
December 2018 and accepted for review in February 2019. 
The safety and tolerability of lemborexant has been comprehensively evaluated in a broad 
patient population that includes subjects with insomnia disorder per Diagnostic and 
Statistical Manual of Mental Disorders, 5th ed (DSM-5) (with or without medical or 
psychiatric comorbidities), subjects with Alzheimer's disease and ISWRD, subjects with mild 
obstructive sleep apnea (OSA), and subjects with severe renal impairment or mild to 
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moderate hepatic impairment.  Exposures included dosing of ≥12 months.  Approximately 
40% of subjects in the development program were elderly (≥65 years), providing extensive 
safety and tolerability profile for this important subpopulation at risk for insomnia.   
Overall, of 2824 subjects with sleep disorders, 1848 received lemborexant, 714 received 
placebo (PBO), and 263 received ZOL.   
No deaths were reported in subjects treated with lemborexant. 
The overall incidence of treatment-emergent serious adverse events (SAEs) for subjects 
treated with lemborexant 5 mg (LEM5) and lemborexant 10 mg (LEM10) in the Phase 3 Pool 
was low (2.8% and 2.3%, respectively) but greater than for PBO (0.9%).  However, when 
adjusted by duration of exposure, the overall incidence (subjects per patient-year) was similar 
to PBO (<0.1 for PBO, 0.1 for LEM5, and 0.1 for LEM10).  The overall rate (events per 
patient-year) of treatment-emergent SAEs when adjusted by duration of exposure was <0.1 
for PBO, <0.1 for LEM5, and <0.1 for LEM10. 
There were no differences in the types of treatment-emergent SAEs reported during 
long-term treatment with lemborexant.  There were no differences in treatment-emergent 
SAEs based on intrinsic factors, including age, sex, and body mass index (BMI) of subjects.  
Notably, the incidence of treatment-emergent SAEs in the elderly was consistent with that in 
younger subjects. 
Across the Phase 3 studies of 303 and 304 (total subjects=1945), the majority of 
treatment-emergent SAEs occurred as singular events in 1 subject only.  The SAEs of 
osteoarthritis (0% for PBO, 0.1% for LEM5, 0.4% for LEM10), rib fracture (0.2% for PBO, 
0% for LEM5, 0.1% for LEM10), and diabetic neuropathy (0% for PBO, 0.3% for LEM5, 
0% for LEM10) occurred in more than 1 subject across the PBO, LEM5, and LEM10 groups.  
One (0.1%) serious event of fall was reported in the LEM5 group. 
7.1.2.2 
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure 
None. 
7.2 
Study Rationale 
Switching of medications for insomnia occurs often in clinical practice based on clinical 
response, AEs, reimbursement patterns, or physician and patient preference.  However, there 
is no clinical trial experience or dosing guidance for transitioning from currently approved 
treatments for insomnia to lemborexant.  Study E2006-A001-312 (Study 312) is designed as 
a pilot study to assess the dosing approach of directly transitioning from ZOL, the most 
commonly prescribed sleep aid (Bertisch, et al., 2014), to lemborexant, without tapering the 
ZOL dose, and with the opportunity for lemborexant dose titration.  This study will provide 
initial information on patient satisfaction after switching to lemborexant, with secondary 
objectives assessing subjective quality of sleep and tolerability.  If issues are identified 
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regarding patient satisfaction, tolerability, or quality of sleep, other dosing paradigms can be 
assessed in future studies to mitigate these issues.   
7.2.1 
Entry Criteria Rationale 
Subjects with insomnia disorder per DSM-5 criteria (with or without medical or psychiatric 
comorbidities) will be eligible for study entry, which is representative of the typical target 
outpatient population.  All subjects who are willing to substitute ZOL with LEM, regardless 
of the reason(s), will be eligible, and the reason(s) will be captured during screening.  While 
it is anticipated that most eligible subjects would substitute ZOL with LEM due to 
dissatisfaction with ZOL, other reasons, as determined by input from Key Opinion Leaders 
(KOLs) in Sleep Medicine, may include, but are not limited to, concerns regarding ZOL side 
effects, eg, parasomnias.  Including subjects with these various reasons is representative of 
the real-world outpatient setting. 
While the approved dosing instructions for women and patients ≥65 stipulate that the lower 
dose of ZOL is to be prescribed, many women and elderly patients may be taking the higher 
dose.  Therefore, for generalizability of the results of the study to the patient population, any 
stable dosing regimen will be eligible, including those subjects taking higher than approved 
doses up to the maximum approved (10 mg IR or 12.5 mg ER). 
7.2.2 
Rationale for Titration Schedule and Duration  
Since this study is designed to reflect common clinical practice, flexibility to titrate the dose 
up or down is built into the dosing regimen.  In the outpatient setting, clinicians typically 
advise patients to allow themselves one week to adjust to a new medication; therefore, 
subjects assigned to LEM5 will be encouraged to remain on their dose of LEM for 1-week 
prior to titrating up to LEM10, and those assigned to LEM10 will be encouraged to remain 
on their dose of LEM prior to titrating down to LEM5 after one week. 
Subjects who intermittently use ZOL are expected to be more likely to be started on LEM5 in 
the outpatient setting, as they are not chronically exposed to, or reliant upon, pharmacologic 
insomnia treatments.  Therefore, all subjects in Cohort 1 will be started on LEM5 during the 
Titration Period of the Treatment Phase.   
The duration of the Treatment Phase of the Core Study is set at 2 weeks, since that amount of 
time is deemed reasonable by expert opinion from consultation with KOLs in Sleep Medicine 
for subjects to decide if they wish to continue on lemborexant.   
 
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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects 
with insomnia disorder taking ZOL immediate release (ZOL-IR) or extended release (ZOL-
ER), intermittently or frequently, who transition to lemborexant 5 mg (LEM5) or 10 mg 
(LEM10), after 2 weeks of receiving lemborexant (LEM). 
8.2 
Secondary Objectives  (revised per Amendment 01) 
• 
To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease 
from LEM10 to LEM5 during the 2-week Titration Period 
• 
To evaluate the subject impression of treatment using the Patient Global Impression of 
Insomnia (PGI-I) at the end of the 2-week Titration Period 
• 
To evaluate the safety and tolerability of LEM in subjects previously taking ZOL 
8.3 
Exploratory Objectives  (revised per Amendment 01) 
• 
To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared 
with Baseline at the end of the 2-week Titration Period 
• 
To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared 
with Baseline at the end of the 2-week Titration Period 
• 
To compare nights on which an evening dose of LEM, LEM5, and LEM10 was taken, to 
nights on which an evening dose of ZOL was taken, for the following sleep-related 
actigraphy variables: 
o Total Sleep Time (TST) 
o Sleep Efficiency (SE) 
o Wake After Sleep Onset (WASO) 
o Wake Bouts 
• 
To compare the daytime after an evening dose of LEM, LEM5, and LEM10 was taken, 
to the daytime after an evening dose of ZOL was taken, for the following wake-related 
actigraphy variable: 
o Sleep Bouts 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multicenter, Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER.  Adult (≥18 years) subjects are 
eligible for participation if they have been diagnosed with insomnia disorder per the 
DSM-5th Ed (American Psychiatric Association, 2014), are currently receiving ZOL as 
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monotherapy for insomnia, and who agree to substitute zolpidem tartrate immediate release 
(ZOL-IR) or ZOL-ER with LEM, regardless of the reason.  
The study will consist of 3 phases:  a Pretreatment Phase (consisting of up to a 3-week 
Screening Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week 
Titration Period), and an Extension Phase consisting of the Maintenance Period up to 
12 weeks and the Follow-up Period 4 weeks in duration immediately following the end of the 
Treatment Phase.  A Follow-up Period visit occurring 4 weeks after the end of the Extension 
Phase (or Treatment Phase, for subjects not entering the Extension Phase) will be conducted.  
The Pretreatment and Treatment Phases will comprise the Core Study.  The Extension Phase 
is described in detail in Appendix 3. 
During the Screening Period, eligible subjects will continuously wear an actigraph and 
prospectively record the number of days ZOL is taken during the 3-week screening period 
using a Data Collection System.  Based on ZOL use, subjects will be assigned to 1 of 2 
cohorts of ZOL use frequency:  (revised per Amendment 01) 
• Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 5  
nights per week, for at least the last 2 weeks of the 3-week Screening Period, or  
• Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for at 
least the last 2 weeks of the 3-week Screening Period   
All subjects in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). Within 
Cohort 2, subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio.   
Subjects who remain eligible for the study will enter the Baseline Period, and continuously 
wear an actigraph during the Titration Period.  (revised per Amendment 01) 
Approximately 110 subjects will be screened to provide approximately 60 subjects for 
randomization (20 subjects in Cohort 1 and 40 subjects in Cohort 2 [20 subjects in LEM5 and 
20 subjects in LEM10]). 
The end of the study will be the date of the last study visit for the last subject. 
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An overview of the study design is presented in Figure 1. 
  
Figure 1 
Study E2006-A001-312 – Study Design 
LEM5 = lemborexant 5 mg, LEM5 = lemborexant 5 mg, R = Randomization 
9.1.1 
Pretreatment Phase (Core Study) 
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day 
Baseline Period, during which subjects will be assessed for eligibility to participate in the 
study. 
9.1.1.1 
Screening Period (Core Study) 
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  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.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3. 
Subjects must have a diagnosis of insomnia per the DSM-5 (American Psychiatric 
Association, 2014), be currently receiving ZOL as monotherapy for insomnia, and agree to 
substitute zolpidem tartrate immediate release (ZOL-IR) or extended release (ZOL-ER) with 
LEM, regardless of the reason. 
During the Screening Period, subjects will be required to bring the container of their 
currently prescribed ZOL to the site for verification of prescribed medication and dose.  
Subjects will be provided with, and trained in the use of, a data collection system to record 
Period: 
R 
Drug  
 3 weeks 
Day 1 
Titration 
2 weeks 
Phase: 
Screening 
12 weeks 
Pretreatment 
Extension 
Cohort 2 (LEM5) 
Cohort 2 (LEM10) 
Cohort 1 (LEM5) 
Maintenance 
Drug 
Treatment 
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the dose and frequency of ZOL which is taken during the 3-week Screening Period.  Site 
staff will instruct subjects to complete data entry every morning and will emphasize the 
importance of providing this data.  During the Screening Period, subjects will continue to 
take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5 mg or 10 
mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection 
system for at least 14 (preferably contiguous) days of the 21-day Screening Period in order to 
be eligible for study inclusion.  Eligible subjects will also be provided with an actigraph (for 
actigraphy) to wear continuously throughout the Screening Period.  Subjects will be provided 
with a daily log (sleep log) to note the start and end times of nocturnal sleep periods and to 
log the approximate times that the actigraph was replaced on the subject’s wrist, if 
inadvertently removed.  Subjects will be trained to use the actigraph and the log.  Site staff 
will instruct subjects to record (with the current date) the following timings in the log: in the 
evening, record the times when the actigraph was not worn; and in the morning, record the 
bedtimes and morning rise times.  Site staff will emphasize the importance of recording these 
timings in the log.  (revised per Amendment 01) 
Subjects will return to clinic at the end of the Screening Period.  Actigraph data will be 
downloaded and transmitted to the central reader, along with the sleep log of bedtimes, 
morning wake times, and the approximate times when the actigraph was replaced on the 
subject’s wrist.  (revised per Amendment 01) 
For subjects who remain eligible for study enrollment, the second Screening Period visit will 
serve as that subject’s Baseline Period, and will occur on the same day.  Based on ZOL use 
during the Screening Period (which must match the treatment history ascertained at the 
beginning of the Screening Period), subjects will be assigned to 1 of 2 cohorts as follows:  
(revised per Amendment 01) 
• 
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 but fewer than 5 
nights per week, for at least the last 2 weeks of the 3-week Screening Period, or  
• 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week for at 
least the last 2 weeks of the 3-week Screening Period   
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5).  
For Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or 
LEM10) in a 1:1 ratio.  
9.1.1.2 
Baseline Period (Core Study) 
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment 
cohort.  Subjects who are not eligible will conclude their participation, return their actigraphs 
and sleep logs to the study site, and will be considered screen failures.  Upon completion of 
the Baseline Period, subjects who remain eligible by meeting the criteria for 
inclusion/exclusion (Sections 9.3.1 and Section 9.3.2) will enter the Titration Period.  
(revised per Amendment 01) 
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9.1.2 
Treatment Phase (Core Study) 
The Treatment Phase will consist of a 2-week Titration Period and 1-day Follow-up Visit to 
occur 4 weeks after completion of the Titration Period (or as soon as possible following early 
discontinuation) for subjects not entering the Extension Phase.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria at the Baseline Visit, and who have 
entered ZOL medication use data into the Data Collection System for at least 14 of the 21-
day Screening Period as specified in the Inclusion Criteria, are eligible to enter the Treatment 
Phase of the study.  
9.1.2.1 
Titration Period (Core Study) 
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and 
LEM10 to be taken at home within a few minutes of the time that they intend to sleep.  
Subjects will continue to wear their actigraphs throughout the Titration Period, with the same 
instructions for use.  Study restrictions pertaining to duration of time spent in bed, use of 
alcohol, and timing of meals will be discussed with the subject at each visit during the 
Treatment and Extension Phases.  Subjects will be instructed to not alter (ie break or cut) 
their tablets of LEM.  (revised per Amendment 01) 
Subjects assigned to Cohorts 1 and 2 will self-administer the study medication according to 
the following regimens: 
• 
Cohort 1 (Intermittent ZOL Use):  Subjects in this cohort will decide when to take LEM 
according to their usual pattern, with the requirement that they take LEM at least once per 
week during the 2-week Titration Period.  (revised per Amendment 01) 
• 
Cohort 2 (Frequent ZOL Use, Treatment Groups A and B):  Subjects in these cohorts will 
take LEM at least 5 nights per week during the 2-week Titration Period. 
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines: 
• 
For subjects starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but 
not mandated) to remain on their assigned dose for 7 days before calling the site to report 
that LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the 
site will then be instructed by phone to take LEM10 within a few minutes of the time 
they intend to sleep.   
• 
For subjects starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain 
on their assigned dose for 7 days before calling the site to report that the dose of LEM10 
should be reduced.  Subjects will then be instructed to take LEM5 within a few minutes 
of the time they intend to go to sleep.   
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the case report form (CRF).   
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Every morning, subjects will enter their insomnia drug use data into the data collection 
system and record their sleep log data, and, provided an insomnia drug was taken the night 
prior, PGI-I and Quality of Sleep Rating will be completed.  The ISI will be completed at 
each clinic visit except Follow-up Visit.  (revised per Amendment 01) 
Upon completion of the Titration Period, actigraphs will be returned to the study site, and 
subjects will be considered for eligibility to enter the Extension Phase (Appendix 3).  
(revised per Amendment 01) 
9.1.2.2 
Follow-Up Period 
For subjects not entering the Extension Phase, the Follow-up Period will start immediately 
after the end of the Treatment Phase and last for 4 weeks.  The purpose of the Follow-up 
Period is to assess adverse events and other safety parameters.  Subjects will be instructed to 
continue insomnia management with the health-care provider who had been treating them 
prior to study entry, if they so desire. 
9.1.3 
Extension Phase 
Subjects who complete the Core Study and wish to continue taking LEM will enter the 
12-week Extension Phase.  Subjects will continue the LEM dose and regimen established 
during the Titration Period; however, the dose may be titrated up or down depending on 
response and tolerability, per subject input and investigator judgement.  For subjects who are 
eligible for the Extension Phase but who do not wish to continue study participation, the 
reason for discontinuation from the study will be recorded.  At the end of the Extension 
Phase, the Follow-up Period will begin, and last for 4 weeks.   
Details of the Extension Phase are provided in Appendix 3. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
See Section 7.2, Study Rationale. 
9.3 
Selection of Study Population 
Approximately 60 subjects will be enrolled at approximately 15 sites in the United States of 
America.  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, 18 years or older, at the time of informed consent 
2. Meets the DSM-5 criteria for Insomnia Disorder, either currently or prior to zolpidem 
use, as follows: 
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• Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying 
asleep and/or awakening earlier in the morning than desired despite adequate 
opportunity for sleep 
• Frequency of complaint ≥3 times per week 
• Duration of complaint ≥3 months 
• Associated with complaint of daytime impairment 
3. Reports spending at least 7 hours in bed per night 
4. History of intermittent (taking ZOL at least 3 but fewer than 5  nights per week), or 
frequent use (at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month  (revised 
per Amendment 01) 
5. Confirmation of intermittent or frequent use of ZOL (based on review of drug use data).  
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for 
at least the last 2 weeks of the 3-week Screening Period.  Frequent use is defined as 
taking ZOL at least 5 nights per week for at least the last 2 weeks of the 3-week 
Screening Period  (revised per Amendment 01) 
6. Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night 
7. Willing not to start another pharmacologic treatment for the management of insomnia 
during the subject’s participation in the study 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive serum pregnancy test).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study 
drug. 
2. Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device or intrauterine hormone-releasing system (IUS) 
o a contraceptive implant 
o an oral contraceptive (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 28 days after study drug discontinuation) 
o have a vasectomized partner with confirmed azoospermia. 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation. 
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NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing). 
3. Any history of moderate or severe OSA 
4. Current evidence of a clinically significant, active respiratory disorder other than mild 
OSA.  This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary 
disease or any other pulmonary disorder identified by review of medical history or 
physical examination, and which in the opinion of the investigator, could compromise the 
subject’s safety or interfere with study assessments 
5. A current diagnosis of periodic limb movement disorder, restless legs syndrome, 
circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule 
out individuals with symptoms of certain sleep disorders other than insomnia as follows: 
• STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not 
excluded) 
• International Restless Legs Scale (IRLS) score ≥16 
6. Habitually naps during the day more than 3 times per week  
7. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy 
8. 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 
sleeping), whether spontaneous or associated with a pharmacological sleep agent. 
9. Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night 
10. Takes a dose of ZOL that is lower than what is prescribed 
11. Reports having altered ZOL tablets 
12. Reports intermittent or frequent use of ZOL at Visit 1 which is not confirmed, based on 
review of drug use data, at Visit 2a.  Intermittent use is defined as taking ZOL at least 3 
but fewer than 5 nights per week, for at least the last 2 weeks each of the 3-week 
Screening Period.  Frequent use is defined as taking ZOL at least 5 nights per week for at 
least the last 2 weeks of the 3-week Screening Period  (revised per Amendment 01) 
13. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study  
14. Used any prohibited prescription or over-the-counter concomitant medications within 
1-week or 5 half-lives, whichever is longer, before the first dose of study medication (A 
list of prohibited concomitant medications is presented in the protocol).   
15. Used any pharmacologic modality of treatment for insomnia other than ZOL, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening 
Period 
16. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG 
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17. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS]) 
18. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS) 
19. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and 
renal disease) 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. 
20. Hypersensitivity to lemborexant or any of the excipients. 
21. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study. 
22. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study.  Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the investigator this operation does not interfere with the 
study procedures and patient safety. 
23. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years. 
24. History of drug or alcohol dependency or abuse within approximately the last 2 years 
25. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days or 5× the half-life, whichever is longer, preceding informed consent. 
26. 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. 
9.4 
Treatments 
9.4.1 
Treatment(s) Administered 
The following treatments will be administered to subjects in the Core Study (Table 1). 
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Table 1 
Treatments Administered 
Drug Name 
Strength 
Oral Dose Form 
Number Dispensed and Frequency 
Duration 
Lemborexant 
5 mg 
Tablet 
1×5 mg tablets, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule 
14 days 
Lemborexant 
10 mg 
Tablet 
1×10 mg tablet, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule 
14 days 
 
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines: 
• 
For Cohorts 1 and 2A (starting dose of LEM5), subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site to report that LEM5 is not fully 
effective for treatment of their insomnia.   Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.   
• 
For Cohort 2B (starting dose of LEM10), subjects will be encouraged to remain on their 
assigned dose for 7 days before calling the site to report that the dose of LEM10 should 
be reduced.  Subjects will then be instructed to take LEM5 within a few minutes of the 
time they intend to go to sleep.   
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the CRF.   
9.4.2 
Identity of Investigational Product 
Lemborexant will be supplied by the sponsor in labeled containers.   
Study drug must be stored as instructed on the study drug label.  Study drug must be kept in a 
secure location and carefully stored at the study site within its original container.  The 
sponsor will provide the study drug packaged as open-label supplies.  Each subject’s study 
drug will consist of lemborexant tablets supplied in bottles.  
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-fluoropyridin-2-yl)cyclopropanecarboxamide) 
• 
Molecular formula:  C22H20F2N4O2 
• 
Molecular weight:  410.42 
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9.4.2.2 
Comparator Drug 
Not applicable. 
9.4.2.3 
Labeling for Study Drug 
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries. 
9.4.2.4 
Storage Conditions 
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
Based on ZOL use during the Screening Period, subjects will be assigned to 1 of 2 cohorts as 
shown below:  (revised per Amendment 01) 
• Cohort 1 (Intermittent ZOL Use):  taking ZOL at least 3 but fewer than 5 nights per week, 
at least the last 2 weeks of the 3-week Screening Period, or  
• Cohort 2 (Frequent ZOL Use):  taking ZOL at least 5 nights per week for at least the last 
2 weeks of the 3-week Screening Period   
All subjects (n=20) in Cohort 1 will receive LEM5. Subjects in Cohort 2 will be randomized 
to 1 of 2 Treatment Groups:  Cohort 2A (20 subjects) will start on LEM5, and Cohort 2B 
(20 subjects) will start on LEM10.  
9.4.4 
Selection of Doses in the Study 
The doses to be administered are LEM5 and LEM10.  In December 2018, these doses were 
submitted for approval in the US for the indication of insomnia.  These doses were originally 
selected after conducting a dose-finding study (E2006-G000-201) after which their safety 
and efficacy were confirmed in 2 Phase 3 studies, Studies 303 and 304. 
9.4.5 
Selection and Timing of Dose for Each Subject 
Subjects will be provided a supply of LEM5 and LEM10 to be taken at home within a few 
minutes of the time they intend to sleep.  Subjects will be instructed on study restrictions 
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pertaining to duration of time spent in bed, use of alcohol, and timing of meals.  Subjects will 
be instructed not to alter (ie, break or cut) their tablets of LEM. 
9.4.6 
Blinding 
This is an open-label study with randomization to treatment for subjects assigned to 
Cohort 2. 
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 or 30 days before first 
dose/administration of study drug, if appropriate) will be recorded.  The adverse event or 
medical condition for which the concomitant medication or therapy was administered will be 
recorded. 
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 Treatment Period. 
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 the protocol, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted. 
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that strong and moderate cytochrome P450 (CYP)3A 
inhibitors and all CYP3A inducers will not be permitted at any time for any duration during 
the study. 
9.4.7.1 
Drug-Drug Interactions 
Coadministration with moderate and strong 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 2.   
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.   
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9.4.7.2 
Prohibited Concomitant Therapies and Drugs 
Prohibited medications (Appendix 2) 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 Treatment Period.  
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A 
inducers.  Prohibited therapies also include:  any pharmacologic treatment for insomnia 
disorder (with the exception of ZOL use during the Screening Period only); medications that 
are used for the purpose of inducing sleep (hypnotics) and medications that have known 
sedating effects.  This prohibition applies even if the entire class to which that medication 
belongs is not prohibited (eg, anticonvulsants). 
If a medication is not on the list of prohibited medications (Appendix 2) 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 2, 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.   
If a subject starts any prohibited medication or a new treatment/modality for insomnia 
disorder, he/she must discontinue from the study. 
Subjects must forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study.  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 bottles returned to the investigator at the end 
of the Titration Period. 
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 for the institution where the study is to be conducted 
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• 
A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study 
• 
The IRB membership list and statutes or Health and Human Services Assurance number 
• 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
• 
An investigator-signed and dated FDA Form FDA 1572 
• 
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable 
• 
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV 
• 
A signed and dated clinical studies agreement 
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s 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, (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, Medicine and Healthcare products Regulatory Agency [MHRA]).  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 
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to the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  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.   
9.5.1.2 
Screening and Baseline Assessments 
9.5.1.2.1 MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Medical, sleep, and psychiatric history will be recorded as designated in the Schedule of 
Procedures/Assessments (Table 3).  All medical and surgical history within 5 years must be 
noted in the Medical History and Current Medical Conditions CRF. 
Physical examinations will be performed, as designated in the Schedule of 
Procedures/Assessments (Table 3).  A full physical examination will be performed, 
excluding a urogenital examination unless there are special circumstances and at the 
discretion of the investigator.  Documentation of the physical examination will be included in 
the source documentation at the site.  Significant findings at the Screening Visit will be 
recorded on the Medical History and Current Medical Conditions CRF.  Changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Events CRF. 
9.5.1.2.2 SLEEP DRUG HISTORY QUESTIONNAIRE 
At Screening, subjects will complete a questionnaire reporting their history and response to 
prior sleep medications, as well as their motivation for participating in the study. 
9.5.1.2.3 SLEEP DISORDER 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 
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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 Sleep Disorders Screening Battery (SDSB) will 
be administered (see below).   
The SDSB will include the following, to be self-administered by subjects:  
• 
The STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects 
for OSA (Chung et al., 2008) 
• 
The IRLS:  a subjective scale comprising 10 questions, which measures disease severity of 
restless legs syndrome (Abetz et al., 2006). 
9.5.1.2.4 
SLEEP DRUG EXPERIENCE INTERVIEW – ZOLPIDEM 
At the end of the Screening Period, subjects will be asked questions about their subjective 
experiences while taking ZOL.  The responses will be compared to the Sleep Drug 
Experience Interview – Lemborexant, which is done at the end of the Treatment Phase, in 
order to provide qualitative information regarding an individual’s subjective experience with 
LEM compared to ZOL. 
9.5.1.3 
Efficacy Assessments 
9.5.1.3.1 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.  The ISI 
will be completed at each study visit except Follow-up Visit.   
9.5.1.3.2 PATIENT’S GLOBAL IMPRESSION – INSOMNIA 
The PGI-I is a self-report assessment of subject perception of the effects of a medication on 
their sleep (Herring, et al., 2018).  The PGI-I has 3 items related to study medication effects 
(a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) 
increased/decreased total sleep time, and 1 item related to perceived appropriateness of study 
medication strength.  The first 3 items are answered on a 3-point scale (1=positive 
medication effect, 2=neutral medication effect, 3=negative medication effect) and the last 
item on a different 3 point scale (medication:  1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior 
evening during the Screening, Baseline, and Titration Periods. 
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9.5.1.3.3 QUALITY OF SLEEP RATING 
The Quality of Sleep Rating (Krystal and Edinger, 2008) is a self-reported scale in which 
subjects are asked, “How would you rate the quality of your sleep last night, with 1 being 
extremely poor, 5 being not good or poor, and 9 being extremely good?” For Quality of 
Sleep, higher values are better.  The Quality of Sleep Rating will be completed each morning 
following a dose of ZOL or LEM taken the prior evening during the Screening, Baseline, and 
Titration Periods. 
9.5.1.3.4 SLEEP DRUG EXPERIENCE INTERVIEW – LEMBOREXANT 
At the end of the Titration Period, subjects will be asked questions about their subjective 
experiences while taking LEM.  The responses will be compared to the Sleep Drug 
Experience Interview – ZOL, which is done at the end of the Screening Period, in order to 
provide qualitative information regarding an individual’s subjective experience with LEM 
compared to ZOL. 
9.5.1.3.5 ACTIGRAPHY  (REVISED PER AMENDMENT 01) 
An actigraph is a device that consists of a compact, wrist-worn, battery-operated activity 
monitor that looks like a wrist watch.  This device incorporates a multidirectional 
accelerometer to monitor degree and intensity of motion.  Data from an actigraph are 
collected at a sampling rate of every 30 seconds and are scored as sleep or wake with a 
validated algorithm.  Sleep/wake parameters are calculated from the scored data.  
Eligible subjects will be provided with an actigraph (for actigraphy) to wear continuously 
throughout the Screening Period, and, for those who qualify at the end of the Screening 
Period for study enrollment, during the Treatment Phase.  Subjects will be provided with a 
daily log (sleep log) for noting the start and end times of nocturnal sleep periods and to log 
the approximate times that the actigraph was replaced on the subject’s wrist, if inadvertently 
removed.  Subjects will be trained to use the actigraph and the log.  Site staff will instruct 
subjects to record (with the current date) the following timings in the log: in the evening, 
record the times when the actigraph was not worn; and in the morning, record the bedtimes 
and morning rise times.  Site staff will emphasize the importance of recording these timings 
in the log. 
 
