Conditions: Hepatic Impairment
Keywords: mild hepatic impairment moderate hepatic impairment lemborexant healthy participants metabolites E2006 pharmacokinetics
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
This study will be conducted to assess the effect of mild and moderate hepatic impairment on the pharmacokinetics (PK) of lemborexant after a single-dose administration.

Detailed description:

Arms:
arm 1: Participants with mild hepatic impairment will receive a single 10 milligram (mg) dose (1 × 10 mg lemborexant \[E2006\] tablet) in the morning with 240 milliliters (mL) of water following an overnight fast of at least 10 hours. arm 2: Participants with moderate hepatic impairment will receive a single 10 mg dose (1 × 10 mg lemborexant \[E2006\] tablet) in the morning with 240 mL of water following an overnight fast of at least 10 hours. arm 3: Healthy participants matched to participants with hepatic impairment in Cohorts A and B (matched with regards to age, sex, body mass index \[BMI\]) will receive a single 10 mg dose (1 × 10 mg lemborexant \[E2006\] tablet) in the morning with 240 mL of water following an overnight fast of at least 10 hours.

Interventions: intervention 1: Lemborexant
Intervention descriptions: intervention 1: oral tablet

Protocol document:
Prot_002.pdf: 
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Revision History 
Previous Version:  v1.0
Current Version:  v2.0
Date of Latest Revision: 28 Feb 2018 (revised per Amendment 01)
Change
Rationale
Affected Protocol Sections
Remove alpha-1-glycoprotein 
(AGP) testing.
Test is not required and was 
included in error. 
•
Section 4
•
Section 9.5.1.5.3 (Table 3)
•
Section 9.5.2.1
(Table 4)
Add creatinine testing
Test is required and was not 
included in error. 
•
Section 9.5.1.5.3 (Table 3)
•
Section 9.5.2.1
(Table 4)
Added Adjudication Committee 
information
Correction
•
Synopsis
•
Section 9.2
Revised serious adverse event 
(SAE) reporting time period
To comply with internal and 
regulatory standards
•
Section 9.5.4.1
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2006-A001-104
Study Protocol 
Title:
An 
Open-label, 
Parallel-Group 
Study 
to 
Evaluate 
the 
Pharmacokinetics of Lemborexant (E2006) and its Metabolites in 
Subjects with Mild and Moderate Hepatic Impairment Compared to 
Healthy Subjects
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Investigational 
Product Name:
E2006/Lemborexant
Indication:
Not applicable
Phase:
1
Approval Date:
V1.0
29 Dec 2017 (original protocol)
V2.0
28 Feb 2018 (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/lemborexant
Name of Active Ingredient
(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-
yl)cyclopropanecarboxamide
Study Protocol Title
An Open-label, Parallel-Group Study to Evaluate the Pharmacokinetics of Lemborexant  (E2006) and its 
Metabolites in Subjects with Mild and Moderate Hepatic Impairment Compared to Healthy Subjects
Investigators
Thomas C. Marbury, MD (Orlando Clinical Research Center)
Kenneth C. Lasseter, MD (Clinical Pharmacology of Miami, LLC., Evolution Research Group)
Sites
Up to 4 sites
Study Period 
The total study duration from the first subject enrolled (screened) to the last subject’s last visit/last assessment 
will be approximately 17 weeks.
Phase of Development
Phase 1
Objectives
Primary Objective
The primary objective is to assess the effect of mild and moderate hepatic impairment on the pharmacokinetics 
(PK) of lemborexant after a single dose administration.
Secondary Objectives
•
To evaluate the effects of hepatic impairment on the PK of lemborexant metabolites M4, M9, and M10.
•
To evaluate the relationship between the PK parameters of lemborexant and its metabolites and the 
Child-Pugh Classification score, serum albumin, total bilirubin, and prothrombin time.
•
To assess safety and tolerability of lemborexant following a single dose administration in subjects with
mild and moderate hepatic impairment and in healthy subjects.
Exploratory Objectives
•
To explore the relationship between the PK parameters of lemborexant and its metabolites and the model 
of end stage liver disease (MELD) score.
Study Design
This is a multicenter, single dose, open-label, parallel-group study in subjects with mild and moderate hepatic 
impairment and matched (with regard to age [±10 years], sex, and body mass index [BMI, ±20%]) healthy 
control subjects. The study will enroll a total of 24 subjects, including 16 subjects with impaired hepatic 
function; 8 subjects each in Child-Pugh class A (mild) and B (moderate).  Approximately 8 healthy subjects 
will be dosed as one control group to match (1:1) to the subjects with hepatic impairment in each Child-Pugh 
class with regard to age, sex, and BMI. 
The study will consist of 2 phases: Prerandomization and Treatment.  The Prerandomization Phase will 
include 2 study periods; Screening and Baseline (Day -1). The subjects will be admitted to the clinical facility 
on Day -1, remain confined to the clinic until Day 8, and then return to the clinical facility for additional PK 