A central actigraphy reader will score daily actigraphy records using a customized algorithm.  
The in-bed intervals will be provided to the central reader based on the sleep logs completed 
by the subject.   
Actigraphy data will be used to evaluate the following sleep and wake parameters for 
subjects during the Screening and Titration Periods: 
• 
TST: The total time spent in sleep according to the epoch-by-epoch wake/sleep 
categorization during time in bed (TIB) 
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• 
SE:  100% × the total duration of sleep epochs during the defined nocturnal sleep 
period/TIB 
• 
WASO:  The total time spent awake according to the epoch-by-epoch wake/sleep 
categorization between sleep start (based on 'lights out') and 'got up' 
• 
Wake Bouts:  Wake of  ≥ 5 minutes that occur during TIB 
• 
Sleep Bouts:  Continuous sleep ≥ 10 minutes that occur during Time Out of Bed (TOB) 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
Not applicable. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades (for both increasing and 
decreasing severity), regular monitoring of hematology, blood chemistry, and urine values; 
periodic measurement of vital signs and ECGs; and performance of physical examinations.  
Subjects will be asked about falls at every visit. 
Sponsor’s grading for laboratory values are presented in Appendix 1.  
Adjudication Committee 
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure.  A set of 
preferred terms (PTs) 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 [ standard 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 SAE form for any of the 
above events considered serious. 
9.5.1.5.1 ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lemborexant (in 
doses of 5 mg and 10 mg).  
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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, x-ray) that results in symptoms, a change in treatment, or discontinuation 
of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase 
and for 7 days or 5× the half-life after the last dose, whichever is longer.  SAEs will be 
collected for 28 days after the last dose or for 5× the half-life, whichever is longer.   
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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 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. 
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 9.5.1.5.8 for a description of the C-SSRS).  
The number (percentage) of subjects with treatment emergent adverse events (TEAEs) of 
cataplexy or other events that are characterized according to the customized MedDRA query 
PT as cataplexy related events will be summarized separately.  The number of adjudicated 
events based on the report of the Adjudication Committee will also reported separately. 
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Customized MedDRA Queries for AEs that could potentially be considered cataplexy will be 
summarized.  The results of the deliberation of the Adjudication Committee will be reported 
separately.  All AEs must be followed for 28 days, or 5× the half-life, whichever is longer 
after the subject’s last dose, or until resolution, whichever comes first.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows: 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating, with inability to work or to perform normal daily activity 
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.5.2 for the definition of an SAE). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
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. 
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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 adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care  
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution. 
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9.5.1.5.3 STUDY-SPECIFIC ADVERSE EVENTS 
The study-specific events, including, cataplexy, potential cataplexy, convulsion, fall, and 
seizure, should always be considered adverse events and reported on the Adverse Event CRF 
and on the event-specific CRFs designed to collect additional information on specific events. 
9.5.1.5.4 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 3) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study (Core Study). 
Table 2  
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils) 
Chemistry 
 
 Electrolytes 
Chloride, potassium, sodium  
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin 
 Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 Other 
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid 
Urinalysis 
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs 
RBC = red blood cell, WBC = white blood cell. 
Clinical laboratory tests during the Screening, Baseline, and Titration Periods 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.  Local laboratories will perform tests to qualify 
subjects for entry into the study.  Laboratory certification as available will be included in the 
final clinical study report for this study. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF. 
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9.5.1.5.5 VITAL SIGNS, HEIGHT, AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3) 
by a validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  Height is measured once at Screening. 
9.5.1.5.6 PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF. 
9.5.1.5.7 ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in 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) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF. 
9.5.1.5.8 OTHER SAFETY ASSESSMENTS 
Columbia-Suicide Severity Rating Scale 
The C-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  Suicidality will be assessed as designated in the Schedule of 
Procedures and Assessments (Table 3), using a site-administered version of the C-SSRS 
(Posner, et al., 2011).   
Pregnancy Test 
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women 
and postmenopausal women who have been amenorrheic for less than 12 months as 
designated in the Schedule of Procedures/Assessments (Table 3). 
Urine Drug Test 
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 3).  This sample will be tested for common 
drugs of use/abuse:  eg, propoxyphene, cocaine metabolites, cannabinoids, methadone, 
phencyclidine (PCP), opiates, benzodiazepines, barbiturates, and amphetamines. 
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9.5.2 
Schedule of Procedures/Assessments – Core Study 
9.5.2.1 
Schedule of Procedures/Assessments 
Table 3 presents the schedule of procedures/assessments for the Core Study. 
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Table 3 
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study  (revised per 
Amendment 01) 
Phase 
Pretreatment 
Treatment 
 
Period 
Screening 
Baseline 
Titration 
Follow-Upa 
 
 
Visit 
1 
2ab 
2bb 
3c 
 
E 
Td,e 
UNSe,f 
Week -3 (Days -
21 to -1) 
- 
0 
2 
6 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Sleep Drug History Questionnaire 
X 
 
 
 
 
 
 
Sleep Disorder Screening Batteryg 
X 
 
 
 
 
 
 
Insomnia Severity Index 
X 
Xh 
X 
X 
 
X 
X 
C-SSRS 
X 
Xh 
X 
X 
X 
X 
X 
Medical, sleep, psychiatric history 
X 
 
 
 
 
 
 
Prior and concomitant medications 
X 
Xh 
X 
X 
X 
X 
X 
Dispense study drug 
 
 
X 
X 
 
 
 
Retrieve unused study drug 
 
 
 
X 
 
X 
 
Study drug compliance 
 
 
 
X 
 
X 
X 
Physical examinationi 
X 
Xh 
X 
X 
X 
X 
X 
Vital signs and weight 
X 
Xh 
X 
X 
X 
X 
X 
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Table 3 
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study  (revised per 
Amendment 01) 
Phase 
Pretreatment 
Treatment 
 
Period 
Screening 
Baseline 
Titration 
Follow-Upa 
 
 
Visit 
1 
2ab 
2bb 
3c 
 
E 
Td,e 
UNSe,f 
Week -3 (Days -
21 to -1) 
- 
0 
2 
6 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Clinical laboratory testsj 
X 
 
X 
X 
 
X 
X 
Urine drug screenk 
X 
Xh 
X 
X 
 
X 
X 
Urine pregnancy testl 
X 
Xh 
X 
X 
 
X 
X 
Serum pregnancy testl,m 
X 
 
 
 
 
 
X 
12-lead ECGn 
X 
Xh 
X 
X 
 
X 
X 
PGI-Io 
X 
Xh 
X 
X 
 
X 
X 
Quality of Sleep Ratingo 
X 
Xh 
X 
X 
 
X 
X 
Sleep Drug Experience Interview - 
zolpidem 
 
X 
 
 
 
X 
X 
Sleep Drug Experience Interview - 
lemborexant 
 
 
 
X 
 
 
 
Dispense actigraph 
X 
 
 
 
 
 
 
Retrieve actigraph 
 
Xp 
 
X 
 
X 
 
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Table 3 
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study  (revised per 
Amendment 01) 
Phase 
Pretreatment 
Treatment 
 
Period 
Screening 
Baseline 
Titration 
Follow-Upa 
 
 
Visit 
1 
2ab 
2bb 
3c 
 
E 
Td,e 
UNSe,f 
Week -3 (Days -
21 to -1) 
- 
0 
2 
6 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Review data from data collection 
system and sleep log 
 
Xh 
X 
X 
 
X 
X 
Adverse eventsq,r 
X 
Xh 
X 
X 
X 
X 
X 
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C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram, PGI-I = Patient Global Impression – Insomnia, T = Termination Visit, UNS = Unscheduled Visits 
All visits to be done within ±7 days of the schedule, except for Visits 2, 3 and 4, which must be done within ±3 days. 
a: 
The Follow-up Visit will be conducted 4 weeks after the End of Study Visit for subjects who completed the Titration Period but do not enter the Extension Phase.  
b: 
Subjects will return to clinic at the end of the Screening Period.  The Baseline Period will occur on the same day for subjects who remain eligible for study enrollment. 
Assessments conducted at the end of the Screening Period (Visit 2a) will serve as the assessments for the Baseline Period (Visit 2b) if a subject is enrolled into the Treatment 
Phase. Assessments will be performed once across Visit 2a and Visit 2b.  Assessments to be conducted at Baseline (but which are not done at Visit 2a) will include clinical 
laboratory tests and dispensing of study drug. 
c: 
This visit will represent the End of Study Visit for subjects who completed the Titration Period but are not entering the Extension Phase.  Subjects should otherwise enter the 
Extension Phase immediately after completion of the Titration Period of the Core Study, in which case this visit will also serve as the first visit of the Extension Phase. 
d: 
Subjects who discontinue study drug prematurely at any time after entering the Treatment Phase will be encouraged to return to the site as soon as practicable (preferably 
within 7 days) to complete the Early Termination Visit. 
e: 
ECG will only be done during Early Termination and Unscheduled Visits if the results from the previous visit were deemed to be clinically significant by the investigator. 
f: 
Assessments during Unscheduled Visits will be conducted at the discretion of the investigator.  
g: 
Sleep Disorders Screening Battery comprises:  STOP Bang and International Restless Legs Scale. 
h: 
Data for Visit 2a will represent the Baseline Period (Visit 2b) assessment if the subject is enrolled.  Assessments will be performed once across Visit 2a and Visit 2b. 
i: 
A full physical examination will be conducted at Visit 1. A brief physical examination will be conducted at Visit 2a, Visit 3, and at the Follow-up Visit. For Early 
Termination and Unscheduled Visits, a physical examination will be conducted at the discretion of the investigator. 
j: 
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.  
k: 
Urine drug test at Unscheduled Visits will be conducted at the discretion of the investigator and at Early Termination only for subjects who withdraw because of an AE  
l: 
Female subjects of child-bearing potential only. 
m: To be conducted at Visit 1, and if urine pregnancy testing is positive.  
n: 
The ECG should be repeated if a clinically significant (as determined by the investigator) abnormality is observed. 
o: 
From the beginning of the Pretreatment Phase to the end of the Treatment Phase, and provided an insomnia drug was taken the night prior, PGI-I and Sleep Quality Rating 
data will be entered into the electronic data capture system by the subject.   
p: 
Actigraphs will be collected from subjects who do not meet Screening criteria after data review at Visit 2a.  (revised per Amendment 01) 
q: 
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a narrative for the 
event, per Section 9.5.1.5, Adjudication Committee.  
r: 
If possible, a blood sample for the measurement of study drug plasma concentration should be drawn at the first report of an SAE or a severe unexpected AE and its 
resolution.  (revised per Amendment 01) 
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Table 5 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.   
9.5.2.2 
Description of Procedures/Assessments Schedule 
The scheduling of study procedures and assessments is shown in Table 3. 
9.5.3 
Appropriateness of Measurements 
The clinical assessments are standard measurements commonly used in studies of drugs for 
the treatment of subjects with insomnia. 
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.  Because the objectives of this study include assessing the 
response to lemborexant of nighttime sleep and daytime impairment complaints, the ISI will 
be evaluated for changes from baseline. 
The PGI-I has been used in studies evaluating the impact of treatment for insomnia on the 
patients’ global perceptions of sleep quality and quality of life. 
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.   
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 1 business day from the date the investigator becomes aware of the event. 
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase, 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 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
The investigator must notify his/her IRB of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the 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 a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, 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 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study.  
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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 
Study-specific events—cataplexy, potential cataplexy, convulsion, fall, seizure—should 
always be considered as serious important medical events and be entered on the Adverse 
Event CRF and reported using the procedures detailed in Reporting of Serious Adverse 
Events (Section 9.5.4.1), even if the study-specific event does not meet other serious criteria.   
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above. 
9.5.4.5 
Breaking the Blind 
Not applicable. 
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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 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states. 
9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early termination procedures indicated in 
the Schedule of Procedures/Assessments (Table 3). 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons:  AE(s), lost to follow-up, subject choice, inadequate therapeutic response, 
withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In addition to the 
primary reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF. 
A subject removed from the study for any reason may not be replaced. 
9.5.6 
Abuse or Diversion of Study Drug 
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event CRF. 
Sites will be assessed for the appropriateness of study drug storage and retrieval at the time 
of site selection.  Required policies and procedures will be clearly communicated to the site 
to assess the site’s capabilities and adherence to storage, dispensing, reconciliation, and 
retention of study drug. 
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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.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and a snapshot of the database is obtained and released) and randomization codes 
have been released.  Statistical analyses will be performed using SAS software or other 
validated statistical software as required.  The study endpoints for efficacy and safety will 
presented by treatment group (LEM5 and LEM10) and by pooling across treatments within 
each cohort and overall.  Missing data will not be imputed.  Further details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of the Core Study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database lock. 
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9.7.1.1 
Study Endpoints 
This study is designed to reflect clinical practice, in which patient satisfaction of the 
treatment after switching is an important consideration for maintaining a patient on that 
treatment.  This was the basis for defining the outcome of transition to lemborexant.  While 
sleep quality assessments are included as secondary outcomes in this pilot study to 
supplement the Phase 3 clinical trial data, it is not necessary to establish the absolute amount 
of improvement in sleep parameters, but rather whether the subject is satisfied enough to 
continue treatment with lemborexant.    
9.7.1.1.1 PRIMARY ENDPOINT 
The primary endpoint is the proportion of overall subjects who transition to LEM at the end 
of the Titration Period. 
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week 
Titration Period and either 1) enters the Extension Phase, or 2) chooses to not enter the 
Extension Phase for reasons not related to LEM (including, but not limited to, time 
commitment related to the study, study-related travel expenses or preference to continue 
insomnia management with another health care provider). 
9.7.1.1.2 SECONDARY ENDPOINTS  (REVISED PER AMENDMENT 01) 
The secondary endpoints are as follows:  
• The proportion of subjects who transition to LEM at the end of the 2-week Titration 
Period within each Cohort. 
• The proportion of subjects in the LEM5 treatment groups with dose increasing to 
LEM10 at the end of the Titration Period by Cohort and overall. 
• The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at 
the end of the Titration Period in Cohort 2. 
• The proportion of subjects with positive medication effect rating on each PGI-I item at 
the end of the 2-week Titration Period by Cohort and overall using end of the Titration 
Period treatment.  
9.7.1.1.3 EXPLORATORY ENDPOINTS  (REVISED PER AMENDMENT 01) 
The exploratory endpoints are as follows:   
• The change from Baseline in mean ISI score at the end of the Titration Period by Cohort 
and overall using end of the Titration Period treatment. 
• The change from baseline in mean Quality of Sleep Rating at the end of the Titration 
Period by cohort and overall using end of the Titration Period treatment 
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• To compare nights on which an evening dose of LEM, LEM5, and LEM10 was taken, to 
nights on which an evening dose of ZOL was taken, for the following sleep-related 
actigraphy variables: 
o Mean TST 
o Mean SE 
o Mean WASO 
o Number of Wake Bouts 
• To compare the daytime after an evening dose of LEM, LEM5, and LEM10 was taken, 
to the daytime after an evening dose of ZOL was taken, for the following wake-related 
actigraphy variable: 
o Mean Duration of Sleep Bouts 
9.7.1.2 
Definitions of Analysis Sets 
Safety Analysis Set (SAS) – The SAS is the group of subjects who received at least 1 dose of 
study drug and had at least 1 postdose safety assessment. 
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included 
in the FAS. 
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 and treatment discontinuation.  Other reasons for study treatment and study 
terminations will also be summarized.  These tabulations will be produced for all randomized 
subjects by randomized treatment groups. 
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
for each randomized and end of the Titration Period treatment groups 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 (<18.5, 18.5 to 
<25, 25 to ≥30), race, and ethnicity. 
Characteristics of insomnia at Study Baseline will be summarized using ISI, PGI-I, and 
Quality of Sleep Rating.  
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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 WHO Drug Global March 2019 or later. The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by randomized treatment group, Anatomical Therapeutic Chemical 
(ATC) class, and WHO-DD PT.   
9.7.1.6 
Efficacy Analyses 
All efficacy analyses will be conducted on the FAS.  Efficacy endpoints may be analyzed by 
modeling methods if warranted.  Details of all of the analyses will be specified in the 
Statistical Analysis Plan.  (revised per Amendment 01) 
9.7.1.6.1 PRIMARY EFFICACY ANALYSIS 
• The proportion of overall subjects who transition to LEM after 2 weeks of treatment in 
the Titration Period will be displayed. 
9.7.1.6.2 SECONDARY EFFICACY ANALYSES  (REVISED PER AMENDMENT 01) 
The secondary analyses are as follows: 
• The proportion of subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed within each cohort.   
• The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall. 
• The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented. 
• The proportion of subjects in each of the 4 items of the PGI-I will be summarized 
separately within each scale over time by Cohort and overall using end of the Titration 
Period dose groups.   
• The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these 
items at the end of the Titration Period, and the proportion of subjects who rated the drug 
as being too strong or too weak at Baseline, but whose rating was “just right” at the end 
of the Titration Period (as data allow) will be reported. 
 
9.7.1.6.3 EXPLORATORY EFFICACY ANALYSES  (REVISED PER AMENDMENT 01) 
• Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on 
the ISI will be summarized at the end of the Titration Period by Cohort and overall 
using end of the Titration Period dose groups. 
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• The change from baseline in mean Quality of Sleep Rating score for subjects at the 
end of the Titration Period will be summarized by cohort and overall using end of 
Titration Period dose groups. 
• Average value of following sleep-related actigraphy variables will be summarized by 
treatment over the nights on which an evening dose of LEM, LEM5, LEM10, and 
ZOL was taken.   
o Mean TST 
o Mean SE 
o Mean WASO 
o Number of Wake Bouts 
• Average value of wake-related actigraphy variable, mean duration of Sleep Bouts will 
be summarized by treatment over the daytime after an evening dose of LEM, LEM5, 
LEM10, and ZOL was taken.   
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
Not applicable. 
9.7.1.8 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
end of Titration Period dose groups, will be summarized on an “as treated” basis using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include TEAEs, 
physical examination, clinical laboratory parameters, vital signs, 12-lead ECG results, and 
the C-SSRS.  Study Day 1 for all safety analyses will be defined as the date of the first dose 
of study drug.   
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics. 
AEs summaries, and abnormal findings will also be displayed based on the dose that the 
subjects were taking at the time of the findings. 
 
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.   
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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 22.0 or higher) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA PT and primary system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
Adverse events will be summarized using the Safety Analysis Set.  The incidence of AEs will 
be summarized by end of Titration Period dose for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics.  To obtain the incidence (%), the 
number of subjects with at least 1 event and the percentage of subjects with AEs by SOC and 
by PT will be calculated.  Incidence (%) by causal relationship with study drug and by 
severity will also be calculated.  For clinically significant events, time of onset, and recovery 
will be reported. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data 
listing of all SAEs will be provided. 
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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 a Customized MedDRA Query (CMQ) PT as cataplexy-related 
events, as well drug abuse liability will be summarized separately.  The number of adjudicated 
events based on the report of the Adjudication Committee will also reported separately.  In 
addition, 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, 
as per the Adjudication Committee description. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.4, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and end of Titration Period dose using 
descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.4 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period. 
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable. 
9.7.1.8.4 VITAL SIGNS 
Mean changes from baseline in vital signs (ie, systolic and diastolic BP, pulse, respiratory 
rate, body temperature, weight) and out-of-range vital signs will be summarized by end of 
Titration Period dose groups for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent 
ZOL use) using descriptive statistics.  
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Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 4).  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 
end of Titration Period dose and time point. 
Table 4 
Clinically Notable Vital Sign Criteria 
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 
ECG assessments will be performed at Screening and at the end of the Titration Period.  The 
incidence of abnormal ECG findings will be summarized by end of Titration Period dose for 
Cohort 1 (Intermittent ZOL Use) and Cohort 2 (Frequent ZOL Use) using descriptive 
statistics.  Shift tables will present changes from baseline in ECG interpretation (categorized 
as normal and abnormal) by time point. 
9.7.1.8.6 OTHER SAFETY ANALYSES 
The results of C-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. 
9.7.2 
Determination of Sample Size 
As a pilot study, sample size estimates are not based on statistical calculations.  
This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 
2B) to evaluate the proportion of subjects who  transition to LEM as a substitute for ZOL.  
Twenty subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be 
assigned to Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to 
receive LEM5 or LEM10 within Cohort 2.  This sample size is deemed sufficient to inform 
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whether the proposed strategies are sufficient to determine whether alternative strategies 
would be required to help understand how best to recommend safe and effective methods for 
transitioning from ZOL to LEM. 
9.7.3 
Interim Analysis 
No interim analysis is planned for this study. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 
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10 REFERENCE LIST 
Abetz L, Arbuckle R, Allen RP, Diego GB, Hening W, Walters SA, et al. The Reliability, 
Validity and Responsiveness of the International Resless Legs Syndrome Study Group 
Rating Scale and Subscales in a Clinical-Trail setting. Sleep Med. 2006;7: 340-49. 
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders, 
5th ed. American Psychiatric Publishing, 2014. 
Bastien CH, Vallieres A, Morin CM.  Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med. 2001;2:297-7. 
Belsomra (suvorexant) tablets, for oral use, Prescribing Information [updated 12 Jul 2018; 
cited 09 Sept 2018]. Available from:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5b72731-1acb-45b7-9c13-
290ad12d3951 
Bertisch SM, Herzig SJ, Winkelman JW, Buettner C.  National use of prescription 
medications for insomnia: NHANES 1999-2010.  Sleep.  2014;37(2):343-9. 
Beuckmann CT, Suzuki M, Ueno T, Nagaoka K, Arai T, Higashiyama H.  In vitro and in 
silico characterization of lemborexant (E2006), a novel dual orexin receptor antagonist. 
J Pharmacol Exp Ther. 2017;362(2):287–95. 
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(5):812-21. 
Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Snyder E, et al. A Phase II 
dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist 
filorexant (MK-6096) in patients with primary insomnia. Int J Neuropsychopharmacol. 
2016;19:1–10. 
De Boer P, Drevets WC, Roael H, van der Ark P, Kent JM, Kezic I, et al. A randomized 
Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with 
insomnia without psychiatric comorbidity. J Psychopharmacol. 2018;32:668–77. 
Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. Orexin receptor 
antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 
2012;79:2265–74. 
Herring WJ, Snyder E, Tao P, Svetnik V, Lines C.  Performance of the Patient Global 
Impressions – Severity Scale as a self-reported patient assessment of insomnia severity. 
Neurology.  2018;90(15 Suppl):1-107. 
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Hoever P, Dorffner G, Beneš H, Penzel T, Danker-Hopfe H, Barbanoj MJ, et al. Orexin 
receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin 
Pharmacol Ther. 2012;91(6):975–85. 
Irish LA, Kline CE, Gunn HE, Buysse DJ, Hall MH.  The role of sleep hygiene in promoting 
public health: A review of empirical evidence. Sleep Med Rev.  2015(22):23–36. 
Krystal AD, Edinger JD. Sleep Med. Measuring sleep quality.  2008;9(Suppl 1):S10-7. 
Kyle SD, Miller CB, Rogers Z, Siriwardena AN, MacMahon KM, Espie CA.  Sleep 
restriction therapy for insomnia is associated with reduced objective total sleep time, 
increased daytime somnolence, and objectively impaired vigilance: implications for the 
clinical management of insomnia disorder. Sleep.  2014;37(2):229–37. 
Morgenthaler T, Kramer M; Alessi C, Friedman L, Boehlecke B, Brown T, et al.  Practice 
parameters for the psychological and behavioral treatment of insomnia: an update.  An 
American Academy of Sleep Medicine report. Sleep.  2006;29(11):1415–19. 
Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a 
dual orexin receptor antagonist (DORA) for the treatment of insomnia disorder:  results from 
a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin Sleep Med. 
2017;13:1289–99. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The 
Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77. 
Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, et al.  Oral 
nonprescription treatment for insomnia: an evaluation of products with limited evidence.  J 
Clin Sleep Med. 2005 Apr 15;1(02):173–87. 
Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M.  Clinical guideline for the 
evaluation and management of chronic insomnia in adults.  J Clin Sleep Med. 
2008;4(5):487–504. 
Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL.  Clinical practice guideline for 
the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep 
Medicine clinical practice guideline, J Clin Sleep Med, 2017;13(2): 307-49. 
Stepanski EJ, Wyatt JK.  Use of sleep hygiene in the treatment of insomnia.  Sleep Med Rev. 
2003 Jun 1;7(3):215–25. 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB 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 detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.3 Monitoring Procedures 
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following: 
• 
Clinic, office, or hospital charts 
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• 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• 
Recorded data from automated instruments such as Interactive Voice/Web Response 
System (IxRS), x-rays, and other imaging reports (eg, sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives 
• 
Pain, quality of life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation) 
• 
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 
• 
Electronic Patient-Reported Outcome by self-reported measures 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
The efficacy assessments are evaluated based on the data entered into electronic Patient-
Reported Outcome.  The applicable data are input directly by each subject from the 
viewpoint of his/her health condition without the interpretation of the investigator.  
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.   
The data collected by electronic Patient-Reported Outcome are also considered source data.   
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11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or designated contractor, or, when approval is given by the sponsor, 
will destroy supplies and containers at the site. 
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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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12 APPENDICES 
Appendix 1 
Sponsor’s Grading for Laboratory Values 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
<LLN – 10.0 g/dL 
<LLN – 100 g/L 
<LLN – 6.2 mmol/L 
<10.0 – 8.0 g/dL 
<100 – 80 g/L 
<6.2 – 4.9 mmol/L  
<8.0 g/dL 
<80 g/L 
<4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
<LLN – 3.0×109/L 
<LLN – 3000/mm3  
<3.0 – 2.0×109/L 
<3000 – 2000/mm3  
<2.0 – 1.0×109/L 
<2000 – 1000/mm3  
<1.0×109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8×109/L 
<800 – 500/mm3 
<0.8 – 0.5×109/L 
<500 – 200/mm3  
<0.5 – 0.2×109/L 
<200/mm3 
<0.2×109/L 
Neutrophils  
<LLN – 1.5×109/L 
<LLN – 1500/mm3 
<1.5 – 1.0×109/L 
<1500 – 1000/mm3 
<1.0 – 0.5×109/L 
<1000 – 500/mm3  
<0.5×109/L 
<500/mm3  
Platelets 
<LLN – 75.0×109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0×109/L 
<75,000 – 50,000/mm3 
<50.0 – 25.0×109/L 
<50,000 – 25,000/mm3 
<25.0×109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
>ULN – 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 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
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Appendix 2 
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  
• 
gamma-aminobutyric acid (GABA) 
analogues  
• 
Hydantoins  
• 
Phenyltriazines 
Antihistamines (centrally-acting H1, including 
over-the-counter [OTC])  
 
• 
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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Confidential 
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Category 
Medication 
Strong CYP3A inhibitors 
 
• 
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 
Moderate CYP3A inhibitors  
• 
Amprenavir 
• 
Aprepitant 
• 
Atazanavir 
• 
Casopitant 
• 
Cimetidine 
• 
Ciprofloxacin 
• 
Clotrimazole 
• 
Crizotinib 
• 
Cyclosporin 
• 
Darunavir 
• 
Dronadarone 
• 
Erythromycin 
• 
Faldaprevir 
• 
Fluconazole 
• 
Fluvoxamine 
• 
Imatinib 
• 
Netupitant 
• 
Tofisopam 
• 
Verapamil 
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Confidential 
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Category 
Medication 
Cytochrome P450 (CYP)3A inducers 
 
• 
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 
• 
- 
Monoamine oxidase inhibitors (MAOIs) 
• 
- 
Opioid Analgesics 
• 
- 
Muscle relaxants (centrally-acting) with known sedating 
effects 
 
• 
GABA analogues  
• 
Hydantoins  
• 
Phenyltriazines 
Other 
 
• 
Warfarin, heparin, ticlopidine 
• 
Systemic isoretinoin 
• 
Systemic glucocorticoids 
 
 
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Appendix 3 
Extension Phase 
Study Design and Plan 
The Extension Phase comprises a Maintenance Period of up to 12 weeks in duration, and a 
Follow-up Period visit that is to occur 4 weeks after the end of the Maintenance Period. 
Maintenance Period 
During the 12-week Maintenance Period, subjects will continue on the dose of Lemborexant 
(LEM) that they took at the end of the Titration Period.  Subjects will subsequently return to 
clinic at the visit as specified in the Schedule of Assessments, and will be instructed to return 
their supply of LEM at each visit.  Unused study drug will be collected, and study drug 
compliance will be assessed.  Subjects will be able to discuss changing the dose of LEM at 
any time during the Maintenance Period, and LEM dose changes may be implemented as 
clinically determined by the investigator with input from the subject. 
Follow-Up Period 
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all 
subjects (eg, 4 weeks after the end of the Maintenance Period). 
End of Study 
The end of the study will be the date of the last study visit for the last subject in the study.   
Study Drug Supplies 
Subjects will enter the Extension Phase from the Titration Phase of the Core Study, taking 
the same dose of LEM that was their final dose of the Titration Phase, ie, LEM5 or LEM10 
taken orally in tablet form at night a few minutes before the time the subject intends to try to 
sleep. 
Schedule of Procedures/Assessments 
Table 5 presents the Schedule of Procedures and Assessments for the 12-week Extension 
Phase.
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Table 5 
Schedule of Procedures and Assessments in Study E2006-A001-312 – Extension  (revised per 
Amendment 01) 
Phase 
Extension 
 
Period 
Maintenance 
Follow-upa 
 
 
Visit 
4 
5 
Early Terminationb,c  
Unscheduledc, d 
Week 
14 
18 
 
 
Procedures/Assessments 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
Study drug compliance 
X 
 
X 
X 
Dispense study drug 
 
 
 
 
Retrieve unused study drug 
X 
 
X 
X 
Physical examinatione 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
Clinical laboratory testsf 
X 
 
X 
X 
Urine drug screeng 
X 
 
X 
X 
Urine pregnancy testh 
X 
 
X 
X 
Serum pregnancy testh,i 
 
 
 
X 
12-Lead ECGj 
X 
 
X 
X 
Adverse eventsk,l 
X 
X 
X 
X 
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Table 5 
Schedule of Procedures and Assessments in Study E2006-A001-312 – Extension  (revised per 
Amendment 01) 
Phase 
Extension 
 
Period 
Maintenance 
Follow-upa 
 
 
Visit 
4 
5 
Early Terminationb,c  
Unscheduledc, d 
Week 
14 
18 
 
 
Procedures/Assessments 
 
 
 
 
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram. 
All visits to be done within ±7 days of the schedule. 
a: 
The Follow-up Visit will be conducted 4 weeks after the end of the Extension Phase. 
b: 
Subjects who discontinue study drug prematurely at any time after entering the Extension will be encouraged to return to the site as soon as practicable 
(preferably within 7 days). 
c: 
During Early Termination and unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by 
the investigator. 
d: 
Assessments during an Unscheduled Visit to be conducted at the discretion of the investigator. 
e: 
A full physical examination will be conducted at Visit 4 and 5 and at the Early Termination and Unscheduled Visit at the discretion of the investigator.  
f: 
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.  
g: 
Urine drug test to be conducted at Unscheduled Visits at the discretion of the investigator and at Early Termination only for subjects who withdraw because 
of an adverse event.  
h: 
Female subjects of child-bearing potential only.  
i: 
To be conducted if urine pregnancy testing is positive 
j: 
The ECG should be repeated if a clinically significant abnormality (as determined by the investigator) is observed. 
k: 
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 9.5.1.5, Adjudication Committee 
l: 
If possible, a blood sample for the measurement of study drug plasma concentration should be drawn at the first report of an SAE or severe unexpected AE 
and at its resolution.  (revised per Amendment 01) 
 
 
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Statistical Analyses 
All statistical analyses will be the responsibility of the Biostatistics Department of Eisai.  
Statistical programming and analyses will be performed using SAS or other validated 
software.  
Safety Analyses 
The primary focus of data summarization for the Extension Phase will be on safety and 
tolerability.  Evaluations of safety data will be performed on the Safety Analysis Set. 
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics. 
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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E2006-A001-312 
Study Protocol Title: 
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia  
Investigational Product 
Name: 
E2006\Lemborexant 
 
IND Number: 
111871 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
Eisai, Inc 
 
Date 
 
 
 
 
 
Eisai Inc. 
 
Date 
 
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PPD
PPD

 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E2006-A001-312 
Study Protocol Title: 
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia 
Investigational Product 
Name: 
E2006\Lemborexant 
IND Number: 
111871 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
<Name of institution> 
Medical Institution 
 
<Name, degree(s)> 
  
  
Investigator 
 Signature 
 Date 
 
 
 
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REVISION HISTORY
  Revisions to Version 1.0 
  New version /date: Version 2.0/12 Apr 2019
Change
Rationale
Affected Protocol Sections
Modified the text in Exclusion 
Criterion No. 1 to replace urine 
pregnancy test with serum 
pregnancy test.
Administrative change

Synopsis –Exclusion criteria

Section 9.3.2
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-A001-312
Study Protocol 
Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition from 
Zolpidem to Lemborexant for the Treatment of Insomnia 
Sponsor: 
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Investigational 
Product Name:
E2006/Lemborexant
Indication:
Insomnia 
Phase:
3b
V1.0
12 Apr 2019 (original protocol)
V2.0
12 Apr 2019 (revised original protocol)
IND Number:
111871
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the 
Treatment of Insomnia
Investigator(s)
Unknown
Sites
Approximately 15 sites within the United States of America
Study Period and Phase of Development
Phase 3b pilot study
Estimated duration of up to 38 weeks from first subject in to last subject’s last visit.
Objectives
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects with 
insomnia disorder taking zolpidem tartrate immediate release (ZOL-IR) or zolpidem tartrate extended
release (ZOL-ER), intermittently or frequently, who  transition to lemborexant 5 mg (LEM5) or 10 
mg (LEM10), after 2 weeks of receiving lemborexant (LEM).
Secondary Objectives

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease from 
LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of Insomnia 
(PGI-I) at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared with 
Baseline at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared with 
Baseline at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking zolpidem (ZOL)
Exploratory Objective(s)
None
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Study Design
E2006-A001-312 is a multicenter Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week Screening 
Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week Titration Period), and 
an Extension Phase consisting of the Maintenance Period up to 12 weeks and the Follow-up Period 
4 weeks in duration immediately following the end of the Treatment Phase.  The Pretreatment 
and Treatment Phases will comprise the Core Study.  A Follow-up Period visit occurring 4 weeks 
after the end of the Extension Phase (or Treatment Phase, for subjects not entering the Extension 
Phase) will be conducted.
Core Study
Pretreatment Phase
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day Baseline Period, 
during which subjects will be assessed for eligibility to participate in the study. 
Screening Period
During the Screening Period, subjects will be required to bring the container of their prescribed ZOL 
to the site for verification of prescribed medication and dose. Subjects will be provided with, and 
trained in the use of, a data collection system to record the frequency of ZOL is taken during the 
3-week Screening Period.  Site staff will instruct subjects to complete data entry every morning and 
will emphasize the importance of providing these data.  During the Screening Period, subjects will 
continue to take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5mg or 
10 mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection system for 
at least 14 (preferably contiguous) days out of the allowable 21-day Screening Period in order to be 
eligible for study inclusion.  
Subjects will return to clinic at the end of the Screening Period.  Based on ZOL use during the 
Screening Period (which must match the treatment history ascertained at the beginning of the 
Screening Period), subjects will be assigned to 1 of 2 cohorts as follows:
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, for 
each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, during, at 
minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). For 
Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio. 
Baseline Periody
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment cohort.  
Subjects who are not eligible will conclude their participation and will be considered screen failures.  
Upon completion of the Baseline Period, subjects who remain eligible will enter the Titration Period.
Treatment Phase
Titration Period
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and LEM10 to 
be taken at home within a few minutes of the time that they intend to sleep at night.  Study 
restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals will be 
discussed. Subjects will be instructed to not alter (ie, break or cut) their tablets of LEM.
Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will determine the nights on which they 
take LEM, with the requirement that they take LEM at least once per week during the 14–day 
Titration Period.  
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Cohort 2 (Frequent Use, Treatment Groups A and B): Subjects in these cohorts will take LEM at 
least 5 nights per week during the 2-week Titration Period.
For subjects with a starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but not 
mandated) to remain on their assigned dose for 7 days before calling the site should they feel that 
LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  
For subjects with a starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site should they feel that LEM10 should be reduced. 
Subjects will then be instructed to take LEM5 within a few minutes of the time they intend to go to 
sleep.  
At the time of LEM dose change during the Core Study, the reason for the dose change will be 
recorded in the case report form (CRF).  Subjects will be allowed 1 LEM dose adjustment during 
the Titration Period.  Every morning, subjects will enter their insomnia drug use data into the data 
collection system, and, provided an insomnia drug was taken the night prior, PGI-I and Quality of 
Sleep Rating. The ISI will be completed at each study visit except Follow-up Visit.  . 
Upon completion of the Titration Period, subjects will be eligible to enter the Extension Phase. 
Extension Phase
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of LEM that they took at 
the end of the Titration Period.  Subjects will subsequently return to clinic as specified in the 
Schedule of Assessments, and will be instructed to return their supply of LEM at each visit.  Unused 
study drug will be collected, study drug compliance will be assessed.  Subjects will be able to discuss 
changing the dose of LEM at any time during the Maintenance Period, and LEM dose changes may 
be implemented as clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all subjects (eg,
4 weeks after the end of the Treatment Phase for subjects not entering the Extension Phase or after 
the end of the Extension Phase, for subjects entering the Extension Phase).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study. 
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Number of Subjects
Approximately 110 subjects will be screened to provide approximately 60 subjects (20 subjects in 
Cohort 1 and 40 subjects in Cohort 2 [20 in LEM5, 20 in LEM10]).
Inclusion Criteria
1.
Male or female, 18 years or older, at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5) criteria for 
Insomnia Disorder, either currently or prior to ZOL use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep 
and/or awakening earlier in the morning than desired despite adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 but fewer than 5 nights per week), or frequent use 
(at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month
5.
Confirmation of intermittent or frequent use of ZOL (based on review of drug use data). 
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for at least 
2 weeks each of the 3-week Screening Period.  Frequent use is defined as taking ZOL at least 5 
nights per week, during, at minimum, the last 2 weeks of the 3-week Screening Period
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 
hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia during the 
subject’s participation in the study
Exclusion Criteria
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
serum pregnancy test).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing and throughout the study and for 28 days 
after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
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dosing).
3.
Any history of moderate or severe obstructive sleep apnea (OSA)
4.
Current evidence of a clinically significant, active respiratory disorder other than mild OSA.  
This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any 
other pulmonary disorder identified by review of medical history or physical examination, and 
which in the opinion of the investigator, could compromise the subject’s safety or interfere with 
study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, circadian 
rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals 
with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator 
indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy
8.
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 sleeping), 
whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
13. Used any prohibited prescription or over-the-counter concomitant medications within 1-week or 
5 half-lives, whichever is longer, before the first dose of study medication (A list of prohibited 
concomitant medications is presented in the protocol).  
14. Used any pharmacologic modality of treatment for insomnia other than zolpidem, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening Period
15. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
16. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
Columbia-Suicide Severity Rating Scale [C-SSRS])
17. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
18. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal 
disease) 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.
19. Hypersensitivity to lemborexant or any of the excipients.
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study.
21. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study. Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the investigator this operation does not interfere with the study procedures and patient safety.
22. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics 
or prior suicide attempt(s) within approximately the last 2 years
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23. History of drug or alcohol dependency or abuse within approximately the last 2 years
24. Currently enrolled in another clinical study or used any investigational drug or device within 28 
days or 5× the half-life, whichever is longer, preceding informed consent
25. Previously participated in any clinical trial of lemborexant
Study Treatment(s)
Core Study
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night within a few minutes of the time the subject 
intends to sleep, according to the subject’s predetermined intermittent or frequent use schedule.
Comparator Drug:  Not applicable 
Extension Phase
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night a few minutes before the time the subject 
intends to try to sleep.
Duration of Treatment
A maximum of 14 weeks: 
2 weeks of LEM5 and/or LEM10 during the Treatment Phase of the Core Study,
12 weeks during the Extension Phase
Concomitant Drug/Therapy
Prohibited medications should not be used during the study.  A subject must not have used any 
prohibited prescription or over-the-counter medications within 1-week or 5 half-lives, whichever is 
longer, before the Treatment Phase.
Prohibited medications include moderate and strong cytochrome P450 (CYP)3A inhibitors and all 
CYP3A inducers, and medications that have known sedating effects.  The prohibition applies even if 
the entire class to which that medication belongs is not prohibited (eg, anticonvulsants).  
If a medication is not on the list of prohibited medications but in the opinion of the investigator 
causes or exacerbates the subject’s insomnia, it must not be used throughout the study.  If a 
medication is not specified as prohibited but is in the same class as a medication that is listed in the 
protocol, and if the investigator is uncertain whether the medication has known sedating or alerting 
effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue 
from the study, with the exception that certain prohibited medications may be used for a short 
duration (not to exceed 2 weeks) to treat an acute condition if this is agreed with the Medical 
Monitor.  Note that strong and moderate CYP3A inhibitors and all CYP3A inducers will not be 
permitted at any time for any duration during the study.  Subjects must forgo alcohol consumption 
within 3 hours of bedtime for the duration of participation in the study.  
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Assessments
Screening Assessments (Core Study only)
Sleep Disorders Screening Battery (SDSB):
The SDSB will include:

STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects for OSA 

IRLS:  a subjective scale comprising 10 questions, which measures severity of symptoms of 
restless legs syndrome
Sleep Drug History Questionnaire
Subjects will be asked questions about their history and response to prior sleep medications.
Sleep Drug Experience Interview – Zolpidem
Subjects will be asked questions about their subjective experiences while taking ZOL at the end of 
the Screening Period.
Efficacy Assessments (Core Study only)
Patient Global Impression – Insomnia
The PGI-I is a self-report assessment of subject perception of the effects of a medication on their 
sleep.  The PGI-I has 3 items related to study medication effects (a) helped/worsened sleep, (b) 
decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to 
perceived appropriateness of study medication strength.  The first 3 items are answered on a 3-point 
scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and 
the last item on a different 3-point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior evening.
Insomnia Severity Index
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia.  
The dimensions evaluated are severity of: sleep onset, sleep maintenance, early-morning awakening 
problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning, 
noticeability of the sleep problems by others, and distress caused by the sleep difficulties.  A 5-point 
Likert scale is used to rate each item (from 0=no problem, to 4=very severe problem), yielding a total 
score from 0 to 28.  The ISI will be completed at each study visit except Follow-up Visit.  
Quality of Sleep Rating
The Quality of Sleep Rating is a self-reported scale in which subjects are asked, “How would you rate 
the quality of your sleep last night, with 1 being extremely poor, 5 being not good or poor, and 9 
being extremely good?” For Quality of Sleep, higher values are better.  The Quality of Sleep Rating 
will be completed each morning following a dose of ZOL or LEM taken the prior evening during the 
Screening, Baseline, and Titration Periods.
Sleep Drug Experience Interview – Lemborexant
Subjects will be asked questions about their subjective experiences while taking LEM at the end of 
the Titration Period.
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable.
Safety Assessments (Core Study and Extension Phase)
Safety assessments will consist of monitoring and recording all adverse events (AEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of 
vital signs, weight and ECGs; and the performance of physical examinations.  Subjects will be asked 
about falls at every visit.
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Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure.  A set of preferred terms (PTs)
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.  
Columbia – Suicide Severity Rating Scale
Suicidality will be assessed using a site-administered version of the C-SSRS.  The C-SSRS assesses 
an individual’s degree of suicidality, including both suicidal ideation and suicidal behavior. 
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months as designated in the 
Schedule of Procedures/Assessments.
Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the Schedule of 
Procedures/Assessments.  This sample will be tested for common drugs of use/abuse:  eg, 
propoxyphene, cocaine metabolites, cannabinoids, methadone, PCP, opiates, benzodiazepines, 
barbiturates, and amphetamines.
Bioanalytical Methods
Not applicable.
Statistical Methods
The study endpoints for efficacy and safety will be presented by treatment group (LEM5 and 
LEM10) and by pooling across treatments within each cohort and overall.  Missing data will not be 
imputed.
Primary Endpoint
The primary endpoint is the proportion of overall subjects who transition to LEM at the end of the 
Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week Titration 
Period and either 1) enters the Extension Phase, or 2) chooses to not enter the Extension Phase for 
reasons not related to LEM (including, but not limited to, time commitment related to the study, 
study-related travel expenses, or preference to continue insomnia management with another health 
care provider).  
Secondary Endpoints
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration Period
within each Cohort.

The proportion of subjects with positive medication effect rating on each PGI-I item at the end 
of the 2-week Titration Period by Cohort and overall using end of the Titration Period treatment.
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
The change from Baseline in mean ISI score at the end of the Titration Period by Cohort and 
overall using end of the Titration Period treatment.

The proportion of subjects in the LEM5 treatment groups with dose increasing to LEM10 at the 
end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at the end 
of the Titration Period in Cohort 2.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration Period by 
cohort and overall using end of the Titration Period treatment.
Analysis Sets
Safety Analysis Set (SAS) –The Safety Analysis Set is the group of subjects who received at least 1 
dose of study drug and had at least 1 postdose safety assessment.
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included in the 
Full Analysis Set.
Efficacy Analyses (Core Study only)
All efficacy analyses will be conducted on the FAS. 

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed.

The proportion of subjects who transition to LEM after 2 weeks of treatment in the Titration 
Period will be displayed within each cohort.  

Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately within 
each scale over time by Cohort and overall using end of the Titration Period dose groups.

The proportion of subjects whose response on the first 3 items of the PGI-I (medication effect) 
was neutral or negative at Baseline, but who recorded a positive effect on these items at the end 
of the Titration Period, and the proportion of subjects who rated the drug as being too strong or 
too weak at Baseline, but whose rating was “just right” at the end of the Titration Period (as data 
allow) will be reported.

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the ISI will 
be summarized at the end of the Titration Period by Cohort and overall using end of the Titration 
Period dose groups

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the Titration 
Period by Cohort and overall, 

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the Titration 
Period will be displayed in Cohort 2.  A graphical representation of changes between the 5 and 
10 mg dose groups in each of the cohorts may also be presented.