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sampling as outpatients until Day 14. In the event of early discontinuation of the subjects, the subjects with 
Child Pugh Class A and B (Cohorts A and B) and the matched controls (Cohort C) may be replaced.
On Day 1, the subjects will be administered a single 10-mg dose of lemborexant with approximately 240 mL 
of water in the morning after an overnight fast.  The blood samples for PK assessments will be collected at 
prespecified intervals up to 312 hours postdose administration.  The subjects will be discharged on Day 14 of 
the study.  In addition, the blood samples for plasma protein binding assessments of lemborexant will be 
collected from each subject at 2 time points; approximately 1 hour and 24 hours postdose.
Adjudication Committee (revised per Amendment 01)
An independent Adjudication Committee will be employed at intervals to review, in a blinded manner, AEs 
that could potentially be considered cataplexy or seizure. A set of preferred terms constituting a customized 
Medical Dictionary for Regulatory Activities (MedDRA) query for cataplexy or seizure will be used to 
identify events for adjudication (including cataplexy, muscle fatigue, muscular weakness, muscle tone 
disorder, hypotonia, drop attacks, slurred speech, diplopia, falls, convulsions [standardized MedDRA query 
(SMQ) narrow and broad], atypical migraine, loss of consciousness, decreased consciousness, myoclonus, 
syncope, transient global amnesia, lipothymia, [faintness] and transient ischemic attack). To assist in the 
preparation of narratives about such events and to support the committee’s adjudication process, investigators 
and site staff will be instructed to query subjects who report any of the above events for supplemental 
information using a questionnaire for events potentially related to cataplexy and the serious adverse event 
(SAE) form for any of the above events considered serious.
Number of Subjects
A total of 24 subjects will be enrolled in the following 3 cohorts:
Cohort A:  8 subjects with mild hepatic impairment (Child Pugh Class A)
Cohort B: 8 subjects with moderate hepatic impairment (Child Pugh Class B)
Cohort C:  At least 8 healthy subjects (control) matched to subjects in Cohorts A and  B
Inclusion Criteria
Inclusion Criteria for All Subjects
Subjects who meet all of the following inclusion criteria will be eligible for participation in the study.
1.
Male or female subjects, ages 18 to 79, inclusive, at the time of informed consent.
2.
BMI between 18 and 40 kg/m2, inclusive, at Screening.
3.
Voluntary agreement to provide written informed consent, and the willingness and ability to comply 
with all aspects of the protocol.
4.
Nonsmokers or smokers who smoke 20 cigarettes or less per day.
5.
For Cohorts A and B:  stable (without any change in disease status for at least 60 days prior to study 
screening) hepatic impairment conforming to Child-Pugh classification A or B, respectively (see the 
following tables) and documented by medical history and a physical examination. 
6.
For Cohort C: healthy subjects matched to subjects with hepatic impairment with regard to age 
(±10 years), sex, and BMI (±20%), and as determined by no clinically significant deviation from 
normal in medical history, physical examination, electrocardiogram (ECG), and clinical laboratory 
determinations.
Criteria for Child-Pugh Classification
Points Scored for Observed Findings
Clinical or Biochemical 
Assessments
1
2
3
Albumin (g/dL)
>3.5
2.8 – 3.5
<2.8
Bilirubin (mg/dL)
<2
2 – 3
>3
PT (seconds prolonged)
<4
4 – 6
>6
    or INR
<1.7
1.7 – 2.3
>2.3
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Ascites
None
Mild/Moderate 
(diuretic-responsive)
Tense 
(diuretic-refractory)
Encephalopathya
None
1 or 2 ( or precipitant-induced)
3 or 4 (chronic)
      cps=cycle per second; INR=international normalized ratio; PT=prothrombin time
a:  Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram;  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, and 5 cps waves;  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves;  Grade 3: 
somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves;  Grade 4: 
unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
Child-Pugh Classification Scoring
Total Points
Child-Pugh Class
5 – 6
A
7 – 9
B
Exclusion Criteria
Exclusion Criteria for All Subjects
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent 
units of ß-hCG).  A separate baseline assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the dose of study drug.
2.
Females of childbearing potential who did not use a highly effective method of contraception (as 
described below) within 28 days before study entry, or who do not agree to use an approved method 
of contraception from 28 days before study entry, throughout the entire study period, and for 28 days 
after study drug discontinuation.  Approved (highly effective) methods of contraception for this study 
include at least one of the following:

Total abstinence (if it is their preferred and usual lifestyle)

An intrauterine device or intrauterine hormone-releasing system (IUS)

A double-barrier method of contraception such as condom plus diaphragm with spermicide

A contraceptive implant

An oral contraceptive (with additional barrier method). 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. 

Have a vasectomized partner with confirmed azoospermia.
(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.
Known to be positive for human immunodeficiency virus (HIV).
4.
Currently enrolled in another clinical study or used any investigational drug or device within 4 weeks, 
or 5 times the half-life of the investigational drug (whichever is longer), preceding informed consent.
5.
Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of 
plasma within 1 week of dosing until study discharge.
6.
Intake of herbal preparations containing St. John’s Wort within 4 weeks prior to dosing until study 
discharge.
7.
Intake of nutritional supplements (including herbal preparations), foods or beverages that may affect 
CYP3A enzyme (eg, alcohol, grapefruit, grapefruit juice, grapefruit-containing beverages, apple or 
orange juice, vegetables from the mustard green family [eg, kale, broccoli, watercress, collard greens, 
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kohlrabi, Brussels sprouts, mustard] and charbroiled meats) within 1 week before dosing until study 
discharge.
8.
Intake of beverages, food, or other products that contain caffeine from 24 hours before until 48 hours 
after dosing with lemborexant. 
9.
Engagement in strenuous exercise (eg, moving large bulky items, bodybuilding) within 2 weeks prior 
to check-in until study discharge.
10. History of clinically significant drug or food allergies, or is presently experiencing significant 
seasonal allergies.
11. A prolonged QT/QTc interval (QTc >480 ms) demonstrated on ECG at Screening or Baseline 
(Day -1).
12. Any major surgery within 4 weeks of study drug administration.
13. Any history of abdominal surgery that may affect PK of lemborexant (eg, hepatectomy, nephrectomy, 
digestive organ resection). 
14. Inability to tolerate oral medication.
15. Inability to tolerate venous access and/or venipuncture. 
16. Unwilling to abide by the study requirements, or in the opinion of the investigator, is not likely to 
complete the study.
Additional Exclusion Criteria for Hepatically Impaired Subjects (Cohorts A and B)
In addition to the Exclusion Criteria above for All Subjects, other standard exclusion criteria for subjects with 
hepatic impairment will be used. These include:
17. Any significant acute medical illness (such as new conditions or exacerbation of pre-existing
conditions) within 8 weeks of dosing.
18. Medical conditions which are not adequately and stably controlled on stable doses of medications or 
which, in the clinical opinion of the Principal Investigator, may interfere with study procedures or 
subject safety within 4 weeks before dosing (eg, psychiatric disorders and disorders of the 
gastrointestinal tract, kidney, respiratory system, endocrine system, hematological system, 
neurological system, or cardiovascular system, or subjects who have a congenital abnormality in 
metabolism).
19. History of esophageal and gastric variceal bleeding within the past 6 months unless the subject has 
completed a course of endoscopic therapy with the appropriate documentation (eg, endoscopy report) 
of successful ablation of esophageal varices; subjects with esophageal varices may be included if not 
bleeding within the past 6 months or have been treated adequately by ablation therapy, as specified 
above.
20. Spontaneous bacterial peritonitis within 3 months of dosing.
21. Treatment with plasmapheresis within 6 months of dosing.
22. Primarily cholestatic liver diseases (eg, primary biliary cirrhosis or primary sclerosing cholangitis).