The change from baseline in mean Quality of Sleep Rating score for subjects at the end of the 
Titration Period will be summarized by cohort and overall using end of the Titration Period dose 
groups.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable.
Safety Analyses (Core Study and Extension Phase)
Evaluations of safety data will be performed on the SAS. 
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG findings, out-of-
range vital signs, and suicidality (C-SSRS) findings, along with changes from baseline in clinical 
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laboratory variables, and vital signs will be summarized for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics using end of titration dose group. AEs
summaries, and abnormal findings will also be displayed based on the dose that the subjects were 
taking at the time of the findings.
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered cataplexy or 
seizure, somnolence, and related events, and PTs related to drug abuse liability, will be summarized
seperately.  The results of the deliberation of the Adjudication Committee will be reported separately.  
In addition, 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, as per the
Adjudication Committee description.
Other Analyses (Core Study)
Primary and secondary endpoints may be analyzed by modeling methods if warranted.  Details of all 
of the analyses will be specified in the Statistical Analysis Plan.
Interim Analyses
No interim analyses are planned for this study.
Sample Size Rationale
As a pilot study, sample size estimates are not based on statistical calculations.
This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 2B) to 
evaluate the proportion of subjects who transition to LEM as a substitute for zolpidem.  Twenty 
subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be assigned to 
Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to receive LEM5 or 
LEM10 within Cohort 2.  This sample size is deemed sufficient to inform whether the proposed 
strategies are sufficient to evaluate whether alternative strategies would be required to help 
understand how best to recommend safe and effective methods for transitioning from ZOL to LEM.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................18
5
ETHICS............................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees ..............................19
5.2
Ethical Conduct of the Study.................................................................................19
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................20
7
INTRODUCTION ...........................................................................................................21
7.1
Indication ...............................................................................................................21
7.1.1
Current Therapeutic Options........................................................................21
7.1.2
Lemborexant ................................................................................................22
7.1.2.1
Clinical Experience With Lemborexant...............................................22
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................23
7.2
Study Rationale......................................................................................................23
7.2.1
Entry Criteria Rationale...............................................................................24
7.2.2
Rationale for Titration Schedule and Duration............................................24
8
STUDY OBJECTIVES....................................................................................................25
8.1
Primary Objective..................................................................................................25
8.2
Secondary Objectives.............................................................................................25
8.3
Exploratory Objective(s)........................................................................................25
9
INVESTIGATIONAL PLAN..........................................................................................25
9.1
Overall Study Design and Plan..............................................................................25
9.1.1
Pretreatment Phase (Core Study).................................................................27
9.1.1.1
Screening Period (Core Study) ............................................................27
9.1.1.2
Baseline Period (Core Study)...............................................................28
9.1.2
Treatment Phase (Core Study).....................................................................28
9.1.2.1
Titration Period (Core Study) ..............................................................28
9.1.2.2
Follow-Up Period.................................................................................29
9.1.3
Extension Phase ...........................................................................................29
9.2
Discussion of Study Design, Including Choice of Control Groups.......................29
9.3
Selection of Study Population................................................................................29
9.3.1
Inclusion Criteria .........................................................................................29
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9.3.2
Exclusion Criteria ........................................................................................30
9.3.3
Removal of Subjects from Therapy or Assessment.....................................32
9.4
Treatments..............................................................................................................32
9.4.1
Treatment(s) Administered..........................................................................32
9.4.2
Identity of Investigational Product...............................................................33
9.4.2.1
Chemical Name, Structural Formula of Lemborexant.........................33
9.4.2.2
Comparator Drug .................................................................................34
9.4.2.3
Labeling for Study Drug......................................................................34
9.4.2.4
Storage Conditions...............................................................................34
9.4.3
Method of Assigning Subjects to Treatment Groups...................................34
9.4.4
Selection of Doses in the Study...................................................................34
9.4.5
Selection and Timing of Dose for Each Subject..........................................34
9.4.6
Blinding........................................................................................................35
9.4.7
Prior and Concomitant Therapy...................................................................35
9.4.7.1
Drug-Drug Interactions........................................................................35
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................36
9.4.8
Treatment Compliance.................................................................................36
9.4.9
Drug Supplies and Accountability...............................................................36
9.5
Study Assessments.................................................................................................38
9.5.1
Assessments.................................................................................................38
9.5.1.1
Demography.........................................................................................38
9.5.1.2
Screening and Baseline Assessments...................................................38
9.5.1.2.1
Medical History and Physical Examinations.................................38
9.5.1.2.2
Sleep Drug History Questionnaire.................................................38
9.5.1.2.3
Sleep Disorder Screening Battery..................................................38
9.5.1.2.4
Sleep Drug Experience Interview – Zolpidem...............................39
9.5.1.3
Efficacy Assessments...........................................................................39
9.5.1.3.1
Insomnia Severity Index ................................................................39
9.5.1.3.2
Patient’s Global Impression – Insomnia........................................39
9.5.1.3.3
Quality of Sleep Rating..................................................................40
9.5.1.3.4
Sleep Drug Experience Interview – Lemborexant.........................40
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................40
9.5.1.5
Safety Assessments..............................................................................40
9.5.1.5.1
Adverse Events ..............................................................................41
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................43
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9.5.1.5.3
Study-Specific Adverse Events......................................................44
9.5.1.5.4
Laboratory Measurements .............................................................44
9.5.1.5.5
Vital Signs, Height, and Weight Measurements............................45
9.5.1.5.6
Physical Examinations...................................................................45
9.5.1.5.7
Electrocardiograms ........................................................................45
9.5.1.5.8
Other Safety Assessments..............................................................45
9.5.2
Schedule of Procedures/Assessments – Core Study....................................46
9.5.2.1
Schedule of Procedures/Assessments ..................................................46
9.5.2.2
Description of Procedures/Assessments Schedule...............................50
9.5.3
Appropriateness of Measurements...............................................................50
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................50
9.5.4.1
Reporting of Serious Adverse Events..................................................50
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................51
9.5.4.3
Reporting of Events Associated with Special Situations.....................52
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................52
9.5.4.3.2
Reporting of Study-Specific Events...............................................52
9.5.4.4
Expedited Reporting ............................................................................52
9.5.4.5
Breaking the Blind...............................................................................52
9.5.4.6
Regulatory Reporting of Adverse Events ............................................53
9.5.5
Completion/Discontinuation of Subjects.....................................................53
9.5.6
Abuse or Diversion of Study Drug ..............................................................53
9.6
Data Quality Assurance .........................................................................................54
9.6.1
Data Collection ............................................................................................54
9.6.2
Clinical Data Management ..........................................................................54
9.7
Statistical Methods.................................................................................................54
9.7.1
Statistical and Analytical Plans....................................................................54
9.7.1.1
Study Endpoints...................................................................................55
9.7.1.1.1
Primary Endpoint...........................................................................55
9.7.1.1.2
Secondary Endpoints .....................................................................55
9.7.1.2
Definitions of Analysis Sets.................................................................55
9.7.1.3
Subject Disposition..............................................................................56
9.7.1.4
Demographic and Other Baseline Characteristics ...............................56
9.7.1.5
Prior and Concomitant Therapy...........................................................56
9.7.1.6
Efficacy Analyses ................................................................................56
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9.7.1.6.1
Primary Efficacy Analysis.............................................................56
9.7.1.6.2
Secondary Efficacy Analyses ........................................................56
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................57
9.7.1.8
Safety Analyses....................................................................................57
9.7.1.8.1
Extent of Exposure.........................................................................58
9.7.1.8.2
Adverse Events ..............................................................................58
9.7.1.8.3
Laboratory Values..........................................................................59
9.7.1.8.4
Vital Signs......................................................................................60
9.7.1.8.5
Electrocardiograms ........................................................................60
9.7.1.8.6
Other Safety Analyses....................................................................60
9.7.2
Determination of Sample Size .....................................................................60
9.7.3
Interim Analysis...........................................................................................61
9.7.4
Other Statistical/Analytical Issues ...............................................................61
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................61
10
REFERENCE LIST .........................................................................................................62
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......64
11.1
Changes to the Protocol .........................................................................................64
11.2
Adherence to the Protocol......................................................................................64
11.3
Monitoring Procedures...........................................................................................64
11.4
Recording of Data..................................................................................................65
11.5
Identification of Source Data.................................................................................65
11.6
Retention of Records..............................................................................................66
11.7
Auditing Procedures and Inspection......................................................................66
11.8
Handling of Study Drug.........................................................................................66
11.9
Publication of Results ............................................................................................67
11.10 Disclosure and Confidentiality ..............................................................................67
11.11 Discontinuation of Study .......................................................................................67
12
APPENDICES .................................................................................................................68
LIST OF IN-TEXT TABLES
Table 1
Treatments Administered...........................................................................33
Table 2 
Clinical Laboratory Tests...........................................................................44
Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core 
Study ..........................................................................................................47
Table 4
Clinically Notable Vital Sign Criteria........................................................60
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 -
Extension....................................................................................................74
LIST OF IN-TEXT FIGURES
Figure 1
Study E2006-A001-312 – Study Design....................................................26
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................68
Appendix 2
Prohibited Concomitant Medications ........................................................70
Appendix 3
Extension Phase .........................................................................................73
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
BMI
Body mass index
BP
blood pressure
CBT-I
Cognitive Behavioral Therapy for Insomnia
CFR
Code of Federal Regulations
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th ed
FAS
full analysis set
GABA
gamma-aminobutyric acid
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ISI
Insomnia Severity Index
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
LEM
lemborexant
LEM5
Lemborexant 5 mg
LEM10
Lemborexant 10 mg
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
OSA
obstructive sleep apnea
PBO
placebo
PGI-I
Patient Global Impression of Insomnia
PT
preferred term
QTcF
Difference between QTc corrected by Fridericia's formulas
SAE
Serious adverse events
SAS
safety analysis set
SDSB
Sleep Disorders Screening Battery
SOC
system organ class
TEAE
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory values
ZOL
zolpidem
ZOL-ER
zolpidem tartrate extended release
ZOL-IR
zolpidem tartrate immediate release
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with ICH E6 (Good Clinical Practice), Section 3, and any local regulations (eg, 
Title 21 of the United States Code of Federal Regulations [CFRs], Part 56). Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, 
change in Clinical Research Associate CRA[s], change of telephone number[s]).  
Documentation of IRB compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension 
or termination by the IRB to the sponsor.
Study progress is to be reported to IRBs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports,
and inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB within 90 days.  The end of the 
study will be the date of the last study visit for the last subject in the study.  The sponsor 
should also provide the IRB with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB 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 (2013)

ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
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Committee for Proprietary Medicinal Products, International Conference on 
Harmonisation of Pharmaceuticals for Human Use

Title 21 of the US CFR regarding clinical studies, including Part 50 and Part 56 
concerning informed subject consent and IRB regulations and applicable sections of US 
21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (eg, Title 21 CFR Part 50).  Each subject must 
sign an approved ICF before study participation.  The form must be signed and dated by the 
appropriate parties.  The original, signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site.  
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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 investigational sites in the United States of America.
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The name, telephone and fax numbers of the Medical Monitor and other contact personnel at 
the contract research organization(s) (CROs) are listed in the Investigator Study File
provided to each site.
7
INTRODUCTION
7.1
Indication
Lemborexant (LEM) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide), also known as E2006, is 
an orally-administered, novel competitive dual orexin receptor antagonist (DORA) that has 
been developed for the treatment of insomnia and Irregular Sleep-Wake Rhythm Disorder 
(ISWRD).  
7.1.1
Current Therapeutic Options
Treatments for insomnia include both non-pharmacological (Schutte-Rodin, et al., 2008; 
Morgenthaler, et al., 2006) and pharmacological treatments (Sateia, et al., 2017).  Patients 
who undergo thorough diagnostic evaluations for insomnia symptoms are asked about their 
sleep and wake habits, since some cases of insomnia can be addressed by improving sleep 
hygiene.  Principles of good sleep hygiene include regular bedtimes and waketimes, limiting 
alerting activities before bedtime, and limiting caffeine and alcohol intake, among others 
(Schutte-Rodin, et al., 2008).  These techniques are often not adequate to address insomnia 
symptoms (Stepanski and Wyatt, 2003; Irish, et al., 2015).
Another commonly recommended non-pharmacological approach is the use of cognitive 
behavioral therapy for insomnia (CBT-I; Schutte-Rodin, et al., 2008).  CBT-I includes 
techniques to minimize wakefulness at the time the patient intends to sleep.  However, while 
there are data to support the effectiveness of CBT-I, sleep restriction is commonly a major 
component, and this may lead to daytime sleepiness, an unintended consequence of short 
sleep (Kyle, et al., 2014).  In contrast, lemborexant’s mechanism of action would avoid the 
daytime sleepiness caused by sleep restriction, while reducing wakefulness and facilitating 
sleep, which is an important underlying goal of CBT-I.  
There are numerous drugs available for the treatment of insomnia, some available by 
prescription and many available over-the-counter.  Many of the over-the-counter medicines 
lack empirical data from adequate, well-designed and controlled clinical trials to support 
their use (Rosen, et al., 2005); these include melatonin and antihistamines.  Pharmacological 
treatments available by prescription and used clinically for insomnia include sedative 
hypnotics (benzodiazepines, nonbenzodiazepine gamma-aminobutyric acid 
(GABA)-releasing [GABAergics] agents), sedating antidepressants, melatonin agonists, and 
a DORA.  
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7.1.2
Lemborexant
Lemborexant belongs to the pharmacologic class of orexin receptor antagonists, a class of
chemical compounds developed for the treatment for insomnia.  To date, clinical proof of 
concept has been achieved by 6 orexin receptor antagonists (lemborexant, almorexant 
[ACT-078573], suvorexant [MK-4305], filorexant [MK-6096]), seltorexant [MIN-202], and 
nemorexant [ACT-541468]), demonstrating validity of the mechanism of action (Herring, 
et al., 2012; Hoever, et al., 2012; Connor, et al., 2016; Murphy, et al., 2017; De Boer, et al., 
2018).
Nonclinical data show that lemborexant binds to and competitively antagonizes human 
orexin-1 receptor (OX1R) and orexin-1 receptor (OX2R) in vitro, with rapid association and 
dissociation kinetics at both receptors.  In vitro data show that lemborexant does not 
substantially interact with other sleep-related receptors and channels (Beuckmann, et al, 
2017).  Lemborexant prevents [Ala11, D-Leu15]-orexin-B-induced plasma adrenocorticotropic 
hormone increase in rats, and promotes physiological sleep in mice and rats.  In mice, 
lemborexant does not promote sleep when the orexin pathway has been functionally 
impaired.  In rats, daily treatment for 3 consecutive weeks with lemborexant did not result in 
tolerance or wakefulness rebound upon treatment cessation, and did not elicit direct 
transitions from wakefulness to rapid eye movement (REM) sleep, a narcolepsy-like 
symptom.  However, in strong emotional contexts, lemborexant induced cataplexy-like 
events in mice (Study W-20140712).  Cataplexy has been noted in dogs dosed with another 
orexin antagonist, suvorexant, when presented with food enrichment (Belsomra, 2018), but 
the relationship to cataplexy symptoms in humans has not been established.  At doses up to 
300 mg/kg (300-fold higher than necessary for sleep promotion), lemborexant did not have 
any negative influence on motor coordination in mice, nor did it show any significant 
interaction with ethanol.
7.1.2.1
Clinical Experience With Lemborexant
The safety and efficacy of lemborexant for the treatment of insomnia disorder was confirmed 
in 2 pivotal Phase 3 studies, E2006-G000-303 (Study 303) and E2006-G000-304 (Study 
304).  In Study 304, lemborexant also demonstrated superior improvement on objective and 
subjective measures of sleep onset and maintenance compared to zolpidem tartrate extended 
release (ZOL-ER).  Additional safety assessments pertinent to insomnia drugs, specifically 
regarding postural stability, were also conducted in study E2006-A001-108 and Study 304.  
In these studies, the safety of lemborexant on postural stability was superior compared to 
zolpidem (ZOL).  Based on these data, a New Drug Application for lemborexant was 
submitted to the US Food and Drug Administration for the treatment of insomnia disorder in 
December 2018 and accepted for review in February 2019.
The safety and tolerability of lemborexant has been comprehensively evaluated in a broad 
patient population that includes subjects with insomnia disorder per Diagnostic and 
Statistical Manual of Mental Disorders, 5th ed (DSM-5) (with or without medical or 
psychiatric comorbidities), subjects with Alzheimer's disease and ISWRD, subjects with mild 
obstructive sleep apnea (OSA), and subjects with severe renal impairment or mild to 
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moderate hepatic impairment.  Exposures included dosing of ≥12 months.  Approximately 
40% of subjects in the development program were elderly (≥65 years), providing extensive 
safety and tolerability profile for this important subpopulation at risk for insomnia.  
Overall, of 2824 subjects with sleep disorders, 1848 received lemborexant, 714 received 
placebo (PBO), and 263 received ZOL.  
No deaths were reported in subjects treated with lemborexant.
The overall incidence of treatment-emergent serious adverse events (SAEs) for subjects 
treated with lemborexant 5 mg (LEM5) and lemborexant 10 mg (LEM10) in the Phase 3 Pool
was low (2.8% and 2.3%, respectively) but greater than for PBO (0.9%).  However, when 
adjusted by duration of exposure, the overall incidence (subjects per patient-year) was similar 
to PBO (<0.1 for PBO, 0.1 for LEM5, and 0.1 for LEM10).  The overall rate (events per 
patient-year) of treatment-emergent SAEs when adjusted by duration of exposure was <0.1 
for PBO, <0.1 for LEM5, and <0.1 for LEM10.
There were no differences in the types of treatment-emergent SAEs reported during 
long-term treatment with lemborexant. There were no differences in treatment-emergent 
SAEs based on intrinsic factors, including age, sex, and body mass index (BMI) of subjects.  
Notably, the incidence of treatment-emergent SAEs in the elderly was consistent with that in 
younger subjects.
Across the Phase 3 studies of 303 and 304 (total subjects=1945), the majority of 
treatment-emergent SAEs occurred as singular events in 1 subject only.  The SAEs of 
osteoarthritis (0% for PBO, 0.1% for LEM5, 0.4% for LEM10), rib fracture (0.2% for PBO, 
0% for LEM5, 0.1% for LEM10), and diabetic neuropathy (0% for PBO, 0.3% for LEM5, 
0% for LEM10) occurred in more than 1 subject across the PBO, LEM5, and LEM10 groups.  
One (0.1%) serious event of fall was reported in the LEM5 group.
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure
None.
7.2
Study Rationale
Switching of medications for insomnia occurs often in clinical practice based on clinical 
response, AEs, reimbursement patterns, or physician and patient preference.  However, there 
is no clinical trial experience or dosing guidance for transitioning from currently approved
treatments for insomnia to lemborexant.  Study E2006-A001-312 (Study 312) is designed as 
a pilot study to assess the dosing approach of directly transitioning from ZOL, the most 
commonly prescribed sleep aid (Bertisch, et al., 2014), to lemborexant, without tapering the 
ZOL dose, and with the opportunity for lemborexant dose titration.  This study will provide 
initial information on patient satisfaction after switching to lemborexant, with secondary 
objectives assessing subjective quality of sleep and tolerability.  If issues are identified 
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regarding patient satisfaction, tolerability, or quality of sleep, other dosing paradigms can be 
assessed in future studies to mitigate these issues.  
7.2.1
Entry Criteria Rationale
Subjects with insomnia disorder per DSM-5 criteria (with or without medical or psychiatric 
comorbidities) will be eligible for study entry, which is representative of the typical target 
outpatient population.  All subjects who are willing to substitute ZOL with LEM, regardless 
of the reason(s), will be eligible, and the reason(s) will be captured during screening.  While 
it is anticipated that most eligible subjects would substitute ZOL with LEM due to 
dissatisfaction with ZOL, other reasons, as determined by input from Key Opinion Leaders 
(KOLs) in Sleep Medicine, may include, but are not limited to, concerns regarding ZOL side 
effects, eg, parasomnias.  Including subjects with these various reasons is representative of 
the real-world outpatient setting.
While the approved dosing instructions for women and patients ≥65 stipulate that the lower 
dose of ZOL is to be prescribed, many women and elderly patients may be taking the higher 
dose.  Therefore, for generalizability of the results of the study to the patient population, any 
stable dosing regimen will be eligible, including those subjects taking higher than approved 
doses up to the maximum approved (10 mg IR or 12.5 mg ER).
7.2.2
Rationale for Titration Schedule and Duration 
Since this study is designed to reflect common clinical practice, flexibility to titrate the dose 
up or down is built into the dosing regimen.  In the outpatient setting, clinicians typically 
advise patients to allow themselves one week to adjust to a new medication; therefore, 
subjects assigned to LEM5 will be encouraged to remain on their dose of LEM for 1-week 
prior to titrating up to LEM10, and those assigned to LEM10 will be encouraged to remain 
on their dose of LEM prior to titrating down to LEM5 after one week.
Subjects who intermittently use ZOL are expected to be more likely to be started on LEM5 in 
the outpatient setting, as they are not chronically exposed to, or reliant upon, pharmacologic 
insomnia treatments.  Therefore, all subjects in Cohort 1 will be started on LEM5 during the 
Titration Period of the Treatment Phase.  
The duration of the Treatment Phase of the Core Study is set at 2 weeks, since that amount of 
time is deemed reasonable by expert opinion from consultation with KOLs in Sleep Medicine 
for subjects to decide if they wish to continue on lemborexant.  
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects 
with insomnia disorder taking ZOL immediate release (ZOL-IR) or extended release (ZOL-
ER), intermittently or frequently, who transition to lemborexant 5 mg (LEM5) or 10 mg 
(LEM10), after 2 weeks of receiving lemborexant (LEM).
8.2
Secondary Objectives

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease 
from LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of 
Insomnia (PGI-I) at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared 
with Baseline at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared 
with Baseline at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking ZOL
8.3
Exploratory Objective(s)
None
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER.  Adult (≥18 years) subjects are 
eligible for participation if they have been diagnosed with insomnia disorder per the 
DSM-5th Ed (American Psychiatric Association, 2014), are currently receiving ZOL as 
monotherapy for insomnia, and who agree to substitute zolpidem tartrate immediate release 
(ZOL-IR) or ZOL-ER with LEM, regardless of the reason. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week
Screening Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week
Titration Period), and an Extension Phase consisting of the Maintenance Period up to 
12 weeks and the Follow-up Period 4 weeks in duration immediately following the end of the 
Treatment Phase.  A Follow-up Period visit occurring 4 weeks after the end of the Extension 
Phase (or Treatment Phase, for subjects not entering the Extension Phase) will be conducted.  
The Pretreatment and Treatment Phases will comprise the Core Study.  The Extension Phase 
is described in detail in Appendix 3.
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During the Screening Period, eligible subjects will prospectively record the number of days 
ZOL is taken over 21 days using a Data Collection System.  Based on these data, subjects 
will be assigned to 1 of 2 cohorts of ZOL use frequency:  
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, during, 
at minimum, the last 2 weeks of the 3-week Screening Period  
All subjects in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). Within 
Cohort 2, subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio.  
Subjects who remain eligible for the study will enter the Baseline Period.
Approximately 110 subjects will be screened to provide approximately 60 subjects for 
randomization (20 subjects in Cohort 1 and 40 subjects in Cohort 2 [20 subjects in LEM5 and 
20 subjects in LEM10]).
The end of the study will be the date of the last study visit for the last subject.
An overview of the study design is presented in Figure 1.
Figure 1
Study E2006-A001-312 – Study Design
LEM5 = lemborexant 5 mg, LEM5 = lemborexant 5 mg, R = Randomization
Period:
R
Drug 
3 weeks
Day 1
Titration
2 weeks
Phase:
Screening
12 weeks
Pretreatment
Extension
Cohort 2 (LEM5)
Cohort 2 (LEM10)
Cohort 1 (LEM5)
Maintenance
Drug
Treatment
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9.1.1
Pretreatment Phase (Core Study)
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day 
Baseline Period, during which subjects will be assessed for eligibility to participate in the 
study.
9.1.1.1
Screening Period (Core Study)
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  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.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a diagnosis of insomnia per the DSM-5 (American Psychiatric 
Association, 2014), be currently receiving ZOL as monotherapy for insomnia, and agree to 
substitute zolpidem tartrate immediate release (ZOL-IR) or extended release (ZOL-ER) with 
LEM, regardless of the reason.
During the Screening Period, subjects will be required to bring the container of their 
currently prescribed ZOL to the site for verification of prescribed medication and dose.  
Subjects will be provided with, and trained in the use of, a data collection system to record 
the dose and frequency of ZOL which is taken during the 3-week Screening Period.  Site 
staff will instruct subjects to complete data entry every morning and will emphasize the 
importance of providing this data.  During the Screening Period, subjects will continue to 
take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5 mg or 10 
mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection 
system for at least 14 (preferably contiguous) days of the 21-day Screening Period in order to 
be eligible for study inclusion.  
Subjects will return to clinic at the end of the Screening Period. For subjects who remain 
eligible for study enrollment, the second Screening Period visit will serve as that subject’s 
Baseline Period, and will occur on the same day. Based on ZOL use during the Screening 
Period (which must match the treatment history ascertained at the beginning of the Screening 
Period), subjects will be assigned to 1 of 2 cohorts as follows:

Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 

Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, 
during, at minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5).
For Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or 
LEM10) in a 1:1 ratio.
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9.1.1.2
Baseline Period (Core Study)
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment 
cohort.  Subjects who are not eligible will conclude their participation and will be considered 
screen failures.  Upon completion of the Baseline Period, subjects who remain eligible by 
meeting the criteria for inclusion/exclusion (Sections 9.3.1 and Section 9.3.2) will enter the 
Titration Period.
9.1.2
Treatment Phase (Core Study)
The Treatment Phase will consist of a 2-week Titration Period and 1-day Follow-up Visit to 
occur 4 weeks after completion of the Titration Period (or as soon as possible following early 
discontinuation) for subjects not entering the Extension Phase.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria at the Baseline Visit, and who have 
entered ZOL medication use data into the Data Collection System for at least 14 of the 21-
day Screening Period as specified in the Inclusion Criteria, are eligible to enter the Treatment
Phase of the study. 
9.1.2.1
Titration Period (Core Study)
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and 
LEM10 to be taken at home within a few minutes of the time that they intend to sleep.  Study 
restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals 
will be discussed with the subject at each visit during the Treatment and Extension Phases.  
Subjects will be instructed to not alter (ie break or cut) their tablets of LEM.
Subjects assigned to Cohorts 1 and 2 will self-administer the study medication according to 
the following regimens:

Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will determine the nights on 
which they take LEM, with the requirement that they take LEM at least once per week 
during the 2-week Titration Period.  

Cohort 2 (Frequent ZOL Use, Treatment Groups A and B): Subjects in these cohorts will 
take LEM at least 5 nights per week during the 2-week Titration Period.
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For subjects starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but 
not mandated) to remain on their assigned dose for 7 days before calling the site to report 
that LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the 
site will then be instructed by phone to take LEM10 within a few minutes of the time 
they intend to sleep.  

For subjects starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain 
on their assigned dose for 7 days before calling the site to report that the dose of LEM10 
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should be reduced. Subjects will then be instructed to take LEM5 within a few minutes 
of the time they intend to go to sleep.  
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the case report form (CRF).  
Every morning, subjects will enter their insomnia drug use data into the data collection 
system, and, provided an insomnia drug was taken the night prior, PGI-I and Quality of Sleep 
Rating will be completed.  The ISI will be completed at each clinic visit except Follow-up 
Visit. 
Upon completion of the Titration Period, subjects may be eligible to enter the Extension 
Phase (Appendix 3).
9.1.2.2
Follow-Up Period
For subjects not entering the Extension Phase, the Follow-up Period will start immediately 
after the end of the Treatment Phase and last for 4 weeks.  The purpose of the Follow-up 
Period is to assess adverse events and other safety parameters.  Subjects will be instructed to 
continue insomnia management with the health-care provider who had been treating them
prior to study entry, if they so desire.
9.1.3
Extension Phase
Subjects who complete the Core Study and wish to continue taking LEM will enter the 
12-week Extension Phase.  Subjects will continue the LEM dose and regimen established 
during the Titration Period; however, the dose may be titrated up or down depending on 
response and tolerability, per subject input and investigator judgement.  For subjects who are 
eligible for the Extension Phase but who do not wish to continue study participation, the 
reason for discontinuation from the study will be recorded.  At the end of the Extension 
Phase, the Follow-up Period will begin, and last for 4 weeks.  
Details of the Extension Phase are provided in Appendix 3.
9.2
Discussion of Study Design, Including Choice of Control Groups
See Section 7.2, Study Rationale.
9.3
Selection of Study Population
Approximately 60 subjects will be enrolled at approximately 15 sites in the United States of 
America.  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:
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1.
Male or female, 18 years or older, at the time of informed consent
2.
Meets the DSM-5 criteria for Insomnia Disorder, either currently or prior to zolpidem 
use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying 
asleep and/or awakening earlier in the morning than desired despite adequate 
opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 or 4 nights per week), or frequent use (at 
least 5 nights per week) of ZOL-IR or -ER, for at least 1 month
5.
Confirmation of intermittent or frequent use of ZOL (based on review of drug use data).  
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for 
at least 2 weeks each of the 3-week Screening Period.  Frequent use is defined as taking 
ZOL at least 5 nights per week, during, at minimum, the last 2 weeks of the 3-week 
Screening Period
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia 
during the subject’s participation in the study
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive serum pregnancy test).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study 
drug.
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 28 days after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.
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
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
3.
Any history of moderate or severe OSA
4.
Current evidence of a clinically significant, active respiratory disorder other than mild 
OSA.  This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary 
disease or any other pulmonary disorder identified by review of medical history or 
physical examination, and which in the opinion of the investigator, could compromise the 
subject’s safety or interfere with study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, 
circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule 
out individuals with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not 
excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week 
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
8.
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 
sleeping), whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
13. Used any prohibited prescription or over-the-counter concomitant medications within 
1-week or 5 half-lives, whichever is longer, before the first dose of study medication (A 
list of prohibited concomitant medications is presented in the protocol).  
14. Used any pharmacologic modality of treatment for insomnia other than ZOL, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening 
Period
15. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
16. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS])
17. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
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18. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and 
renal disease) 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.
19. Hypersensitivity to lemborexant or any of the excipients.
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study.
21. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study. Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the investigator this operation does not interfere with the 
study procedures and patient safety.
22. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
23. History of drug or alcohol dependency or abuse within approximately the last 2 years
24. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days or 5× the half-life, whichever is longer, preceding informed consent.
25. 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.
9.4
Treatments
9.4.1
Treatment(s) Administered
The following treatments will be administered to subjects in the Core Study (Table 1).
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Table 1
Treatments Administered
Drug Name
Strength
Oral Dose Form
Number Dispensed and Frequency
Duration
Lemborexant
5 mg
Tablet
1×5 mg tablets, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Lemborexant
10 mg
Tablet
1×10 mg tablet, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For Cohorts 1 and 2A (starting dose of LEM5), subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site to report that LEM5 is not fully 
effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  

For Cohort 2B (starting dose of LEM10), subjects will be encouraged to remain on their 
assigned dose for 7 days before calling the site to report that the dose of LEM10 should 
be reduced.  Subjects will then be instructed to take LEM5 within a few minutes of the 
time they intend to go to sleep.  
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the CRF.  
9.4.2
Identity of Investigational Product
Lemborexant will be supplied by the sponsor in labeled containers.  
Study drug must be stored as instructed on the study drug label.  Study drug must be kept in a 
secure location and carefully stored at the study site within its original container.  The 
sponsor will provide the study drug packaged as open-label supplies.  Each subject’s study 
drug will consist of lemborexant tablets supplied in bottles.
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-fluoropyridin-2-yl)cyclopropanecarboxamide)

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
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9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Based on ZOL use during the Screening Period, subjects will be assigned to 1 of 2 cohorts as 
shown below:
Cohort 1 (Intermittent ZOL Use):  taking ZOL at least 3 but fewer than 5 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  taking ZOL at least 5 nights per week, during, at 
minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will receive LEM5. Subjects in Cohort 2 will be randomized 
to 1 of 2 Treatment Groups: Cohort 2A (20 subjects) will start on LEM5, and Cohort 2B 
(20 subjects) will start on LEM10.
9.4.4
Selection of Doses in the Study
The doses to be administered are LEM5 and LEM10.  In December 2018, these doses were 
submitted for approval in the US for the indication of insomnia.  These doses were originally 
selected after conducting a dose-finding study (E2006-G000-201) after which their safety 
and efficacy were confirmed in 2 Phase 3 studies, Studies 303 and 304.
9.4.5
Selection and Timing of Dose for Each Subject
Subjects will be provided a supply of LEM5 and LEM10 to be taken at home within a few 
minutes of the time they intend to sleep.  Subjects will be instructed on study restrictions 
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pertaining to duration of time spent in bed, use of alcohol, and timing of meals.  Subjects will 
be instructed not to alter (ie, break or cut) their tablets of LEM.
9.4.6
Blinding
This is an open-label study with randomization to treatment for subjects assigned to 
Cohort 2.
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 or 30 days before first 
dose/administration of study drug, if appropriate) will be recorded.  The adverse event or 
medical condition for which the concomitant medication or therapy was administered will be 
recorded.
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 Treatment Period.
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 the protocol, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that strong and moderate cytochrome P450 (CYP)3A 
inhibitors and all CYP3A inducers will not be permitted at any time for any duration during 
the study.
9.4.7.1
Drug-Drug Interactions
Coadministration with moderate and strong 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 2.  
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.  
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9.4.7.2
Prohibited Concomitant Therapies and Drugs
Prohibited medications (Appendix 2) 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 Treatment Period.
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A 
inducers.  Prohibited therapies also include: any pharmacologic treatment for insomnia 
disorder (with the exception of ZOL use during the Screening Period only); medications that 
are used for the purpose of inducing sleep (hypnotics) and medications that have known 
sedating effects.  This prohibition applies even if the entire class to which that medication 
belongs is not prohibited (eg, anticonvulsants).
If a medication is not on the list of prohibited medications (Appendix 2) 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 2, 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.  
If a subject starts any prohibited medication or a new treatment/modality for insomnia 
disorder, he/she must discontinue from the study.
Subjects must forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study.  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 bottles returned to the investigator at the end 
of the Titration Period.
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 for the institution where the study is to be conducted
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
A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study

The IRB membership list and statutes or Health and Human Services Assurance number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV

A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s 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, (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, Medicine and Healthcare products Regulatory Agency [MHRA]).  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 
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to the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  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.  
9.5.1.2
Screening and Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical, sleep, and psychiatric history will be recorded as designated in the Schedule of 
Procedures/Assessments (Table 3).  All medical and surgical history within 5 years must be 
noted in the Medical History and Current Medical Conditions CRF.
Physical examinations will be performed, as designated in the Schedule of 
Procedures/Assessments (Table 3).  A full physical examination will be performed, 
excluding a urogenital examination unless there are special circumstances and at the 
discretion of the investigator.  Documentation of the physical examination will be included in 
the source documentation at the site.  Significant findings at the Screening Visit will be 
recorded on the Medical History and Current Medical Conditions CRF.  Changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Events CRF.
9.5.1.2.2
SLEEP DRUG HISTORY QUESTIONNAIRE
At Screening, subjects will complete a questionnaire reporting their history and response to 
prior sleep medications, as well as their motivation for participating in the study.
9.5.1.2.3
SLEEP DISORDER 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 
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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 Sleep Disorders Screening Battery (SDSB) will 
be administered (see below).  
The SDSB will include the following, to be self-administered by subjects: 

The STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects 
for OSA (Chung et al., 2008)

The IRLS:  a subjective scale comprising 10 questions, which measures disease severity 
of restless legs syndrome (Abetz et al., 2006).
9.5.1.2.4
SLEEP DRUG EXPERIENCE INTERVIEW – ZOLPIDEM
At the end of the Screening Period, subjects will be asked questions about their subjective 
experiences while taking ZOL.  The responses will be compared to the Sleep Drug 
Experience Interview – Lemborexant, which is done at the end of the Treatment Phase, in 
order to provide qualitative information regarding an individual’s subjective experience with 
LEM compared to ZOL.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
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. The ISI 
will be completed at each study visit except Follow-up Visit.  
9.5.1.3.2
PATIENT’S GLOBAL IMPRESSION – INSOMNIA
The PGI-I is a self-report assessment of subject perception of the effects of a medication on 
their sleep (Herring, et al., 2018).  The PGI-I has 3 items related to study medication effects 
(a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) 
increased/decreased total sleep time, and 1 item related to perceived appropriateness of study 
medication strength.  The first 3 items are answered on a 3-point scale (1=positive 
medication effect, 2=neutral medication effect, 3=negative medication effect) and the last 
item on a different 3 point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior 
evening during the Screening, Baseline, and Titration Periods.
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9.5.1.3.3
QUALITY OF SLEEP RATING
The Quality of Sleep Rating (Krystal and Edinger, 2008) is a self-reported scale in which 
subjects are asked, “How would you rate the quality of your sleep last night, with 1 being 
extremely poor, 5 being not good or poor, and 9 being extremely good?” For Quality of 
Sleep, higher values are better.  The Quality of Sleep Rating will be completed each morning 
following a dose of ZOL or LEM taken the prior evening during the Screening, Baseline, and 
Titration Periods.
9.5.1.3.4
SLEEP DRUG EXPERIENCE INTERVIEW – LEMBOREXANT
At the end of the Titration Period, subjects will be asked questions about their subjective 
experiences while taking LEM.  The responses will be compared to the Sleep Drug 
Experience Interview – ZOL, which is done at the end of the Screening Period, in order to 
provide qualitative information regarding an individual’s subjective experience with LEM 
compared to ZOL.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
Not applicable.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades (for both increasing and 
decreasing severity), regular monitoring of hematology, blood chemistry, and urine values; 
periodic measurement of vital signs and ECGs; and performance of physical examinations.  
Subjects will be asked about falls at every visit.
Sponsor’s grading for laboratory values are presented in Appendix 1. 
Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure.  A set of 
preferred terms (PTs) 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 [ standard 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 SAE form for any of the 
above events considered serious.
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9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug is 
lemborexant (in doses of 5 mg and 10 mg). 
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, x-ray) that results in symptoms, a change in treatment, or discontinuation 
of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase
and for 7 days or 5× the half-life after the last dose, whichever is longer.  SAEs will be 
collected for 28 days after the last dose or for 5× the half-life, whichever is longer.  
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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 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.
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 9.5.1.5.8 for a description of the C-SSRS). 
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The number (percentage) of subjects with treatment emergent adverse events (TEAEs) of 
cataplexy or other events that are characterized according to the customized MedDRA query 
PT as cataplexy related events will be summarized separately.  The number of adjudicated 
events based on the report of the Adjudication Committee will also reported separately.
Customized MedDRA Queries for AEs that could potentially be considered cataplexy will be 
summarized.  The results of the deliberation of the Adjudication Committee will be reported 
separately.  All AEs must be followed for 28 days, or 5× the half-life, whichever is longer
after the subject’s last dose, or until resolution, whichever comes first.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

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
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
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
STUDY-SPECIFIC ADVERSE EVENTS
The study-specific events, including, cataplexy, potential cataplexy, convulsion, fall, and
seizure, should always be considered adverse events and reported on the Adverse Event CRF 
and on the event-specific CRFs designed to collect additional information on specific events.
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 3) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study (Core Study).
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the Screening, Baseline, and Titration Periods 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.  Local laboratories will perform tests to qualify 
subjects for entry into the study.  Laboratory certification as available will be included in the 
final clinical study report for this study.
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A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.5
VITAL SIGNS, HEIGHT, AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3) 
by a validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  Height is measured once at Screening.
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in 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) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
Columbia-Suicide Severity Rating Scale
The C-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  Suicidality will be assessed as designated in the Schedule of 
Procedures and Assessments (Table 3), using a site-administered version of the C-SSRS 
(Posner, et al., 2011).  
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women 
and postmenopausal women who have been amenorrheic for less than 12 months as 
designated in the Schedule of Procedures/Assessments (Table 3).
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Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 3).  This sample will be tested for common 
drugs of use/abuse: eg, propoxyphene, cocaine metabolites, cannabinoids, methadone, 
phencyclidine (PCP), opiates, benzodiazepines, barbiturates, and amphetamines.
9.5.2
Schedule of Procedures/Assessments – Core Study
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments for the Core Study.
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Sleep Drug History Questionnaire
X
Sleep Disorder Screening Batteryg
X
Insomnia Severity Index
X
X
X
X
X
X
C-SSRS
X
Xh
X
X
X
X
X
Medical, sleep, psychiatric history
X
Prior and concomitant medications
X
X
X
X
X
X
X
Dispense study drug
X
X
Retrieve unused study drug
X
X
Study drug compliance
X
X
X
Physical examinationi
X
X
X
X
X
X
X
Vital signs and weight
X
X
X
X
X
X
X
Height
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
Clinical laboratory testsj
X
X
X
X
X
Urine drug screenk
X
X
X
X
X
X
Urine pregnancy testl
X
X
X
X
X
X
Serum pregnancy testl,m
X
X
12-lead ECGn
X
X
X
X
X
X
PGI-Io
X
Xh
X
X
X
X
Quality of Sleep Ratingo
X
Xh
X
X
X
X
Sleep Drug Experience Interview -
zolpidem
X
X
X
Sleep Drug Experience Interview -
lemborexant
X
Adverse eventsp
X
X
X
X
X
X
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0
2
6
Procedures/Assessments
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram, PGI-I = Patient Global Impression – Insomnia, T = Termination Visit, UNS = Unscheduled Visits
All visits to be done within ±7 days of the schedule, except for Visits 2, 3 and 4, which must be done within ±3 days.
a:
The Follow-up Visit will be conducted 4 weeks after the End of Study Visit for subjects who completed the Titration Period but do not enter the Extension Phase.
b:
Subjects will return to clinic at the end of the Screening Period.  The Baseline Period will occur on the same day for subjects who remain eligible for study enrollment. 
Assessments conducted at the end of the Screening Period (Visit 2a) will serve as the assessments for the Baseline Period (Visit 2b) if a subject is enrolled into the Treatment 
Phase. Assessments will be performed once across Visit 2a and Visit 2b.  Assessments to be conducted at Baseline (but which are not done at Visit 2a) will include clinical 
laboratory tests and dispensing of study drug.
c:
This visit will represent the End of Study Visit for subjects who completed the Titration Period but are not entering the Extension Phase.  Subjects should otherwise enter the 
Extension Phase immediately after completion of the Titration Period of the Core Study, in which case this visit will also serve as the first visit of the Extension Phase.
d:
Subjects who discontinue study drug prematurely at any time after entering the Treatment Phase will be encouraged to return to the site as soon as practicable (preferably 
within 7 days) to complete the Early Termination Visit.
e:
ECG will only be done during Early Termination and Unscheduled Visits if the results from the previous visit were deemed to be clinically significant by the investigator.
f:
Assessments during Unscheduled Visits will be conducted at the discretion of the investigator.
g:
Sleep Disorders Screening Battery comprises: STOP Bang and International Restless Legs Scale.
h:
Data for Visit 2a will represent the Baseline Period (Visit 2b) assessment if the subject is enrolled.  Assessments will be performed once across Visit 2a and Visit 2b.
i:
A full physical examination will be conducted at Visit 1. A brief physical examination will be conducted at Visit 2a, Visit 3, and at the Follow-up Visit. For Early 
Termination and Unscheduled Visits, a physical examination will be conducted at the discretion of the investigator.
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
k:
Urine drug test at Unscheduled Visits will be conducted at the discretion of the investigator and at Early Termination only for subjects who withdraw because of an adverse 
event.
l:
Female subjects of child-bearing potential only.
m:
To be conducted at Visit 1, and if urine pregnancy testing is positive.
n:
The ECG should be repeated if a clinically significant (as determined by the investigator) abnormality is observed.
o:
From the beginning of the Pretreatment Phase to the end of the Treatment Phase, and provided an insomnia drug was taken the night prior, PGI-I and Sleep Quality Rating 
data will be entered into the electronic data capture system by the subject. 
p:
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a narrative for the 
event, per Section 9.5.1.5, Adjudication Committee.
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Table 5 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 3.
9.5.3
Appropriateness of Measurements
The clinical assessments are standard measurements commonly used in studies of drugs for 
the treatment of subjects with insomnia.
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. Because the objectives of this study include assessing the 
response to lemborexant of nighttime sleep and daytime impairment complaints, the ISI will 
be evaluated for changes from baseline.
The PGI-I has been used in studies evaluating the impact of treatment for insomnia on the 
patients’ global perceptions of sleep quality and quality of life.
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.  
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 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase, after the subject’s last dose.  All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator 
to be related to the study treatment or any protocol-required procedure should be reported to 
the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
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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 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the 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 a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, 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 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
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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
Study-specific events—cataplexy, potential cataplexy, convulsion, fall, seizure—should 
always be considered as serious important medical events and be entered on the Adverse 
Event CRF and reported using the procedures detailed in Reporting of Serious Adverse 
Events (Section 9.5.4.1), even if the study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
Not applicable.
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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 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early termination procedures indicated in 
the Schedule of Procedures/Assessments (Table 3).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic response, 
withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In addition to the 
primary reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event CRF.
Sites will be assessed for the appropriateness of study drug storage and retrieval at the time 
of site selection.  Required policies and procedures will be clearly communicated to the site 
to assess the site’s capabilities and adherence to storage, dispensing, reconciliation, and 
retention of study drug.
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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.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and a snapshot of the database is obtained and released) and randomization codes 
have been released.  Statistical analyses will be performed using SAS software or other 
validated statistical software as required.  The study endpoints for efficacy and safety will 
presented by treatment group (LEM5 and LEM10) and by pooling across treatments within 
each cohort and overall.  Missing data will not be imputed. Further details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of the Core Study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database lock.
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9.7.1.1
Study Endpoints
This study is designed to reflect clinical practice, in which patient satisfaction of the 
treatment after switching is an important consideration for maintaining a patient on that 
treatment.  This was the basis for defining the outcome of transition to lemborexant.  While 
sleep quality assessments are included as secondary outcomes in this pilot study to 
supplement the Phase 3 clinical trial data, it is not necessary to establish the absolute amount 
of improvement in sleep parameters, but rather whether the subject is satisfied enough to 
continue treatment with lemborexant.   
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of overall subjects who transition to LEM at the end 
of the Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week 
Titration Period and either 1) enters the Extension Phase, or 2) chooses to not enter the 
Extension Phase for reasons not related to LEM (including, but not limited to, time 
commitment related to the study, study-related travel expenses or preference to continue 
insomnia management with another health care provider).
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration 
Period within each Cohort.

The proportion of subjects with positive medication effect rating on each PGI-I item at 
the end of the 2-week Titration Period by Cohort and overall using end of the Titration 
Period treatment.

The change from Baseline in mean ISI score at the end of the Titration Period by Cohort 
and overall using end of the Titration Period treatment.

The proportion of subjects in the LEM5 treatment groups with dose increasing to 
LEM10 at the end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at 
the end of the Titration Period in Cohort 2.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration 
Period by cohort and overall using end of the Titration Period treatment.
9.7.1.2
Definitions of Analysis Sets
Safety Analysis Set (SAS) – The SAS is the group of subjects who received at least 1 dose of 
study drug and had at least 1 postdose safety assessment.
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included 
in the FAS.
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9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination and treatment discontinuation.  Other reasons for study treatment and study 
terminations will also be summarized.  These tabulations will be produced for all randomized 
subjects by randomized treatment groups.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each randomized and end of the Titration Period treatment groups 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 
(<18.5, 18.5 to <25, 25 to ≥30), race, and ethnicity.
Characteristics of insomnia at Study Baseline will be summarized using ISI, PGI-I, and 
Quality of Sleep Rating. 
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 WHO Drug Global March 2019 or later. The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by randomized treatment group, Anatomical Therapeutic Chemical 
(ATC) class, and WHO-DD PT.  
9.7.1.6
Efficacy Analyses
All efficacy analyses will be conducted on the FAS.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in 
the Titration Period will be displayed.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The secondary analyses are as follows:

The proportion of subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed within each cohort.  
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
Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately 
within each scale over time by Cohort and overall using end of the Titration Period dose 
groups. 

The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these 
items at the end of the Titration Period, and the proportion of subjects who rated the drug 
as being too strong or too weak at Baseline, but whose rating was “just right” at the end 
of the Titration Period (as data allow) will be reported.

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the 
ISI will be summarized at the end of the Titration Period by Cohort and overall using end 
of the Titration Period dose groups.

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall.

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented.

The change from baseline in mean Quality of Sleep Rating score for subjects at the end of 
the Titration Period will be summarized by cohort and overall using end of Titration 
Period dose groups.
Primary and Secondary endpoints may be analyzed by modeling methods if warranted.  
Details of all of the analyses will be specified in the Statistical Analysis Plan.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
Not applicable.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
end of Titration Period dose groups, will be summarized on an “as treated” basis using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include TEAEs,
physical examination, clinical laboratory parameters, vital signs, 12-lead ECG results, and 
the C-SSRS.  Study Day 1 for all safety analyses will be defined as the date of the first dose 
of study drug.  
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
AEs summaries, and abnormal findings will also be displayed based on the dose that the 
subjects were taking at the time of the findings.
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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.  
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 22.0 or higher) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA PT and primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
Adverse events will be summarized using the Safety Analysis Set.  The incidence of AEs will 
be summarized by end of Titration Period dose for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics.  To obtain the incidence (%), the 
number of subjects with at least 1 event and the percentage of subjects with AEs by SOC and 
by PT will be calculated.  Incidence (%) by causal relationship with study drug and by 
severity will also be calculated.  For clinically significant events, time of onset, and recovery 
will be reported.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
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The number (percentage) of subjects with treatment-emergent serious adverse events (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 a Customized MedDRA Query (CMQ) PT as cataplexy-related 
events, as well drug abuse liability will be summarized separately.  The number of 
adjudicated events based on the report of the Adjudication Committee will also reported 
separately.  In addition, 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, as per the Adjudication Committee description.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.4, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and end of Titration Period dose using 
descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.4 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs). Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
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9.7.1.8.4
VITAL SIGNS
Mean changes from baseline in vital signs (ie, systolic and diastolic BP, pulse, respiratory 
rate, body temperature, weight) and out-of-range vital signs will be summarized by end of 
Titration Period dose groups for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent
ZOL use) using descriptive statistics.
Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 4).  Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital 
sign ranges will also be presented for change from Study Baseline (Safety Analysis Set), by 
end of Titration Period dose and time point.
Table 4
Clinically Notable Vital Sign Criteria
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
ECG assessments will be performed at Screening and at the end of the Titration Period.  The 
incidence of abnormal ECG findings will be summarized by end of Titration Period dose for 
Cohort 1 (Intermittent ZOL Use) and Cohort 2 (Frequent ZOL Use) using descriptive 
statistics.  Shift tables will present changes from baseline in ECG interpretation (categorized 
as normal and abnormal) by time point.
9.7.1.8.6
OTHER SAFETY ANALYSES
The results of C-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.
9.7.2
Determination of Sample Size
As a pilot study, sample size estimates are not based on statistical calculations. 
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This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 
2B) to evaluate the proportion of subjects who  transition to LEM as a substitute for ZOL.  
Twenty subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be 
assigned to Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to 
receive LEM5 or LEM10 within Cohort 2.  This sample size is deemed sufficient to inform 
whether the proposed strategies are sufficient to determine whether alternative strategies 
would be required to help understand how best to recommend safe and effective methods for 
transitioning from ZOL to LEM.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
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Bertisch SM, Herzig SJ, Winkelman JW, Buettner C.  National use of prescription 
medications for insomnia: NHANES 1999-2010.  Sleep.  2014;37(2):343-9.
Beuckmann CT, Suzuki M, Ueno T, Nagaoka K, Arai T, Higashiyama H.  In vitro and in 
silico characterization of lemborexant (E2006), a novel dual orexin receptor antagonist.
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Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, et al.  STOP 
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De Boer P, Drevets WC, Roael H, van der Ark P, Kent JM, Kezic I, et al. A randomized 
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parameters for the psychological and behavioral treatment of insomnia: an update.  An 
American Academy of Sleep Medicine report. Sleep.  2006;29(11):1415–19.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB 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 detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts

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 Interactive Voice/Web Response 
System (IxRS), x-rays, and other imaging reports (eg, sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation)

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

Electronic Patient-Reported Outcome by self-reported measures
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
The efficacy assessments are evaluated based on the data entered into electronic Patient-
Reported Outcome.  The applicable data are input directly by each subject from the 
viewpoint of his/her health condition without the interpretation of the investigator. 
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
The data collected by electronic Patient-Reported Outcome are also considered source data.  
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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or designated contractor, or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
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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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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 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; 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
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 

gamma-aminobutyric acid (GABA)
analogues 

Hydantoins 

Phenyltriazines
Antihistamines (centrally-acting H1, including 
over-the-counter [OTC]) 

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

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
Moderate CYP3A inhibitors 

Amprenavir

Aprepitant

Atazanavir

Casopitant

Cimetidine

Ciprofloxacin

Clotrimazole

Crizotinib

Cyclosporin

Darunavir

Dronadarone

Erythromycin

Faldaprevir

Fluconazole

Fluvoxamine

Imatinib

Netupitant

Tofisopam

Verapamil
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Category
Medication
Cytochrome P450 (CYP)3A inducers

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

-
Monoamine oxidase inhibitors (MAOIs)

-
Opioid Analgesics

-
Muscle relaxants (centrally-acting) with known sedating 
effects

GABA analogues 

Hydantoins 

Phenyltriazines
Other

Warfarin, heparin, ticlopidine

Systemic isoretinoin

Systemic glucocorticoids
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Appendix 3
Extension Phase
Study Design and Plan
The Extension Phase comprises a Maintenance Period of up to 12 weeks in duration, and a 
Follow-up Period visit that is to occur 4 weeks after the end of the Maintenance Period.
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of Lemborexant 
(LEM) that they took at the end of the Titration Period.  Subjects will subsequently return to 
clinic at the visit as specified in the Schedule of Assessments, and will be instructed to return 
their supply of LEM at each visit.  Unused study drug will be collected, and study drug 
compliance will be assessed. Subjects will be able to discuss changing the dose of LEM at 
any time during the Maintenance Period, and LEM dose changes may be implemented as 
clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all 
subjects (eg, 4 weeks after the end of the Maintenance Period).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study.  
Study Drug Supplies
Subjects will enter the Extension Phase from the Titration Phase of the Core Study, taking 
the same dose of LEM that was their final dose of the Titration Phase, ie, LEM5 or LEM10 
taken orally in tablet form at night a few minutes before the time the subject intends to try to 
sleep.
Schedule of Procedures/Assessments
Table 5 presents the Schedule of Procedures and Assessments for the 12-week Extension 
Phase.
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 - Extension
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS
X
X
X
X
Prior and concomitant medications
X
X
X
X
Study drug compliance
X
X
X
Dispense study drug
Retrieve unused study drug
X
X
X
Physical examinatione
X
X
X
X
Vital signs and weight
X
X
X
X
Clinical laboratory testsf
X
X
X
Urine drug screeng
X
X
X
Urine pregnancy testh
X
X
X
Serum pregnancy testh,i
X
12-Lead ECGj
X
X
X
Adverse eventsk
X
X
X
X
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 - Extension
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram.
All visits to be done within ±7 days of the schedule.
a:
The Follow-up Visit will be conducted 4 weeks after the end of the Extension Phase.
b:
Subjects who discontinue study drug prematurely at any time after entering the Extension will be encouraged to return to the site as soon as practicable 
(preferably within 7 days).
c:
During Early Termination and unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the 
investigator.
d:
Assessments during an Unscheduled Visit to be conducted at the discretion of the investigator.
e:
A full physical examination will be conducted at Visit 4 and 5 and at the Early Termination and Unscheduled Visit at the discretion of the investigator.
f:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
g:
Urine drug test to be conducted at Unscheduled Visits at the discretion of the investigator and at Early Termination only for subjects who withdraw because of 
an adverse event. 
h:
Female subjects of child-bearing potential only. 
i:
To be conducted if urine pregnancy testing is positive
j:
The ECG should be repeated if a clinically significant abnormality (as determined by the investigator) is observed.
k:
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 9.5.1.5, Adjudication Committee
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Statistical Analyses
All statistical analyses will be the responsibility of the Biostatistics Department of Eisai.  
Statistical programming and analyses will be performed using SAS or other validated 
software. 
Safety Analyses
The primary focus of data summarization for the Extension Phase will be on safety and 
tolerability.  Evaluations of safety data will be performed on the Safety Analysis Set.
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product 
Name:
E2006\Lemborexant
IND Number:
111871
SIGNATURES
Authors:
Eisai, Inc
Date
Eisai Inc.
Date
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PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product
Name:
E2006\Lemborexant
IND Number:
111871
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2006-A001-312
Study Protocol 
Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition from 
Zolpidem to Lemborexant for the Treatment of Insomnia 
Sponsor: 
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Investigational 
Product Name:
E2006/Lemborexant
Indication:
Insomnia 
Phase:
3b
V1.0
12 Apr 2019 (original protocol)
IND Number:
111871
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential. It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2006
Name of Active Ingredient:  Lemborexant
Study Protocol Title
A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the 
Treatment of Insomnia
Investigator(s)
Unknown
Sites
Approximately 15 sites within the United States of America
Study Period and Phase of Development
Phase 3b pilot study
Estimated duration of up to 38 weeks from first subject in to last subject’s last visit.
Objectives
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects with 
insomnia disorder taking zolpidem tartrate immediate release (ZOL-IR) or zolpidem tartrate extended 
release (ZOL-ER), intermittently or frequently, who  transition to lemborexant 5 mg (LEM5) or 10 
mg (LEM10), after 2 weeks of receiving lemborexant (LEM).
Secondary Objectives