23. Current or recent (within 3 months prior to screening) history of significant gastrointestinal disease 
other than that secondary to hepatic impairment.
24. Autoimmune liver disease.
25. Active alcoholic hepatitis determined either clinically or by histology.
26. History of hepatoma or metastatic disease of the liver.
27. Presence of severe ascites or edema.
28. Presence of hepatopulmonary syndrome or hydrothorax, or hepatorenal syndrome.
29. Known significant bleeding diathesis that could preclude multiple venipunctures (INR >2.5).
30. Creatinine clearance <60 mL/min at Screening or Baseline as calculated using Cockroft and Gault 
Equation. 
31. The subject’s standard therapy/concomitant medication for diseases related to cirrhosis has 
not remained stable/unchanged for at least 14 days before the first dose of study drug.
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32. History of drug or alcohol dependency or abuse within 4 weeks prior to Screening, or those who have 
a positive urine drug test or breath alcohol test at Screening or Baseline unless a prescribed 
medication for the underlying condition is the cause of the positive urine screen.
Additional Exclusion Criteria for Healthy Subjects (Cohort C)
In addition to the Exclusion Criteria for All Subjects, other standard exclusion criteria for healthy subjects in 
Phase 1 studies will be used. These include:
33. Presence of active liver disease, or acute liver injury, as indicated by (1) an abnormal liver function 
test, or (2) clinical or laboratory signs of active viral hepatitis (including B and C as demonstrated by 
positive serology at Screening).   
34. Clinically significant illness, within 4 weeks prior to dosing, that requires medical treatment or  may 
influence the outcome of the study; eg, psychiatric disorders and disorders of the gastrointestinal 
tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, 
or cardiovascular system, or subjects who have a congenital abnormality in metabolism.
35. Any abnormal finding based on physical examination, assessment of vital signs, ECG, or laboratory 
test results that require treatment or clinical follow-up based on the investigator’s opinion.
36. History of drug or alcohol use disorder within the 2 years prior to Screening, or those who have a 
positive urine drug test or breathalyzer alcohol test at Screening or Baseline.
37. Use of any prescription drugs within 4 weeks prior to dosing until study discharge.
38. Intake of any over-the-counter (OTC) medications within 2 weeks prior to dosing until study 
discharge.
Study Treatment
Test drug: Lemborexant (E2006)
All subjects enrolled in the study will receive a single 10-mg dose (1 × 10 mg lemborexant tablet)
Comparator Drug: Not applicable
Duration of Treatment
The study duration per subject will be as follows:
Prerandomization Phase: Up to 21 days
Treatment Phase: 14 days
Concomitant Drug/Therapy/ Lifestyle Restrictions
For all subjects enrolled in the study, any medication or therapy administered during the study will be 
recorded. The following are prohibited for all subjects during the study:

Smokers must not smoke more than 20 cigarettes per day.

Nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the 
various drug metabolizing enzymes and transporters (eg, alcohol, grapefruit, grapefruit juice, grapefruit-
containing beverages, apple or orange juice, vegetables from the mustard green family [eg, kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard], and charbroiled meats) within 1 week 
before dosing until study discharge.

Intake of beverages, food, or other products that contain caffeine from 24 hours before until 48 hours after 
dosing with lemborexant. 

Herbal preparations containing St. John’s Wort within 4 weeks before dosing until study discharge.