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease from 
LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of Insomnia 
(PGI-I) at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared with 
Baseline at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared with 
Baseline at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking zolpidem (ZOL)
Exploratory Objective(s)
None
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Study Design
E2006-A001-312 is a multicenter Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week Screening 
Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week Titration Period), and 
an Extension Phase consisting of the Maintenance Period up to 12 weeks and the Follow-up Period 
4 weeks in duration immediately following the end of the Treatment Phase.  The Pretreatment 
and Treatment Phases will comprise the Core Study.  A Follow-up Period visit occurring 4 weeks 
after the end of the Extension Phase (or Treatment Phase, for subjects not entering the Extension 
Phase) will be conducted.
Core Study
Pretreatment Phase
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day Baseline Period, 
during which subjects will be assessed for eligibility to participate in the study. 
Screening Period
During the Screening Period, subjects will be required to bring the container of their prescribed ZOL 
to the site for verification of prescribed medication and dose. Subjects will be provided with, and 
trained in the use of, a data collection system to record the frequency of ZOL is taken during the 
3-week Screening Period.  Site staff will instruct subjects to complete data entry every morning and 
will emphasize the importance of providing these data.  During the Screening Period, subjects will 
continue to take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5mg or 
10 mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection system for 
at least 14 (preferably contiguous) days out of the allowable 21-day Screening Period in order to be 
eligible for study inclusion.  
Subjects will return to clinic at the end of the Screening Period.  Based on ZOL use during the 
Screening Period (which must match the treatment history ascertained at the beginning of the 
Screening Period), subjects will be assigned to 1 of 2 cohorts as follows:
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, for 
each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, during, at 
minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). For 
Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio. 
Baseline Periody
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment cohort.  
Subjects who are not eligible will conclude their participation and will be considered screen failures.  
Upon completion of the Baseline Period, subjects who remain eligible will enter the Titration Period.
Treatment Phase
Titration Period
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and LEM10 to 
be taken at home within a few minutes of the time that they intend to sleep at night.  Study 
restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals will be 
discussed. Subjects will be instructed to not alter (ie, break or cut) their tablets of LEM.
Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will determine the nights on which they 
take LEM, with the requirement that they take LEM at least once per week during the 14–day 
Titration Period.  
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Cohort 2 (Frequent Use, Treatment Groups A and B): Subjects in these cohorts will take LEM at 
least 5 nights per week during the 2-week Titration Period.
For subjects with a starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but not 
mandated) to remain on their assigned dose for 7 days before calling the site should they feel that 
LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  
For subjects with a starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site should they feel that LEM10 should be reduced. 
Subjects will then be instructed to take LEM5 within a few minutes of the time they intend to go to 
sleep.  
At the time of LEM dose change during the Core Study, the reason for the dose change will be 
recorded in the case report form (CRF).  Subjects will be allowed 1 LEM dose adjustment during 
the Titration Period.  Every morning, subjects will enter their insomnia drug use data into the data 
collection system, and, provided an insomnia drug was taken the night prior, PGI-I and Quality of 
Sleep Rating. The ISI will be completed at each study visit except Follow-up Visit.  . 
Upon completion of the Titration Period, subjects will be eligible to enter the Extension Phase. 
Extension Phase
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of LEM that they took at 
the end of the Titration Period.  Subjects will subsequently return to clinic as specified in the 
Schedule of Assessments, and will be instructed to return their supply of LEM at each visit.  Unused 
study drug will be collected, study drug compliance will be assessed.  Subjects will be able to discuss 
changing the dose of LEM at any time during the Maintenance Period, and LEM dose changes may 
be implemented as clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all subjects (eg,
4 weeks after the end of the Treatment Phase for subjects not entering the Extension Phase or after 
the end of the Extension Phase, for subjects entering the Extension Phase).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study. 
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Number of Subjects
Approximately 110 subjects will be screened to provide approximately 60 subjects (20 subjects in 
Cohort 1 and 40 subjects in Cohort 2 [20 in LEM5, 20 in LEM10]).
Inclusion Criteria
1.
Male or female, 18 years or older, at the time of informed consent
2.
Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5) criteria for 
Insomnia Disorder, either currently or prior to ZOL use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep 
and/or awakening earlier in the morning than desired despite adequate opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 but fewer than 5 nights per week), or frequent use 
(at least 5 nights per week) of ZOL-IR or -ER, for at least 1 month
5.
Confirmation of intermittent or frequent use of ZOL (based on review of drug use data). 
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for at least 
2 weeks each of the 3-week Screening Period.  Frequent use is defined as taking ZOL at least 5 
nights per week, during, at minimum, the last 2 weeks of the 3-week Screening Period
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 
hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia during the 
subject’s participation in the study
Exclusion Criteria
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
urine pregnancy test).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing and throughout the study and for 28 days 
after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
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dosing).
3.
Any history of moderate or severe obstructive sleep apnea (OSA)
4.
Current evidence of a clinically significant, active respiratory disorder other than mild OSA.  
This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any 
other pulmonary disorder identified by review of medical history or physical examination, and 
which in the opinion of the investigator, could compromise the subject’s safety or interfere with 
study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, circadian 
rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals 
with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator 
indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy
8.
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 sleeping), 
whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
13. Used any prohibited prescription or over-the-counter concomitant medications within 1-week or 
5 half-lives, whichever is longer, before the first dose of study medication (A list of prohibited 
concomitant medications is presented in the protocol).  
14. Used any pharmacologic modality of treatment for insomnia other than zolpidem, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening Period
15. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
16. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
Columbia-Suicide Severity Rating Scale [C-SSRS])
17. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
18. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal 
disease) 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.
19. Hypersensitivity to lemborexant or any of the excipients.
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) would 
compromise the subject’s ability to safely complete the study.
21. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during 
the study. Planned surgery, which requires only local anesthesia and which can be undertaken as 
a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of 
the investigator this operation does not interfere with the study procedures and patient safety.
22. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics 
or prior suicide attempt(s) within approximately the last 2 years
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23. History of drug or alcohol dependency or abuse within approximately the last 2 years
24. Currently enrolled in another clinical study or used any investigational drug or device within 28 
days or 5× the half-life, whichever is longer, preceding informed consent
25. Previously participated in any clinical trial of lemborexant
Study Treatment(s)
Core Study
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night within a few minutes of the time the subject 
intends to sleep, according to the subject’s predetermined intermittent or frequent use schedule.
Comparator Drug:  Not applicable 
Extension Phase
Test drug:  
LEM5 or LEM10 taken orally in tablet form at night a few minutes before the time the subject 
intends to try to sleep.
Duration of Treatment
A maximum of 14 weeks: 
2 weeks of LEM5 and/or LEM10 during the Treatment Phase of the Core Study,
12 weeks during the Extension Phase
Concomitant Drug/Therapy
Prohibited medications should not be used during the study.  A subject must not have used any 
prohibited prescription or over-the-counter medications within 1-week or 5 half-lives, whichever is 
longer, before the Treatment Phase.
Prohibited medications include moderate and strong cytochrome P450 (CYP)3A inhibitors and all 
CYP3A inducers, and medications that have known sedating effects.  The prohibition applies even if 
the entire class to which that medication belongs is not prohibited (eg, anticonvulsants).  
If a medication is not on the list of prohibited medications but in the opinion of the investigator 
causes or exacerbates the subject’s insomnia, it must not be used throughout the study.  If a 
medication is not specified as prohibited but is in the same class as a medication that is listed in the 
protocol, and if the investigator is uncertain whether the medication has known sedating or alerting 
effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must discontinue 
from the study, with the exception that certain prohibited medications may be used for a short 
duration (not to exceed 2 weeks) to treat an acute condition if this is agreed with the Medical 
Monitor.  Note that strong and moderate CYP3A inhibitors and all CYP3A inducers will not be 
permitted at any time for any duration during the study.  Subjects must forgo alcohol consumption 
within 3 hours of bedtime for the duration of participation in the study.  
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Assessments
Screening Assessments (Core Study only)
Sleep Disorders Screening Battery (SDSB):
The SDSB will include:

STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects for OSA 

IRLS:  a subjective scale comprising 10 questions, which measures severity of symptoms of 
restless legs syndrome
Sleep Drug History Questionnaire
Subjects will be asked questions about their history and response to prior sleep medications.
Sleep Drug Experience Interview – Zolpidem
Subjects will be asked questions about their subjective experiences while taking ZOL at the end of 
the Screening Period.
Efficacy Assessments (Core Study only)
Patient Global Impression – Insomnia
The PGI-I is a self-report assessment of subject perception of the effects of a medication on their 
sleep.  The PGI-I has 3 items related to study medication effects (a) helped/worsened sleep, (b) 
decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to 
perceived appropriateness of study medication strength.  The first 3 items are answered on a 3-point 
scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and 
the last item on a different 3-point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior evening.
Insomnia Severity Index
The ISI is a 7-item self-report questionnaire assessing the nature, severity and impact of insomnia.  
The dimensions evaluated are severity of: sleep onset, sleep maintenance, early-morning awakening 
problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning, 
noticeability of the sleep problems by others, and distress caused by the sleep difficulties.  A 5-point 
Likert scale is used to rate each item (from 0=no problem, to 4=very severe problem), yielding a total 
score from 0 to 28.  The ISI will be completed at each study visit except Follow-up Visit.  
Quality of Sleep Rating
The Quality of Sleep Rating is a self-reported scale in which subjects are asked, “How would you rate 
the quality of your sleep last night, with 1 being extremely poor, 5 being not good or poor, and 9 
being extremely good?” For Quality of Sleep, higher values are better.  The Quality of Sleep Rating 
will be completed each morning following a dose of ZOL or LEM taken the prior evening during the 
Screening, Baseline, and Titration Periods.
Sleep Drug Experience Interview – Lemborexant
Subjects will be asked questions about their subjective experiences while taking LEM at the end of 
the Titration Period.
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable.
Safety Assessments (Core Study and Extension Phase)
Safety assessments will consist of monitoring and recording all adverse events (AEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of 
vital signs, weight and ECGs; and the performance of physical examinations.  Subjects will be asked 
about falls at every visit.
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Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a blinded 
manner, AEs that could potentially be considered cataplexy or seizure.  A set of preferred terms (PTs)
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.  
Columbia – Suicide Severity Rating Scale
Suicidality will be assessed using a site-administered version of the C-SSRS.  The C-SSRS assesses 
an individual’s degree of suicidality, including both suicidal ideation and suicidal behavior. 
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months as designated in the 
Schedule of Procedures/Assessments.
Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the Schedule of 
Procedures/Assessments.  This sample will be tested for common drugs of use/abuse:  eg, 
propoxyphene, cocaine metabolites, cannabinoids, methadone, PCP, opiates, benzodiazepines, 
barbiturates, and amphetamines.
Bioanalytical Methods
Not applicable.
Statistical Methods
The study endpoints for efficacy and safety will be presented by treatment group (LEM5 and 
LEM10) and by pooling across treatments within each cohort and overall.  Missing data will not be 
imputed.
Primary Endpoint
The primary endpoint is the proportion of overall subjects who transition to LEM at the end of the 
Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week Titration 
Period and either 1) enters the Extension Phase, or 2) chooses to not enter the Extension Phase for 
reasons not related to LEM (including, but not limited to, time commitment related to the study, 
study-related travel expenses, or preference to continue insomnia management with another health 
care provider).  
Secondary Endpoints
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration Period
within each Cohort.

The proportion of subjects with positive medication effect rating on each PGI-I item at the end 
of the 2-week Titration Period by Cohort and overall using end of the Titration Period treatment.
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
The change from Baseline in mean ISI score at the end of the Titration Period by Cohort and 
overall using end of the Titration Period treatment.

The proportion of subjects in the LEM5 treatment groups with dose increasing to LEM10 at the 
end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at the end 
of the Titration Period in Cohort 2.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration Period by 
cohort and overall using end of the Titration Period treatment.
Analysis Sets
Safety Analysis Set (SAS) –The Safety Analysis Set is the group of subjects who received at least 1 
dose of study drug and had at least 1 postdose safety assessment.
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included in the 
Full Analysis Set.
Efficacy Analyses (Core Study only)
All efficacy analyses will be conducted on the FAS. 

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed.

The proportion of subjects who transition to LEM after 2 weeks of treatment in the Titration 
Period will be displayed within each cohort.  

Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately within 
each scale over time by Cohort and overall using end of the Titration Period dose groups.

The proportion of subjects whose response on the first 3 items of the PGI-I (medication effect) 
was neutral or negative at Baseline, but who recorded a positive effect on these items at the end 
of the Titration Period, and the proportion of subjects who rated the drug as being too strong or 
too weak at Baseline, but whose rating was “just right” at the end of the Titration Period (as data 
allow) will be reported.

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the ISI will 
be summarized at the end of the Titration Period by Cohort and overall using end of the Titration 
Period dose groups

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the Titration 
Period by Cohort and overall, 

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the Titration 
Period will be displayed in Cohort 2.  A graphical representation of changes between the 5 and 
10 mg dose groups in each of the cohorts may also be presented.

The change from baseline in mean Quality of Sleep Rating score for subjects at the end of the 
Titration Period will be summarized by cohort and overall using end of the Titration Period dose 
groups.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable.
Safety Analyses (Core Study and Extension Phase)
Evaluations of safety data will be performed on the SAS. 
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG findings, out-of-
range vital signs, and suicidality (C-SSRS) findings, along with changes from baseline in clinical 
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laboratory variables, and vital signs will be summarized for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics using end of titration dose group. AEs
summaries, and abnormal findings will also be displayed based on the dose that the subjects were 
taking at the time of the findings.
Customized MedDRA Queries (CMQ) for AEs that could potentially be considered cataplexy or 
seizure, somnolence, and related events, and PTs related to drug abuse liability, will be summarized
seperately.  The results of the deliberation of the Adjudication Committee will be reported separately.  
In addition, 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, as per the
Adjudication Committee description.
Other Analyses (Core Study)
Primary and secondary endpoints may be analyzed by modeling methods if warranted.  Details of all 
of the analyses will be specified in the Statistical Analysis Plan.
Interim Analyses
No interim analyses are planned for this study.
Sample Size Rationale
As a pilot study, sample size estimates are not based on statistical calculations.
This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 2B) to 
evaluate the proportion of subjects who transition to LEM as a substitute for zolpidem.  Twenty 
subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be assigned to 
Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to receive LEM5 or 
LEM10 within Cohort 2.  This sample size is deemed sufficient to inform whether the proposed 
strategies are sufficient to evaluate whether alternative strategies would be required to help 
understand how best to recommend safe and effective methods for transitioning from ZOL to LEM.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................12
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees ..............................18
5.2
Ethical Conduct of the Study.................................................................................18
5.3
Subject Information and Informed Consent...........................................................19
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................19
7
INTRODUCTION ...........................................................................................................20
7.1
Indication ...............................................................................................................20
7.1.1
Current Therapeutic Options........................................................................20
7.1.2
Lemborexant ................................................................................................21
7.1.2.1
Clinical Experience With Lemborexant...............................................21
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................22
7.2
Study Rationale......................................................................................................22
7.2.1
Entry Criteria Rationale...............................................................................23
7.2.2
Rationale for Titration Schedule and Duration............................................23
8
STUDY OBJECTIVES....................................................................................................24
8.1
Primary Objective..................................................................................................24
8.2
Secondary Objectives.............................................................................................24
8.3
Exploratory Objective(s)........................................................................................24
9
INVESTIGATIONAL PLAN..........................................................................................24
9.1
Overall Study Design and Plan..............................................................................24
9.1.1
Pretreatment Phase (Core Study).................................................................26
9.1.1.1
Screening Period (Core Study) ............................................................26
9.1.1.2
Baseline Period (Core Study)...............................................................27
9.1.2
Treatment Phase (Core Study).....................................................................27
9.1.2.1
Titration Period (Core Study) ..............................................................27
9.1.2.2
Follow-Up Period.................................................................................28
9.1.3
Extension Phase ...........................................................................................28
9.2
Discussion of Study Design, Including Choice of Control Groups.......................28
9.3
Selection of Study Population................................................................................28
9.3.1
Inclusion Criteria .........................................................................................28
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9.3.2
Exclusion Criteria ........................................................................................29
9.3.3
Removal of Subjects from Therapy or Assessment.....................................31
9.4
Treatments..............................................................................................................31
9.4.1
Treatment(s) Administered..........................................................................31
9.4.2
Identity of Investigational Product...............................................................32
9.4.2.1
Chemical Name, Structural Formula of Lemborexant.........................32
9.4.2.2
Comparator Drug .................................................................................33
9.4.2.3
Labeling for Study Drug......................................................................33
9.4.2.4
Storage Conditions...............................................................................33
9.4.3
Method of Assigning Subjects to Treatment Groups...................................33
9.4.4
Selection of Doses in the Study...................................................................33
9.4.5
Selection and Timing of Dose for Each Subject..........................................33
9.4.6
Blinding........................................................................................................34
9.4.7
Prior and Concomitant Therapy...................................................................34
9.4.7.1
Drug-Drug Interactions........................................................................34
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................35
9.4.8
Treatment Compliance.................................................................................35
9.4.9
Drug Supplies and Accountability...............................................................35
9.5
Study Assessments.................................................................................................37
9.5.1
Assessments.................................................................................................37
9.5.1.1
Demography.........................................................................................37
9.5.1.2
Screening and Baseline Assessments...................................................37
9.5.1.2.1
Medical History and Physical Examinations.................................37
9.5.1.2.2
Sleep Drug History Questionnaire.................................................37
9.5.1.2.3
Sleep Disorder Screening Battery..................................................37
9.5.1.2.4
Sleep Drug Experience Interview – Zolpidem...............................38
9.5.1.3
Efficacy Assessments...........................................................................38
9.5.1.3.1
Insomnia Severity Index ................................................................38
9.5.1.3.2
Patient’s Global Impression – Insomnia........................................38
9.5.1.3.3
Quality of Sleep Rating..................................................................39
9.5.1.3.4
Sleep Drug Experience Interview – Lemborexant.........................39
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................39
9.5.1.5
Safety Assessments..............................................................................39
9.5.1.5.1
Adverse Events ..............................................................................40
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................42
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9.5.1.5.3
Study-Specific Adverse Events......................................................43
9.5.1.5.4
Laboratory Measurements .............................................................43
9.5.1.5.5
Vital Signs, Height, and Weight Measurements............................44
9.5.1.5.6
Physical Examinations...................................................................44
9.5.1.5.7
Electrocardiograms ........................................................................44
9.5.1.5.8
Other Safety Assessments..............................................................44
9.5.2
Schedule of Procedures/Assessments – Core Study....................................45
9.5.2.1
Schedule of Procedures/Assessments ..................................................45
9.5.2.2
Description of Procedures/Assessments Schedule...............................49
9.5.3
Appropriateness of Measurements...............................................................49
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................49
9.5.4.1
Reporting of Serious Adverse Events..................................................49
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................50
9.5.4.3
Reporting of Events Associated with Special Situations.....................51
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................51
9.5.4.3.2
Reporting of Study-Specific Events...............................................51
9.5.4.4
Expedited Reporting ............................................................................51
9.5.4.5
Breaking the Blind...............................................................................51
9.5.4.6
Regulatory Reporting of Adverse Events ............................................52
9.5.5
Completion/Discontinuation of Subjects.....................................................52
9.5.6
Abuse or Diversion of Study Drug ..............................................................52
9.6
Data Quality Assurance .........................................................................................53
9.6.1
Data Collection ............................................................................................53
9.6.2
Clinical Data Management ..........................................................................53
9.7
Statistical Methods.................................................................................................53
9.7.1
Statistical and Analytical Plans....................................................................53
9.7.1.1
Study Endpoints...................................................................................54
9.7.1.1.1
Primary Endpoint...........................................................................54
9.7.1.1.2
Secondary Endpoints .....................................................................54
9.7.1.2
Definitions of Analysis Sets.................................................................54
9.7.1.3
Subject Disposition..............................................................................55
9.7.1.4
Demographic and Other Baseline Characteristics ...............................55
9.7.1.5
Prior and Concomitant Therapy...........................................................55
9.7.1.6
Efficacy Analyses ................................................................................55
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9.7.1.6.1
Primary Efficacy Analysis.............................................................55
9.7.1.6.2
Secondary Efficacy Analyses ........................................................55
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................56
9.7.1.8
Safety Analyses....................................................................................56
9.7.1.8.1
Extent of Exposure.........................................................................57
9.7.1.8.2
Adverse Events ..............................................................................57
9.7.1.8.3
Laboratory Values..........................................................................58
9.7.1.8.4
Vital Signs......................................................................................59
9.7.1.8.5
Electrocardiograms ........................................................................59
9.7.1.8.6
Other Safety Analyses....................................................................59
9.7.2
Determination of Sample Size .....................................................................59
9.7.3
Interim Analysis...........................................................................................60
9.7.4
Other Statistical/Analytical Issues ...............................................................60
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................60
10
REFERENCE LIST .........................................................................................................61
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......63
11.1
Changes to the Protocol .........................................................................................63
11.2
Adherence to the Protocol......................................................................................63
11.3
Monitoring Procedures...........................................................................................63
11.4
Recording of Data..................................................................................................64
11.5
Identification of Source Data.................................................................................64
11.6
Retention of Records..............................................................................................65
11.7
Auditing Procedures and Inspection......................................................................65
11.8
Handling of Study Drug.........................................................................................65
11.9
Publication of Results ............................................................................................66
11.10 Disclosure and Confidentiality ..............................................................................66
11.11 Discontinuation of Study .......................................................................................66
12
APPENDICES .................................................................................................................67
LIST OF IN-TEXT TABLES
Table 1
Treatments Administered...........................................................................32
Table 2 
Clinical Laboratory Tests...........................................................................43
Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core 
Study ..........................................................................................................46
Table 4
Clinically Notable Vital Sign Criteria........................................................59
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 -
Extension....................................................................................................73
LIST OF IN-TEXT FIGURES
Figure 1
Study E2006-A001-312 – Study Design....................................................25
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................67
Appendix 2
Prohibited Concomitant Medications ........................................................69
Appendix 3
Extension Phase .........................................................................................72
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
BMI
Body mass index
BP
blood pressure
CBT-I
Cognitive Behavioral Therapy for Insomnia
CFR
Code of Federal Regulations
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A
Cytochrome P450
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th ed
FAS
full analysis set
GABA
gamma-aminobutyric acid
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ISI
Insomnia Severity Index
IRB
Institutional Review Board
IRLS
International Restless Legs Scale
LEM
lemborexant
LEM5
Lemborexant 5 mg
LEM10
Lemborexant 10 mg
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
OSA
obstructive sleep apnea
PBO
placebo
PGI-I
Patient Global Impression of Insomnia
PT
preferred term
QTcF
Difference between QTc corrected by Fridericia's formulas
SAE
Serious adverse events
SAS
safety analysis set
SDSB
Sleep Disorders Screening Battery
SOC
system organ class
TEAE
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory values
ZOL
zolpidem
ZOL-ER
zolpidem tartrate extended release
ZOL-IR
zolpidem tartrate immediate release
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with ICH E6 (Good Clinical Practice), Section 3, and any local regulations (eg, 
Title 21 of the United States Code of Federal Regulations [CFRs], Part 56). Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, 
change in Clinical Research Associate CRA[s], change of telephone number[s]).  
Documentation of IRB compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension 
or termination by the IRB to the sponsor.
Study progress is to be reported to IRBs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports,
and inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB within 90 days.  The end of the 
study will be the date of the last study visit for the last subject in the study.  The sponsor 
should also provide the IRB with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB 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 (2013)

ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
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Committee for Proprietary Medicinal Products, International Conference on 
Harmonisation of Pharmaceuticals for Human Use

Title 21 of the US CFR regarding clinical studies, including Part 50 and Part 56 
concerning informed subject consent and IRB regulations and applicable sections of US 
21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (eg, Title 21 CFR Part 50).  Each subject must 
sign an approved ICF before study participation.  The form must be signed and dated by the 
appropriate parties.  The original, signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site.  
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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 investigational sites in the United States of America.
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The name, telephone and fax numbers of the Medical Monitor and other contact personnel at 
the contract research organization(s) (CROs) are listed in the Investigator Study File
provided to each site.
7
INTRODUCTION
7.1
Indication
Lemborexant (LEM) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide), also known as E2006, is 
an orally-administered, novel competitive dual orexin receptor antagonist (DORA) that has 
been developed for the treatment of insomnia and Irregular Sleep-Wake Rhythm Disorder 
(ISWRD).  
7.1.1
Current Therapeutic Options
Treatments for insomnia include both non-pharmacological (Schutte-Rodin, et al., 2008; 
Morgenthaler, et al., 2006) and pharmacological treatments (Sateia, et al., 2017).  Patients 
who undergo thorough diagnostic evaluations for insomnia symptoms are asked about their 
sleep and wake habits, since some cases of insomnia can be addressed by improving sleep 
hygiene.  Principles of good sleep hygiene include regular bedtimes and waketimes, limiting 
alerting activities before bedtime, and limiting caffeine and alcohol intake, among others 
(Schutte-Rodin, et al., 2008).  These techniques are often not adequate to address insomnia 
symptoms (Stepanski and Wyatt, 2003; Irish, et al., 2015).
Another commonly recommended non-pharmacological approach is the use of cognitive 
behavioral therapy for insomnia (CBT-I; Schutte-Rodin, et al., 2008).  CBT-I includes 
techniques to minimize wakefulness at the time the patient intends to sleep.  However, while 
there are data to support the effectiveness of CBT-I, sleep restriction is commonly a major 
component, and this may lead to daytime sleepiness, an unintended consequence of short 
sleep (Kyle, et al., 2014).  In contrast, lemborexant’s mechanism of action would avoid the 
daytime sleepiness caused by sleep restriction, while reducing wakefulness and facilitating 
sleep, which is an important underlying goal of CBT-I.  
There are numerous drugs available for the treatment of insomnia, some available by 
prescription and many available over-the-counter.  Many of the over-the-counter medicines 
lack empirical data from adequate, well-designed and controlled clinical trials to support 
their use (Rosen, et al., 2005); these include melatonin and antihistamines.  Pharmacological 
treatments available by prescription and used clinically for insomnia include sedative 
hypnotics (benzodiazepines, nonbenzodiazepine gamma-aminobutyric acid 
(GABA)-releasing [GABAergics] agents), sedating antidepressants, melatonin agonists, and 
a DORA.  
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7.1.2
Lemborexant
Lemborexant belongs to the pharmacologic class of orexin receptor antagonists, a class of 
chemical compounds developed for the treatment for insomnia.  To date, clinical proof of 
concept has been achieved by 6 orexin receptor antagonists (lemborexant, almorexant 
[ACT-078573], suvorexant [MK-4305], filorexant [MK-6096]), seltorexant [MIN-202], and 
nemorexant [ACT-541468]), demonstrating validity of the mechanism of action (Herring, 
et al., 2012; Hoever, et al., 2012; Connor, et al., 2016; Murphy, et al., 2017; De Boer, et al., 
2018).
Nonclinical data show that lemborexant binds to and competitively antagonizes human 
orexin-1 receptor (OX1R) and orexin-1 receptor (OX2R) in vitro, with rapid association and 
dissociation kinetics at both receptors.  In vitro data show that lemborexant does not 
substantially interact with other sleep-related receptors and channels (Beuckmann, et al, 
2017).  Lemborexant prevents [Ala11, D-Leu15]-orexin-B-induced plasma adrenocorticotropic 
hormone increase in rats, and promotes physiological sleep in mice and rats.  In mice, 
lemborexant does not promote sleep when the orexin pathway has been functionally 
impaired.  In rats, daily treatment for 3 consecutive weeks with lemborexant did not result in 
tolerance or wakefulness rebound upon treatment cessation, and did not elicit direct 
transitions from wakefulness to rapid eye movement (REM) sleep, a narcolepsy-like 
symptom.  However, in strong emotional contexts, lemborexant induced cataplexy-like 
events in mice (Study W-20140712).  Cataplexy has been noted in dogs dosed with another 
orexin antagonist, suvorexant, when presented with food enrichment (Belsomra, 2018), but 
the relationship to cataplexy symptoms in humans has not been established.  At doses up to 
300 mg/kg (300-fold higher than necessary for sleep promotion), lemborexant did not have 
any negative influence on motor coordination in mice, nor did it show any significant 
interaction with ethanol.
7.1.2.1
Clinical Experience With Lemborexant
The safety and efficacy of lemborexant for the treatment of insomnia disorder was confirmed 
in 2 pivotal Phase 3 studies, E2006-G000-303 (Study 303) and E2006-G000-304 (Study 
304).  In Study 304, lemborexant also demonstrated superior improvement on objective and 
subjective measures of sleep onset and maintenance compared to zolpidem tartrate extended 
release (ZOL-ER).  Additional safety assessments pertinent to insomnia drugs, specifically 
regarding postural stability, were also conducted in study E2006-A001-108 and Study 304.  
In these studies, the safety of lemborexant on postural stability was superior compared to 
zolpidem (ZOL).  Based on these data, a New Drug Application for lemborexant was 
submitted to the US Food and Drug Administration for the treatment of insomnia disorder in 
December 2018 and accepted for review in February 2019.
The safety and tolerability of lemborexant has been comprehensively evaluated in a broad 
patient population that includes subjects with insomnia disorder per Diagnostic and 
Statistical Manual of Mental Disorders, 5th ed (DSM-5) (with or without medical or 
psychiatric comorbidities), subjects with Alzheimer's disease and ISWRD, subjects with mild 
obstructive sleep apnea (OSA), and subjects with severe renal impairment or mild to 
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moderate hepatic impairment.  Exposures included dosing of ≥12 months.  Approximately 
40% of subjects in the development program were elderly (≥65 years), providing extensive 
safety and tolerability profile for this important subpopulation at risk for insomnia.  
Overall, of 2824 subjects with sleep disorders, 1848 received lemborexant, 714 received 
placebo (PBO), and 263 received ZOL.  
No deaths were reported in subjects treated with lemborexant.
The overall incidence of treatment-emergent serious adverse events (SAEs) for subjects 
treated with lemborexant 5 mg (LEM5) and lemborexant 10 mg (LEM10) in the Phase 3 Pool
was low (2.8% and 2.3%, respectively) but greater than for PBO (0.9%).  However, when 
adjusted by duration of exposure, the overall incidence (subjects per patient-year) was similar 
to PBO (<0.1 for PBO, 0.1 for LEM5, and 0.1 for LEM10).  The overall rate (events per 
patient-year) of treatment-emergent SAEs when adjusted by duration of exposure was <0.1 
for PBO, <0.1 for LEM5, and <0.1 for LEM10.
There were no differences in the types of treatment-emergent SAEs reported during 
long-term treatment with lemborexant. There were no differences in treatment-emergent 
SAEs based on intrinsic factors, including age, sex, and body mass index (BMI) of subjects.  
Notably, the incidence of treatment-emergent SAEs in the elderly was consistent with that in 
younger subjects.
Across the Phase 3 studies of 303 and 304 (total subjects=1945), the majority of 
treatment-emergent SAEs occurred as singular events in 1 subject only.  The SAEs of 
osteoarthritis (0% for PBO, 0.1% for LEM5, 0.4% for LEM10), rib fracture (0.2% for PBO, 
0% for LEM5, 0.1% for LEM10), and diabetic neuropathy (0% for PBO, 0.3% for LEM5, 
0% for LEM10) occurred in more than 1 subject across the PBO, LEM5, and LEM10 groups.  
One (0.1%) serious event of fall was reported in the LEM5 group.
7.1.2.2
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure
None.
7.2
Study Rationale
Switching of medications for insomnia occurs often in clinical practice based on clinical 
response, AEs, reimbursement patterns, or physician and patient preference.  However, there 
is no clinical trial experience or dosing guidance for transitioning from currently approved 
treatments for insomnia to lemborexant.  Study E2006-A001-312 (Study 312) is designed as 
a pilot study to assess the dosing approach of directly transitioning from ZOL, the most 
commonly prescribed sleep aid (Bertisch, et al., 2014), to lemborexant, without tapering the 
ZOL dose, and with the opportunity for lemborexant dose titration.  This study will provide 
initial information on patient satisfaction after switching to lemborexant, with secondary 
objectives assessing subjective quality of sleep and tolerability.  If issues are identified 
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regarding patient satisfaction, tolerability, or quality of sleep, other dosing paradigms can be 
assessed in future studies to mitigate these issues.  
7.2.1
Entry Criteria Rationale
Subjects with insomnia disorder per DSM-5 criteria (with or without medical or psychiatric 
comorbidities) will be eligible for study entry, which is representative of the typical target 
outpatient population.  All subjects who are willing to substitute ZOL with LEM, regardless 
of the reason(s), will be eligible, and the reason(s) will be captured during screening.  While 
it is anticipated that most eligible subjects would substitute ZOL with LEM due to 
dissatisfaction with ZOL, other reasons, as determined by input from Key Opinion Leaders 
(KOLs) in Sleep Medicine, may include, but are not limited to, concerns regarding ZOL side 
effects, eg, parasomnias.  Including subjects with these various reasons is representative of 
the real-world outpatient setting.
While the approved dosing instructions for women and patients ≥65 stipulate that the lower 
dose of ZOL is to be prescribed, many women and elderly patients may be taking the higher 
dose.  Therefore, for generalizability of the results of the study to the patient population, any 
stable dosing regimen will be eligible, including those subjects taking higher than approved 
doses up to the maximum approved (10 mg IR or 12.5 mg ER).
7.2.2
Rationale for Titration Schedule and Duration 
Since this study is designed to reflect common clinical practice, flexibility to titrate the dose 
up or down is built into the dosing regimen.  In the outpatient setting, clinicians typically 
advise patients to allow themselves one week to adjust to a new medication; therefore, 
subjects assigned to LEM5 will be encouraged to remain on their dose of LEM for 1-week 
prior to titrating up to LEM10, and those assigned to LEM10 will be encouraged to remain 
on their dose of LEM prior to titrating down to LEM5 after one week.
Subjects who intermittently use ZOL are expected to be more likely to be started on LEM5 in 
the outpatient setting, as they are not chronically exposed to, or reliant upon, pharmacologic 
insomnia treatments.  Therefore, all subjects in Cohort 1 will be started on LEM5 during the 
Titration Period of the Treatment Phase.  
The duration of the Treatment Phase of the Core Study is set at 2 weeks, since that amount of 
time is deemed reasonable by expert opinion from consultation with KOLs in Sleep Medicine 
for subjects to decide if they wish to continue on lemborexant.  
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate the proportion of adult (≥18 years) subjects 
with insomnia disorder taking ZOL immediate release (ZOL-IR) or extended release (ZOL-
ER), intermittently or frequently, who transition to lemborexant 5 mg (LEM5) or 10 mg 
(LEM10), after 2 weeks of receiving lemborexant (LEM).
8.2
Secondary Objectives

To evaluate the proportion of subjects who increase from LEM5 to LEM10 or decrease 
from LEM10 to LEM5 during the 2-week Titration Period

To evaluate the subject impression of treatment using the Patient Global Impression of 
Insomnia (PGI-I) at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Insomnia Severity Index (ISI) compared 
with Baseline at the end of the 2-week Titration Period

To evaluate LEM5 and/or LEM10 scores on the Quality of Sleep Rating scale compared 
with Baseline at the end of the 2-week Titration Period

To evaluate the safety and tolerability of LEM in subjects previously taking ZOL
8.3
Exploratory Objective(s)
None
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, Phase 3b pilot study evaluating the transition of LEM when 
administered as a replacement for ZOL-IR or ZOL-ER.  Adult (≥18 years) subjects are 
eligible for participation if they have been diagnosed with insomnia disorder per the 
DSM-5th Ed (American Psychiatric Association, 2014), are currently receiving ZOL as 
monotherapy for insomnia, and who agree to substitute zolpidem tartrate immediate release 
(ZOL-IR) or ZOL-ER with LEM, regardless of the reason. 
The study will consist of 3 phases: a Pretreatment Phase (consisting of up to a 3-week
Screening Period and a 1-day Baseline Period), a Treatment Phase (consisting of a 2-week
Titration Period), and an Extension Phase consisting of the Maintenance Period up to 
12 weeks and the Follow-up Period 4 weeks in duration immediately following the end of the 
Treatment Phase.  A Follow-up Period visit occurring 4 weeks after the end of the Extension 
Phase (or Treatment Phase, for subjects not entering the Extension Phase) will be conducted.  
The Pretreatment and Treatment Phases will comprise the Core Study.  The Extension Phase 
is described in detail in Appendix 3.
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During the Screening Period, eligible subjects will prospectively record the number of days 
ZOL is taken over 21 days using a Data Collection System.  Based on these data, subjects 
will be assigned to 1 of 2 cohorts of ZOL use frequency:  
Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, during, 
at minimum, the last 2 weeks of the 3-week Screening Period  
All subjects in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5). Within 
Cohort 2, subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or LEM10) in a 
1:1 ratio.  
Subjects who remain eligible for the study will enter the Baseline Period.
Approximately 110 subjects will be screened to provide approximately 60 subjects for 
randomization (20 subjects in Cohort 1 and 40 subjects in Cohort 2 [20 subjects in LEM5 and 
20 subjects in LEM10]).
The end of the study will be the date of the last study visit for the last subject.
An overview of the study design is presented in Figure 1.
Figure 1
Study E2006-A001-312 – Study Design
LEM5 = lemborexant 5 mg, LEM5 = lemborexant 5 mg, R = Randomization
Period:
R
Drug 
3 weeks
Day 1
Titration
2 weeks
Phase:
Screening
12 weeks
Pretreatment
Extension
Cohort 2 (LEM5)
Cohort 2 (LEM10)
Cohort 1 (LEM5)
Maintenance
Drug
Treatment
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9.1.1
Pretreatment Phase (Core Study)
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks) and 1-day 
Baseline Period, during which subjects will be assessed for eligibility to participate in the 
study.
9.1.1.1
Screening Period (Core Study)
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  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.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a diagnosis of insomnia per the DSM-5 (American Psychiatric 
Association, 2014), be currently receiving ZOL as monotherapy for insomnia, and agree to 
substitute zolpidem tartrate immediate release (ZOL-IR) or extended release (ZOL-ER) with 
LEM, regardless of the reason.
During the Screening Period, subjects will be required to bring the container of their 
currently prescribed ZOL to the site for verification of prescribed medication and dose.  
Subjects will be provided with, and trained in the use of, a data collection system to record 
the dose and frequency of ZOL which is taken during the 3-week Screening Period.  Site 
staff will instruct subjects to complete data entry every morning and will emphasize the 
importance of providing this data.  During the Screening Period, subjects will continue to 
take ZOL at the dosage strength prescribed by their health-care provider (ZOL-IR 5 mg or 10 
mg or ZOL-ER 6.25 mg or 12.5 mg).  Subjects must enter data into the data collection 
system for at least 14 (preferably contiguous) days of the 21-day Screening Period in order to 
be eligible for study inclusion.  
Subjects will return to clinic at the end of the Screening Period. For subjects who remain 
eligible for study enrollment, the second Screening Period visit will serve as that subject’s 
Baseline Period, and will occur on the same day. Based on ZOL use during the Screening 
Period (which must match the treatment history ascertained at the beginning of the Screening 
Period), subjects will be assigned to 1 of 2 cohorts as follows:

Cohort 1 (Intermittent ZOL Use):  Subjects who took ZOL at least 3 or 4 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 

Cohort 2 (Frequent ZOL Use):  Subjects who took ZOL at least 5 nights per week, 
during, at minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will begin the Titration Period on lemborexant 5 mg (LEM5).
For Cohort 2, (n=40), subjects will be randomized to 1 of 2 Treatment Groups (LEM5 or 
LEM10) in a 1:1 ratio.
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9.1.1.2
Baseline Period (Core Study)
The Baseline Period (1-day) begins when eligible subjects have been assigned to a treatment 
cohort.  Subjects who are not eligible will conclude their participation and will be considered 
screen failures.  Upon completion of the Baseline Period, subjects who remain eligible by 
meeting the criteria for inclusion/exclusion (Sections 9.3.1 and Section 9.3.2) will enter the 
Titration Period.
9.1.2
Treatment Phase (Core Study)
The Treatment Phase will consist of a 2-week Titration Period and 1-day Follow-up Visit to 
occur 4 weeks after completion of the Titration Period (or as soon as possible following early 
discontinuation) for subjects not entering the Extension Phase.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria at the Baseline Visit, and who have 
entered ZOL medication use data into the Data Collection System for at least 14 of the 21-
day Screening Period as specified in the Inclusion Criteria, are eligible to enter the Treatment 
Phase of the study. 
9.1.2.1
Titration Period (Core Study)
During the 2-week Titration Period, subjects will be provided with a supply of LEM5 and 
LEM10 to be taken at home within a few minutes of the time that they intend to sleep.  Study 
restrictions pertaining to duration of time spent in bed, use of alcohol, and timing of meals 
will be discussed with the subject at each visit during the Treatment and Extension Phases.  
Subjects will be instructed to not alter (ie break or cut) their tablets of LEM.
Subjects assigned to Cohorts 1 and 2 will self-administer the study medication according to 
the following regimens:

Cohort 1 (Intermittent ZOL Use): Subjects in this cohort will determine the nights on 
which they take LEM, with the requirement that they take LEM at least once per week 
during the 2-week Titration Period.  

Cohort 2 (Frequent ZOL Use, Treatment Groups A and B): Subjects in these cohorts will 
take LEM at least 5 nights per week during the 2-week Titration Period.
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For subjects starting dose of LEM5 in Cohorts 1 and 2, subjects will be encouraged (but 
not mandated) to remain on their assigned dose for 7 days before calling the site to report 
that LEM5 is not fully effective for treatment of their insomnia.  Subjects who call the 
site will then be instructed by phone to take LEM10 within a few minutes of the time 
they intend to sleep.  

For subjects starting dose of LEM10 in Cohort 2, subjects will be encouraged to remain 
on their assigned dose for 7 days before calling the site to report that the dose of LEM10 
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should be reduced. Subjects will then be instructed to take LEM5 within a few minutes 
of the time they intend to go to sleep.  
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the case report form (CRF).  
Every morning, subjects will enter their insomnia drug use data into the data collection 
system, and, provided an insomnia drug was taken the night prior, PGI-I and Quality of Sleep 
Rating will be completed.  The ISI will be completed at each clinic visit except Follow-up 
Visit. 
Upon completion of the Titration Period, subjects may be eligible to enter the Extension 
Phase (Appendix 3).
9.1.2.2
Follow-Up Period
For subjects not entering the Extension Phase, the Follow-up Period will start immediately 
after the end of the Treatment Phase and last for 4 weeks.  The purpose of the Follow-up 
Period is to assess adverse events and other safety parameters.  Subjects will be instructed to 
continue insomnia management with the health-care provider who had been treating them 
prior to study entry, if they so desire.
9.1.3
Extension Phase
Subjects who complete the Core Study and wish to continue taking LEM will enter the 
12-week Extension Phase.  Subjects will continue the LEM dose and regimen established 
during the Titration Period; however, the dose may be titrated up or down depending on 
response and tolerability, per subject input and investigator judgement.  For subjects who are 
eligible for the Extension Phase but who do not wish to continue study participation, the 
reason for discontinuation from the study will be recorded.  At the end of the Extension 
Phase, the Follow-up Period will begin, and last for 4 weeks.  
Details of the Extension Phase are provided in Appendix 3.
9.2
Discussion of Study Design, Including Choice of Control Groups
See Section 7.2, Study Rationale.
9.3
Selection of Study Population
Approximately 60 subjects will be enrolled at approximately 15 sites in the United States of 
America.  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:
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1.
Male or female, 18 years or older, at the time of informed consent
2.
Meets the DSM-5 criteria for Insomnia Disorder, either currently or prior to zolpidem 
use, as follows:

Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying 
asleep and/or awakening earlier in the morning than desired despite adequate 
opportunity for sleep

Frequency of complaint ≥3 times per week

Duration of complaint ≥3 months

Associated with complaint of daytime impairment
3.
Reports spending at least 7 hours in bed per night
4.
History of intermittent (taking ZOL at least 3 or 4 nights per week), or frequent use (at 
least 5 nights per week) of ZOL-IR or -ER, for at least 1 month
5.
Confirmation of intermittent or frequent use of ZOL (based on review of drug use data).  
Intermittent use is defined as taking ZOL at least 3 but fewer than 5 nights per week, for 
at least 2 weeks each of the 3-week Screening Period.  Frequent use is defined as taking 
ZOL at least 5 nights per week, during, at minimum, the last 2 weeks of the 3-week 
Screening Period
6.
Willing and able to comply with all aspects of the protocol, including staying in bed for 
at least 7 hours each night
7.
Willing not to start another pharmacologic treatment for the management of insomnia 
during the subject’s participation in the study
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive urine pregnancy test).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study 
drug.
2.
Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 28 days after study drug discontinuation)
o
have a vasectomized partner with confirmed azoospermia.
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
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
3.
Any history of moderate or severe OSA
4.
Current evidence of a clinically significant, active respiratory disorder other than mild 
OSA.  This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary 
disease or any other pulmonary disorder identified by review of medical history or 
physical examination, and which in the opinion of the investigator, could compromise the 
subject’s safety or interfere with study assessments
5.
A current diagnosis of periodic limb movement disorder, restless legs syndrome, 
circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule 
out individuals with symptoms of certain sleep disorders other than insomnia as follows:

STOP-Bang score ≥5 (subjects previously diagnosed with mild OSA are not 
excluded)

International Restless Legs Scale (IRLS) score ≥16
6.
Habitually naps during the day more than 3 times per week 
7.
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the 
investigator indicates the need for referral for a diagnostic evaluation for the presence of 
narcolepsy
8.
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 
sleeping), whether spontaneous or associated with a pharmacological sleep agent.
9.
Takes a dose of ZOL-IR >10 mg per night, or ZOL-ER>12.5 mg per night
10. Takes a dose of ZOL that is lower than what is prescribed
11. Reports having altered ZOL tablets
12. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study 
13. Used any prohibited prescription or over-the-counter concomitant medications within 
1-week or 5 half-lives, whichever is longer, before the first dose of study medication (A 
list of prohibited concomitant medications is presented in the protocol).  
14. Used any pharmacologic modality of treatment for insomnia other than ZOL, including 
marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening 
Period
15. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG
16. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS])
17. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)
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18. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and 
renal disease) 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.
19. Hypersensitivity to lemborexant or any of the excipients.
20. Any history of or concomitant medical condition that in the opinion of the investigator(s) 
would compromise the subject’s ability to safely complete the study.
21. Planned surgery that requires general, spinal, or epidural anesthesia that would take place 
during the study. Planned surgery, which requires only local anesthesia and which can be 
undertaken as a day case without inpatient stay postoperatively, need not result in 
exclusion if in the opinion of the investigator this operation does not interfere with the 
study procedures and patient safety.
22. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
23. History of drug or alcohol dependency or abuse within approximately the last 2 years
24. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days or 5× the half-life, whichever is longer, preceding informed consent.
25. 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.
9.4
Treatments
9.4.1
Treatment(s) Administered
The following treatments will be administered to subjects in the Core Study (Table 1).
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Table 1
Treatments Administered
Drug Name
Strength
Oral Dose Form
Number Dispensed and Frequency
Duration
Lemborexant
5 mg
Tablet
1×5 mg tablets, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Lemborexant
10 mg
Tablet
1×10 mg tablet, once at night within a 
few minutes of the time the subject 
intends to sleep, according to the 
predetermined intermittent or frequent 
use schedule
14 days
Subjects will be allowed 1 LEM dose adjustment during the Titration Period, according to 
the following guidelines:

For Cohorts 1 and 2A (starting dose of LEM5), subjects will be encouraged to remain on 
their assigned dose for 7 days before calling the site to report that LEM5 is not fully 
effective for treatment of their insomnia.  Subjects who call the site will then be 
instructed by phone to take LEM10 within a few minutes of the time they intend to sleep.  

For Cohort 2B (starting dose of LEM10), subjects will be encouraged to remain on their 
assigned dose for 7 days before calling the site to report that the dose of LEM10 should 
be reduced.  Subjects will then be instructed to take LEM5 within a few minutes of the 
time they intend to go to sleep.  
At the time of any LEM dose change during the Titration Period, the reason for the dose 
change will be recorded in the CRF.  
9.4.2
Identity of Investigational Product
Lemborexant will be supplied by the sponsor in labeled containers.  
Study drug must be stored as instructed on the study drug label.  Study drug must be kept in a 
secure location and carefully stored at the study site within its original container.  The 
sponsor will provide the study drug packaged as open-label supplies.  Each subject’s study 
drug will consist of lemborexant tablets supplied in bottles.
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-fluoropyridin-2-yl)cyclopropanecarboxamide)

Molecular formula:  C22H20F2N4O2

Molecular weight:  410.42
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9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Based on ZOL use during the Screening Period, subjects will be assigned to 1 of 2 cohorts as 
shown below:
Cohort 1 (Intermittent ZOL Use):  taking ZOL at least 3 but fewer than 5 nights per week, 
for each of at least 2 weeks of the 3-week Screening Period, or 
Cohort 2 (Frequent ZOL Use):  taking ZOL at least 5 nights per week, during, at 
minimum, the last 2 weeks of the 3-week Screening Period  
All subjects (n=20) in Cohort 1 will receive LEM5. Subjects in Cohort 2 will be randomized 
to 1 of 2 Treatment Groups: Cohort 2A (20 subjects) will start on LEM5, and Cohort 2B 
(20 subjects) will start on LEM10.
9.4.4
Selection of Doses in the Study
The doses to be administered are LEM5 and LEM10.  In December 2018, these doses were 
submitted for approval in the US for the indication of insomnia.  These doses were originally 
selected after conducting a dose-finding study (E2006-G000-201) after which their safety 
and efficacy were confirmed in 2 Phase 3 studies, Studies 303 and 304.
9.4.5
Selection and Timing of Dose for Each Subject
Subjects will be provided a supply of LEM5 and LEM10 to be taken at home within a few 
minutes of the time they intend to sleep.  Subjects will be instructed on study restrictions 
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pertaining to duration of time spent in bed, use of alcohol, and timing of meals.  Subjects will 
be instructed not to alter (ie, break or cut) their tablets of LEM.
9.4.6
Blinding
This is an open-label study with randomization to treatment for subjects assigned to 
Cohort 2.
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 or 30 days before first 
dose/administration of study drug, if appropriate) will be recorded.  The adverse event or 
medical condition for which the concomitant medication or therapy was administered will be 
recorded.
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 Treatment Period.
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 the protocol, and if the investigator is uncertain whether the medication has 
known sedating or alerting effects, the Medical Monitor must be consulted.
If a subject starts any prohibited medication or therapy during the study, he/she must 
discontinue from the study, with the exception that certain prohibited medications may be 
used for a short duration (not to exceed 2 weeks) to treat an acute condition if this is agreed 
with the Medical Monitor.  Note that strong and moderate cytochrome P450 (CYP)3A 
inhibitors and all CYP3A inducers will not be permitted at any time for any duration during 
the study.
9.4.7.1
Drug-Drug Interactions
Coadministration with moderate and strong 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 2.  
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.  
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9.4.7.2
Prohibited Concomitant Therapies and Drugs
Prohibited medications (Appendix 2) 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 Treatment Period.
Prohibited medications include strong and moderate CYP3A inhibitors and all CYP3A 
inducers.  Prohibited therapies also include: any pharmacologic treatment for insomnia 
disorder (with the exception of ZOL use during the Screening Period only); medications that 
are used for the purpose of inducing sleep (hypnotics) and medications that have known 
sedating effects.  This prohibition applies even if the entire class to which that medication 
belongs is not prohibited (eg, anticonvulsants).
If a medication is not on the list of prohibited medications (Appendix 2) 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 2, 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.  
If a subject starts any prohibited medication or a new treatment/modality for insomnia 
disorder, he/she must discontinue from the study.
Subjects must forgo alcohol consumption within 3 hours of bedtime for the duration of 
participation in the study.  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 bottles returned to the investigator at the end 
of the Titration Period.
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 for the institution where the study is to be conducted
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
A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study

The IRB membership list and statutes or Health and Human Services Assurance number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV

A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s 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, (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, Medicine and Healthcare products Regulatory Agency [MHRA]).  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 
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to the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  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.  
9.5.1.2
Screening and Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical, sleep, and psychiatric history will be recorded as designated in the Schedule of 
Procedures/Assessments (Table 3).  All medical and surgical history within 5 years must be 
noted in the Medical History and Current Medical Conditions CRF.
Physical examinations will be performed, as designated in the Schedule of 
Procedures/Assessments (Table 3).  A full physical examination will be performed, 
excluding a urogenital examination unless there are special circumstances and at the 
discretion of the investigator.  Documentation of the physical examination will be included in 
the source documentation at the site.  Significant findings at the Screening Visit will be 
recorded on the Medical History and Current Medical Conditions CRF.  Changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Events CRF.
9.5.1.2.2
SLEEP DRUG HISTORY QUESTIONNAIRE
At Screening, subjects will complete a questionnaire reporting their history and response to 
prior sleep medications, as well as their motivation for participating in the study.
9.5.1.2.3
SLEEP DISORDER 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 
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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 Sleep Disorders Screening Battery (SDSB) will 
be administered (see below).  
The SDSB will include the following, to be self-administered by subjects: 

The STOP Bang:  a list of 8 questions to be answered Yes or No, which screens subjects 
for OSA (Chung et al., 2008)