Engagement in strenuous exercise is prohibited within 2 weeks before check-in and until study discharge.
For healthy subjects, use of prescription drugs is prohibited from 4 weeks before dosing until study discharge.
Intake of over-the-counter (OTC) medications is prohibited within 2 weeks or 5 half-lives (whichever is 
longer) before dosing until study discharge. A list of prohibited medications is located in the protocol 
appendices.
Subjects with hepatic impairment may receive standard therapy approved by Medical Monitor for diseases 
related to cirrhosis, and the identity, dose, and regimen of such concomitant drugs must be recorded in the 
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CRF. All such concomitant medications should remain unchanged for 14 days before dosing with study drug 
and for the duration of the study. Concomitant medication may not be administered 4 hours before or after 
study drug administration on Day 1. Additionally, concomitant therapy of any agent known to induce or 
inhibit drug metabolizing enzymes is prohibited within 2 weeks before dosing until study discharge. 
A full list of prohibited concomitant medications is located in the protocol appendices.
Assessments
Efficacy Assessments
Not applicable.
Pharmacokinetic Assessments
Blood samples (4 mL each) for PK assessments of lemborexant and its metabolites (M4, M9, and M10) will be 
collected at predose (0 hour), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 216, 264 and 312 hours 
postdose.  In addition, blood samples (12 mL per time point) for protein binding of lemborexant and its 
metabolites (M4, M9 and M10) will be collected at 1 and 24 hours postdose.
Safety Assessments
Safety will be assessed by monitoring and documenting adverse events (AEs), ECGs, vital signs, physical 
examinations, and clinical laboratory tests (urinalysis, hematology, and blood chemistry). Blood samples will 
be collected at Baseline and again if AEs of infection occur, for investigation of suspected infective pathogens.
Bioanalytical Methods
Total plasma concentrations of lemborexant and its main metabolites (M4, M9, and M10) will be measured by 
validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods.  The unbound 
concentrations of lemborexant and its main metabolites will also be measured using a similar validated 
LC-MS/MS method following equilibrium dialysis.
Statistical Methods
Study Endpoints
The endpoints include the following PK parameters derived by non-compartmental analysis using the plasma 
concentration-time data of lemborexant and its metabolites:
Cmax
Maximum plasma concentration
tmax
Time to reach maximum plasma concentration
AUC(0-t)
Area under plasma concentration vs. time curve from time = 0 
to time of last quantifiable concentration 
AUC(0-inf)
Area under plasma concentration vs. time curve from time = 0 
to infinity
t1/2
Terminal phase plasma half-life
CL/F
Apparent total body clearance ( for lemborexant only)
Vz/F
Apparent volume of distribution (for lemborexant only)
AUC Metabolite Ratio
Ratio of AUC(0-inf) of individual metabolite to AUC(0-inf) of 
lemborexant, corrected for molecular weights
fu
Plasma protein unbound fraction
AUCu
AUC(0-inf) values adjusted by unbound fraction in plasma 
(for lemborexant only)
CLu/F
Apparent clearance relative to the unbound plasma concentration 
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based on AUCu (for lemborexant only)
The Cmax, AUC(0-t), and AUC(0-inf) of lemborexant will be the primary PK endpoints.  The rest of the 
parameters, including the PK parameters of the metabolites, will be secondary endpoints.
Analysis Sets
The Safety Analysis Set is the group of subjects who dosed with the test drug and had at least 1 postdose 
safety assessment.
The Pharmacokinetic Analysis Set is the group of subjects who had sufficient PK data to derive at least 1 PK 
parameter.
Efficacy Analyses
Not applicable.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual plasma concentration listings.  The PK Analysis Set will 
be used for summaries of plasma concentrations and for analyses, summaries, and listings of PK parameters.
The effect of hepatic impairment on the PK of lemborexant, the primary PK parameters based on total Cmax, 
AUC(0-t), and AUC(0-inf) will be compared between the cohort of healthy normal controls and the cohorts of 
subjects with mild and moderate hepatic impairment as defined by Child-Pugh classes A or B.  A general 
linear model of logarithmically transformed values with hepatic function class as a fixed effect will be utilized 
to estimate the geometric mean ratio (and two-sided 90% confidence intervals) of subjects with mild/normal 
and moderate/normal hepatic function.  Similar statistical analyses will be conducted for the PK parameters of 
the metabolites and unbound lemborexant as secondary endpoints. Protein binding will be calculated for 
metabolites without any assessment of PK parameters.
Scatter plots of PK parameters of lemborexant and its metabolites versus Child-Pugh Score will be provided.  
The association between the primary PK parameters and Child-Pugh Score will be evaluated by regression 
analysis (the PK parameter as a dependent variable and Child-Pugh Score as an independent variable).  Similar 
analyses will be performed for MELD score, serum albumin, total bilirubin, and PT.  Additionally, association 
between the PK parameters and liver transaminase levels will be performed, if deemed necessary. 
Summary statistics will be generated for each of the PK parameters for each Child-Pugh class and healthy 
controls. 
Safety Analyses
An evaluation of safety will be performed on the Safety Analysis Set.  Safety data that will be evaluated 