The IRLS:  a subjective scale comprising 10 questions, which measures disease severity 
of restless legs syndrome (Abetz et al., 2006).
9.5.1.2.4
SLEEP DRUG EXPERIENCE INTERVIEW – ZOLPIDEM
At the end of the Screening Period, subjects will be asked questions about their subjective 
experiences while taking ZOL.  The responses will be compared to the Sleep Drug 
Experience Interview – Lemborexant, which is done at the end of the Treatment Phase, in 
order to provide qualitative information regarding an individual’s subjective experience with 
LEM compared to ZOL.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
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. The ISI 
will be completed at each study visit except Follow-up Visit.  
9.5.1.3.2
PATIENT’S GLOBAL IMPRESSION – INSOMNIA
The PGI-I is a self-report assessment of subject perception of the effects of a medication on 
their sleep (Herring, et al., 2018).  The PGI-I has 3 items related to study medication effects 
(a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) 
increased/decreased total sleep time, and 1 item related to perceived appropriateness of study 
medication strength.  The first 3 items are answered on a 3-point scale (1=positive 
medication effect, 2=neutral medication effect, 3=negative medication effect) and the last 
item on a different 3 point scale (medication: 1=too strong, 2=just right, 3=too weak).  The 
PGI-I will be completed each morning following a dose of ZOL or LEM taken the prior 
evening during the Screening, Baseline, and Titration Periods.
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9.5.1.3.3
QUALITY OF SLEEP RATING
The Quality of Sleep Rating (Krystal and Edinger, 2008) is a self-reported scale in which 
subjects are asked, “How would you rate the quality of your sleep last night, with 1 being 
extremely poor, 5 being not good or poor, and 9 being extremely good?” For Quality of 
Sleep, higher values are better.  The Quality of Sleep Rating will be completed each morning 
following a dose of ZOL or LEM taken the prior evening during the Screening, Baseline, and 
Titration Periods.
9.5.1.3.4
SLEEP DRUG EXPERIENCE INTERVIEW – LEMBOREXANT
At the end of the Titration Period, subjects will be asked questions about their subjective 
experiences while taking LEM.  The responses will be compared to the Sleep Drug 
Experience Interview – ZOL, which is done at the end of the Screening Period, in order to 
provide qualitative information regarding an individual’s subjective experience with LEM 
compared to ZOL.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
Not applicable.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades (for both increasing and 
decreasing severity), regular monitoring of hematology, blood chemistry, and urine values; 
periodic measurement of vital signs and ECGs; and performance of physical examinations.  
Subjects will be asked about falls at every visit.
Sponsor’s grading for laboratory values are presented in Appendix 1. 
Adjudication Committee
An independent Adjudication Committee will be employed at intervals to review, in a 
blinded manner, AEs that could potentially be considered cataplexy or seizure.  A set of 
preferred terms (PTs) 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 [ standard 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 SAE form for any of the 
above events considered serious.
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9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug is 
lemborexant (in doses of 5 mg and 10 mg). 
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, x-ray) that results in symptoms, a change in treatment, or discontinuation 
of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase
and for 7 days or 5× the half-life after the last dose, whichever is longer.  SAEs will be 
collected for 28 days after the last dose or for 5× the half-life, whichever is longer.  
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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 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.
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 9.5.1.5.8 for a description of the C-SSRS). 
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The number (percentage) of subjects with treatment emergent adverse events (TEAEs) of 
cataplexy or other events that are characterized according to the customized MedDRA query 
PT as cataplexy related events will be summarized separately.  The number of adjudicated 
events based on the report of the Adjudication Committee will also reported separately.
Customized MedDRA Queries for AEs that could potentially be considered cataplexy will be 
summarized.  The results of the deliberation of the Adjudication Committee will be reported 
separately.  All AEs must be followed for 28 days, or 5× the half-life, whichever is longer
after the subject’s last dose, or until resolution, whichever comes first.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

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
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
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
STUDY-SPECIFIC ADVERSE EVENTS
The study-specific events, including, cataplexy, potential cataplexy, convulsion, fall, and
seizure, should always be considered adverse events and reported on the Adverse Event CRF 
and on the event-specific CRFs designed to collect additional information on specific events.
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 3) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study (Core Study).
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the Screening, Baseline, and Titration Periods 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.  Local laboratories will perform tests to qualify 
subjects for entry into the study.  Laboratory certification as available will be included in the 
final clinical study report for this study.
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A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.5
VITAL SIGNS, HEIGHT, AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3) 
by a validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  Height is measured once at Screening.
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in 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) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
Columbia-Suicide Severity Rating Scale
The C-SSRS assesses an individual’s degree of suicidality, including both suicidal ideation 
and suicidal behavior.  Suicidality will be assessed as designated in the Schedule of 
Procedures and Assessments (Table 3), using a site-administered version of the C-SSRS 
(Posner, et al., 2011).  
Pregnancy Test
A urine pregnancy test or serum pregnancy test will be performed for premenopausal women 
and postmenopausal women who have been amenorrheic for less than 12 months as 
designated in the Schedule of Procedures/Assessments (Table 3).
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Urine Drug Test
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 3).  This sample will be tested for common 
drugs of use/abuse: eg, propoxyphene, cocaine metabolites, cannabinoids, methadone, 
phencyclidine (PCP), opiates, benzodiazepines, barbiturates, and amphetamines.
9.5.2
Schedule of Procedures/Assessments – Core Study
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments for the Core Study.
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0g
2
6
Procedures/Assessments
Demography
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Sleep Drug History Questionnaire
X
Sleep Disorder Screening Batteryg
X
Insomnia Severity Index
X
X
X
X
X
X
C-SSRS
X
Xh
X
X
X
X
X
Medical, sleep, psychiatric history
X
Prior and concomitant medications
X
X
X
X
X
X
X
Dispense study drug
X
X
Retrieve unused study drug
X
X
Study drug compliance
X
X
X
Physical examinationi
X
X
X
X
X
X
X
Vital signs and weight
X
X
X
X
X
X
X
Height
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0g
2
6
Procedures/Assessments
Clinical laboratory testsj
X
X
X
X
X
Urine drug screenk
X
X
X
X
X
X
Urine pregnancy testl
X
X
X
X
X
X
Serum pregnancy testl,m
X
X
12-lead ECGn
X
X
X
X
X
X
PGI-Io
X
Xh
X
X
X
X
Quality of Sleep Ratingo
X
Xh
X
X
X
X
Sleep Drug Experience Interview -
zolpidem
X
X
X
Sleep Drug Experience Interview -
lemborexant
X
Adverse eventsp
X
X
X
X
X
X
X
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Table 3
Schedule of Procedures and Assessments in E2006-A001-312 – Core Study
Phase
Pretreatment
Treatment
Period
Screening
Baseline
Titration
Follow-Upa
Visit
1
2ab
2bb
3c
E
Td,e
UNSe,f
Week -3 (Days -
21 to -1)
-
0g
2
6
Procedures/Assessments
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram, PGI-I = Patient Global Impression – Insomnia, T = Termination Visit, UNS = Unscheduled Visits
All visits to be done within ±7 days of the schedule, except for Visits 2, 3 and 4, which must be done within ±3 days.
a:
The Follow-up Visit will be conducted 4 weeks after the End of Study Visit for subjects who completed the Titration Period but do not enter the Extension Phase.
b:
Subjects will return to clinic at the end of the Screening Period.  The Baseline Period will occur on the same day for subjects who remain eligible for study enrollment. 
Assessments conducted at the end of the Screening Period (V2a) will serve as the assessments for the Baseline Period (V2b) if a subject is enrolled into the Treatment Phase. 
Assessments to be conducted at Baseline (but which are not done at V2a) will include clinical laboratory tests and dispensing of study drug.
c:
This visit will represent the End of Study Visit for subjects who completed the Titration Period but are not entering the Extension Phase.  Subjects should otherwise enter the 
Extension Phase immediately after completion of the Titration Period of the Core Study, in which case this visit will also serve as the first visit of the Extension Phase.
d:
Subjects who discontinue study drug prematurely at any time after entering the Treatment Phase will be encouraged to return to the site as soon as practicable (preferably 
within 7 days) to complete the Early Termination Visit.
e:
ECG will only be done during Early Termination and Unscheduled Visits if the results from the previous visit were deemed to be clinically significant by the investigator.
f:
Assessments during Unscheduled Visits will be conducted at the discretion of the investigator.
g:
Sleep Disorders Screening Battery comprises: STOP Bang and International Restless Legs Scale.
h:
Data for Visit 2a will represent the Baseline Period (V2b) assessment if the subject is enrolled.
i:
A full physical examination will be conducted at Visit 1. A brief physical examination will be conducted at Visit 2a, Visit 2b, Visit 3, and at the Follow-up Visit. For Early 
Termination and Unscheduled Visits, a physical examination will be conducted at the discretion of the investigator.
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
k:
Urine drug test at Unscheduled Visits will be conducted at the discretion of the investigator and at Early Termination only for subjects who withdraw because of an adverse 
event.
l:
Female subjects of child-bearing potential only.
m:
To be conducted at Visit 1, and if urine pregnancy testing is positive.
n:
The ECG should be repeated if a clinically significant (as determined by the investigator) abnormality is observed.
o:
From the beginning of the Pretreatment Phase to the end of the Treatment Phase, and provided an insomnia drug was taken the night prior, PGI-I and Sleep Quality Rating 
data will be entered into the electronic data capture system by the subject. 
p:
At each visit, subjects will be asked whether they have had a fall since the previous visit.  If yes, supplemental information must be obtained to support a narrative for the 
event, per Section 9.5.1.5, Adjudication Committee.
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Table 5 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 3.
9.5.3
Appropriateness of Measurements
The clinical assessments are standard measurements commonly used in studies of drugs for 
the treatment of subjects with insomnia.
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. Because the objectives of this study include assessing the 
response to lemborexant of nighttime sleep and daytime impairment complaints, the ISI will 
be evaluated for changes from baseline.
The PGI-I has been used in studies evaluating the impact of treatment for insomnia on the 
patients’ global perceptions of sleep quality and quality of life.
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.  
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 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase, after the subject’s last dose.  All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator 
to be related to the study treatment or any protocol-required procedure should be reported to 
the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
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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 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the 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 a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, 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 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
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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
Study-specific events—cataplexy, potential cataplexy, convulsion, fall, seizure—should 
always be considered as serious important medical events and be entered on the Adverse 
Event CRF and reported using the procedures detailed in Reporting of Serious Adverse 
Events (Section 9.5.4.1), even if the study-specific event does not meet other serious criteria.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
Not applicable.
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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 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early termination procedures indicated in 
the Schedule of Procedures/Assessments (Table 3).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic response, 
withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In addition to the 
primary reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event CRF.
Sites will be assessed for the appropriateness of study drug storage and retrieval at the time 
of site selection.  Required policies and procedures will be clearly communicated to the site 
to assess the site’s capabilities and adherence to storage, dispensing, reconciliation, and 
retention of study drug.
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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.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and a snapshot of the database is obtained and released) and randomization codes 
have been released.  Statistical analyses will be performed using SAS software or other 
validated statistical software as required.  The study endpoints for efficacy and safety will 
presented by treatment group (LEM5 and LEM10) and by pooling across treatments within 
each cohort and overall.  Missing data will not be imputed. Further details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of the Core Study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database lock.
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9.7.1.1
Study Endpoints
This study is designed to reflect clinical practice, in which patient satisfaction of the 
treatment after switching is an important consideration for maintaining a patient on that 
treatment.  This was the basis for defining the outcome of transition to lemborexant.  While 
sleep quality assessments are included as secondary outcomes in this pilot study to 
supplement the Phase 3 clinical trial data, it is not necessary to establish the absolute amount 
of improvement in sleep parameters, but rather whether the subject is satisfied enough to 
continue treatment with lemborexant.   
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of overall subjects who transition to LEM at the end 
of the Titration Period.
Transition to LEM is defined as a subject who remains on LEM at the end of the 2-week 
Titration Period and either 1) enters the Extension Phase, or 2) chooses to not enter the 
Extension Phase for reasons not related to LEM (including, but not limited to, time 
commitment related to the study, study-related travel expenses or preference to continue 
insomnia management with another health care provider).
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are as follows:

The proportion of subjects who transition to LEM at the end of the 2-week Titration 
Period within each Cohort.

The proportion of subjects with positive medication effect rating on each PGI-I item at 
the end of the 2-week Titration Period by Cohort and overall using end of the Titration 
Period treatment.

The change from Baseline in mean ISI score at the end of the Titration Period by Cohort 
and overall using end of the Titration Period treatment.

The proportion of subjects in the LEM5 treatment groups with dose increasing to 
LEM10 at the end of the Titration Period by Cohort and overall.

The proportion of subjects in LEM10 treatment group with dose decreasing to LEM5 at 
the end of the Titration Period in Cohort 2.

The change from baseline in mean Quality of Sleep Rating at the end of the Titration 
Period by cohort and overall using end of the Titration Period treatment.
9.7.1.2
Definitions of Analysis Sets
Safety Analysis Set (SAS) – The SAS is the group of subjects who received at least 1 dose of 
study drug and had at least 1 postdose safety assessment.
Full Analysis Set (FAS) – All subjects who received at least 1 dose of LEM will be included 
in the FAS.
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9.7.1.3
Subject Disposition
The number of subjects screened and the number failing screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects in each of the study populations will also be 
presented.
The number of subjects completing the study will be presented.  Subjects who prematurely 
terminated their participation in the study will be summarized by their primary reason for 
study termination and treatment discontinuation.  Other reasons for study treatment and study 
terminations will also be summarized.  These tabulations will be produced for all randomized 
subjects by randomized treatment groups.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each randomized and end of the Titration Period treatment groups 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 
(<18.5, 18.5 to <25, 25 to ≥30), race, and ethnicity.
Characteristics of insomnia at Study Baseline will be summarized using ISI, PGI-I, and 
Quality of Sleep Rating. 
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 WHO Drug Global March 2019 or later. The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by randomized treatment group, Anatomical Therapeutic Chemical 
(ATC) class, and WHO-DD PT.  
9.7.1.6
Efficacy Analyses
All efficacy analyses will be conducted on the FAS.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS

The proportion of overall subjects who transition to LEM after 2 weeks of treatment in 
the Titration Period will be displayed.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The secondary analyses are as follows:

The proportion of subjects who transition to LEM after 2 weeks of treatment in the 
Titration Period will be displayed within each cohort.  
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
Proportion of subjects in each of the 4 items of the PGI-I will be summarized separately 
within each scale over time by Cohort and overall using end of the Titration Period dose 
groups. 

The proportion of subjects whose response on the first 3 items of the PGI-I (medication 
effect) was neutral or negative at Baseline, but who recorded a positive effect on these 
items at the end of the Titration Period, and the proportion of subjects who rated the drug 
as being too strong or too weak at Baseline, but whose rating was “just right” at the end 
of the Titration Period (as data allow) will be reported.

Change from Baseline of the total score from items 1 to 7 as well as items 4 to 7 on the 
ISI will be summarized at the end of the Titration Period by Cohort and overall using end 
of the Titration Period dose groups.

The proportion of subjects in LEM5 who increased the dose to LEM10 at the end of the 
Titration Period by Cohort and overall.

The proportion of subjects in LEM10 who decreased the dose to LEM5 at the end of the 
Titration Period will be displayed in Cohort 2.  A graphical representation of changes 
between the 5 and 10 mg dose groups in each of the cohorts may also be presented.

The change from baseline in mean Quality of Sleep Rating score for subjects at the end of 
the Titration Period will be summarized by cohort and overall using end of Titration 
Period dose groups.
Primary and Secondary endpoints may be analyzed by modeling methods if warranted.  
Details of all of the analyses will be specified in the Statistical Analysis Plan.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
Not applicable.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
end of Titration Period dose groups, will be summarized on an “as treated” basis using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables).  Safety variables include TEAEs,
physical examination, clinical laboratory parameters, vital signs, 12-lead ECG results, and 
the C-SSRS.  Study Day 1 for all safety analyses will be defined as the date of the first dose 
of study drug.  
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
AEs summaries, and abnormal findings will also be displayed based on the dose that the 
subjects were taking at the time of the findings.
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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.  
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 22.0 or higher) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA PT and primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
Adverse events will be summarized using the Safety Analysis Set.  The incidence of AEs will 
be summarized by end of Titration Period dose for Cohort 1 (Intermittent ZOL use) and 
Cohort 2 (Frequent ZOL use) using descriptive statistics.  To obtain the incidence (%), the 
number of subjects with at least 1 event and the percentage of subjects with AEs by SOC and 
by PT will be calculated.  Incidence (%) by causal relationship with study drug and by 
severity will also be calculated.  For clinically significant events, time of onset, and recovery 
will be reported.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
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The number (percentage) of subjects with treatment-emergent serious adverse events (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 a Customized MedDRA Query (CMQ) PT as cataplexy-related 
events, as well drug abuse liability will be summarized separately.  The number of 
adjudicated events based on the report of the Adjudication Committee will also reported 
separately.  In addition, 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, as per the Adjudication Committee description.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.4, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and end of Titration Period dose using 
descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.4 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs). Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter 
high and in the laboratory parameter low categories, as applicable.
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9.7.1.8.4
VITAL SIGNS
Mean changes from baseline in vital signs (ie, systolic and diastolic BP, pulse, respiratory 
rate, body temperature, weight) and out-of-range vital signs will be summarized by end of 
Titration Period dose groups for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent
ZOL use) using descriptive statistics.
Vital sign values will be listed.  Clinically notable vital sign values will be identified on the 
listings as those above (H) or below (L) a clinically notable range (Table 4).  Categorical 
analyses of subjects (number and percent) who fall outside the below clinically notable vital 
sign ranges will also be presented for change from Study Baseline (Safety Analysis Set), by 
end of Titration Period dose and time point.
Table 4
Clinically Notable Vital Sign Criteria
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
ECG assessments will be performed at Screening and at the end of the Titration Period.  The 
incidence of abnormal ECG findings will be summarized by end of Titration Period dose for 
Cohort 1 (Intermittent ZOL Use) and Cohort 2 (Frequent ZOL Use) using descriptive 
statistics.  Shift tables will present changes from baseline in ECG interpretation (categorized 
as normal and abnormal) by time point.
9.7.1.8.6
OTHER SAFETY ANALYSES
The results of C-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.
9.7.2
Determination of Sample Size
As a pilot study, sample size estimates are not based on statistical calculations. 
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This study will enroll 60 subjects across 3 treatment arms (Cohort 1, Cohort 2A, and Cohort 
2B) to evaluate the proportion of subjects who  transition to LEM as a substitute for ZOL.  
Twenty subjects will be assigned to Cohort 1 (Intermittent ZOL Use), and 40 subjects will be 
assigned to Cohort 2 (Frequent ZOL Use), with approximately 20 subjects randomized to 
receive LEM5 or LEM10 within Cohort 2.  This sample size is deemed sufficient to inform 
whether the proposed strategies are sufficient to determine whether alternative strategies 
would be required to help understand how best to recommend safe and effective methods for 
transitioning from ZOL to LEM.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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Irish LA, Kline CE, Gunn HE, Buysse DJ, Hall MH.  The role of sleep hygiene in promoting 
public health: A review of empirical evidence. Sleep Med Rev.  2015(22):23–36.
Krystal AD, Edinger JD. Sleep Med. Measuring sleep quality.  2008;9(Suppl 1):S10-7.
Kyle SD, Miller CB, Rogers Z, Siriwardena AN, MacMahon KM, Espie CA.  Sleep 
restriction therapy for insomnia is associated with reduced objective total sleep time, 
increased daytime somnolence, and objectively impaired vigilance: implications for the 
clinical management of insomnia disorder. Sleep.  2014;37(2):229–37.
Morgenthaler T, Kramer M; Alessi C, Friedman L, Boehlecke B, Brown T, et al.  Practice 
parameters for the psychological and behavioral treatment of insomnia: an update.  An 
American Academy of Sleep Medicine report. Sleep.  2006;29(11):1415–19.
Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a 
dual orexin receptor antagonist (DORA) for the treatment of insomnia disorder:  results from 
a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin Sleep Med. 
2017;13:1289–99.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The 
Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77.
Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, et al.  Oral 
nonprescription treatment for insomnia: an evaluation of products with limited evidence.  J 
Clin Sleep Med. 2005 Apr 15;1(02):173–87.
Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M.  Clinical guideline for the 
evaluation and management of chronic insomnia in adults.  J Clin Sleep Med.
2008;4(5):487–504.
Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL.  Clinical practice guideline for 
the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep 
Medicine clinical practice guideline, J Clin Sleep Med, 2017;13(2): 307-49.
Stepanski EJ, Wyatt JK.  Use of sleep hygiene in the treatment of insomnia.  Sleep Med Rev.
2003 Jun 1;7(3):215–25.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB 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 detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts

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 Interactive Voice/Web Response 
System (IxRS), x-rays, and other imaging reports (eg, sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation)

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

Electronic Patient-Reported Outcome by self-reported measures
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
The efficacy assessments are evaluated based on the data entered into electronic Patient-
Reported Outcome.  The applicable data are input directly by each subject from the 
viewpoint of his/her health condition without the interpretation of the investigator. 
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
The data collected by electronic Patient-Reported Outcome are also considered source data.  
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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or designated contractor, or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
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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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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 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; 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
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 

gamma-aminobutyric acid (GABA)
analogues 

Hydantoins 

Phenyltriazines
Antihistamines (centrally-acting H1, including 
over-the-counter [OTC]) 

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

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
Moderate CYP3A inhibitors 

Amprenavir

Aprepitant

Atazanavir

Casopitant

Cimetidine

Ciprofloxacin

Clotrimazole

Crizotinib

Cyclosporin

Darunavir

Dronadarone

Erythromycin

Faldaprevir

Fluconazole

Fluvoxamine

Imatinib

Netupitant

Tofisopam

Verapamil
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Category
Medication
Cytochrome P450 (CYP)3A inducers

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

-
Monoamine oxidase inhibitors (MAOIs)

-
Opioid Analgesics

-
Muscle relaxants (centrally-acting) with known sedating 
effects

GABA analogues 

Hydantoins 

Phenyltriazines
Other

Warfarin, heparin, ticlopidine

Systemic isoretinoin

Systemic glucocorticoids
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Appendix 3
Extension Phase
Study Design and Plan
The Extension Phase comprises a Maintenance Period of up to 12 weeks in duration, and a 
Follow-up Period visit that is to occur 4 weeks after the end of the Maintenance Period.
Maintenance Period
During the 12-week Maintenance Period, subjects will continue on the dose of Lemborexant 
(LEM) that they took at the end of the Titration Period.  Subjects will subsequently return to 
clinic at the visit as specified in the Schedule of Assessments, and will be instructed to return 
their supply of LEM at each visit.  Unused study drug will be collected, and study drug 
compliance will be assessed. Subjects will be able to discuss changing the dose of LEM at 
any time during the Maintenance Period, and LEM dose changes may be implemented as 
clinically determined by the investigator with input from the subject.
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for all 
subjects (eg, 4 weeks after the end of the Maintenance Period).
End of Study
The end of the study will be the date of the last study visit for the last subject in the study.  
Study Drug Supplies
Subjects will enter the Extension Phase from the Titration Phase of the Core Study, taking 
the same dose of LEM that was their final dose of the Titration Phase, ie, LEM5 or LEM10 
taken orally in tablet form at night a few minutes before the time the subject intends to try to 
sleep.
Schedule of Procedures/Assessments
Table 5 presents the Schedule of Procedures and Assessments for the 12-week Extension 
Phase.
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 - Extension
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS
X
X
X
X
Prior and concomitant medications
X
X
X
X
Study drug compliance
X
X
X
Dispense study drug
Retrieve unused study drug
X
X
X
Physical examinatione
X
X
X
X
Vital signs and weight
X
X
X
X
Clinical laboratory testsf
X
X
X
Urine drug screeng
X
X
X
Urine pregnancy testh
X
X
X
Serum pregnancy testh,i
X
12-Lead ECGj
X
X
X
Adverse eventsk
X
X
X
X
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Table 5
Schedule of Procedures and Assessments in Study E2006-A001-312 - Extension
Phase
Extension
Period
Maintenance
Follow-upa
Visit
4
5
Early Terminationb,c
Unscheduledc, d
Week
14
18
Procedures/Assessments
C-SSRS = Columbia-Suicide Severity Rating Score, ECG = electrocardiogram.
All visits to be done within ±7 days of the schedule.
a:
The Follow-up Visit will be conducted 4 weeks after the end of the Extension Phase.
b:
Subjects who discontinue study drug prematurely at any time after entering the Extension will be encouraged to return to the site as soon as practicable 
(preferably within 7 days).
c:
During Early Termination and unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the 
investigator.
d:
Assessments during an Unscheduled Visit to be conducted at the discretion of the investigator.
e:
A full physical examination will be conducted at Visit 4 and 5 and at the Early Termination and Unscheduled Visit at the discretion of the investigator.
f:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis. 
g:
Urine drug test to be conducted at Unscheduled Visits at the discretion of the investigator and at Early Termination only for subjects who withdraw because of 
an adverse event. 
h:
Female subjects of child-bearing potential only. 
i:
To be conducted if urine pregnancy testing is positive
j:
The ECG should be repeated if a clinically significant abnormality (as determined by the investigator) is observed.
k:
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 9.5.1.5, Adjudication Committee
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Clinical Study Protocol
E2006-A001-312
Eisai
FINAL (V1):  12 Apr 2019 
Confidential
Page 75 of 77
Statistical Analyses
All statistical analyses will be the responsibility of the Biostatistics Department of Eisai.  
Statistical programming and analyses will be performed using SAS or other validated 
software. 
Safety Analyses
The primary focus of data summarization for the Extension Phase will be on safety and 
tolerability.  Evaluations of safety data will be performed on the Safety Analysis Set.
The incidence of AEs, out-of-normal-range laboratory test variables, abnormal ECG 
findings, out-of-range vital signs, and suicidality (C-SSRS) findings, along with changes 
from baseline in clinical laboratory variables, and vital signs will be summarized by modal 
dose for Cohort 1 (Intermittent ZOL use) and Cohort 2 (Frequent ZOL use) using descriptive 
statistics.
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Clinical Study Protocol
E2006-A001-312
Eisai
FINAL (V1):  12 Apr 2019 
Confidential
Page 76 of 77
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product 
Name:
E2006\Lemborexant
IND Number:
111871
SIGNATURES
Authors:
Eisai, Inc
Date
Eisai Inc.
Date
Page 326 of 327
PPD
PPD

Clinical Study Protocol
E2006-A001-312
Eisai
FINAL (V1):  12 Apr 2019 
Confidential
Page 77 of 77
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-312
Study Protocol Title:
A Multicenter, Pilot Study to Evaluate Next-Dose Transition 
from Zolpidem to Lemborexant for the Treatment of Insomnia
Investigational Product
Name:
E2006\Lemborexant
IND Number:
111871
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
Page 327 of 327