include AEs, clinical laboratory results, vital signs, and ECGs.
Treatment-emergent adverse events (TEAEs) will be summarized for each Child-Pugh class and healthy 
controls. Descriptive summary statistics (eg, mean, standard deviation [SD], median, minimum, maximum for 
continuous variables, and number and percent for categorical variables) including shift tables of the laboratory, 
vital signs, ECG parameters. Changes from Baseline for the clinical laboratory, vital signs and ECG 
parameters will be evaluated for each Child-Pugh class and healthy controls by time point.
Interim Analyses
Not applicable. 
Sample Size Rationale
A sample size of 8 subjects per each cohort of mild and moderate hepatic impairment, as defined by 
Child-Pugh classes A or B, is based on the recommendations in regulatory guidelines for a minimum number 
of subjects to be enrolled for moderate liver impairment cohort (FDA, 2003).  Additionally, from single-dose 
studies of the 10-mg tablet (E2006-A001-004, E2006-A001-005, and E2006-A001-008), the pooled 
between-subject standard deviations of logarithmically transformed Cmax and AUC(0-inf) of lemborexant were 
0.334 and 0.391 respectively. With a sample size of 8 subjects in each Child-Pugh category and at least 8 
matched controls, a 2-sided 90% confidence interval (CI) for the ratio for AUC(0-inf) will extend 0.322 from the 
observed mean difference on the log scale.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................10
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................14
5
ETHICS............................................................................................................................16
5.1
Institutional Review Boards/Independent Ethics Committees ..............................16
5.2
Ethical Conduct of the Study.................................................................................16
5.3
Subject Information and Informed Consent...........................................................17
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................17
7
INTRODUCTION ...........................................................................................................17
7.1
Indication ...............................................................................................................17
7.1.1
Lemborexant ................................................................................................18
7.1.1.1
Therapeutic Pathway............................................................................18
7.1.1.2
Clinical Experience With Lemborexant...............................................18
7.2
Study Rationale......................................................................................................20
7.2.1
Study Design................................................................................................20
7.2.2
Assessment of Severity of Liver Impairment ..............................................21
7.2.3
Choice of Dose, Regimen, and PK Assessments.........................................21
8
STUDY OBJECTIVES....................................................................................................22
8.1
Primary Objective..................................................................................................22
8.2
Secondary Objectives.............................................................................................22
8.3
Exploratory Objectives ..........................................................................................23
9
INVESTIGATIONAL PLAN..........................................................................................23
9.1
Overall Study Design and Plan..............................................................................23
9.1.1
Prerandomization Phase...............................................................................23
9.1.1.1
Screening Period..................................................................................24
9.1.1.2
Baseline Period ....................................................................................24
9.1.2
Treatment Phase...........................................................................................24
9.2
Discussion of Study Design, Including Choice of Control Groups.......................24
9.3
Selection of Study Population................................................................................25
9.3.1
Inclusion Criteria .........................................................................................25
9.3.2
Exclusion Criteria ........................................................................................26
9.4
Treatments..............................................................................................................29
9.4.1
Treatments Administered.............................................................................30
9.4.2
Identity of Investigational Product...............................................................30
9.4.2.1
Chemical Name, Structural Formula of E2006....................................30
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9.4.2.2
Comparator Drug .................................................................................30
9.4.2.3
Labeling for Study Drug......................................................................30
9.4.2.4
Storage Conditions...............................................................................30
9.4.3
Method of Assigning Subjects to Treatment Groups...................................30
9.4.4
Selection of Doses in the Study...................................................................31
9.4.5
Selection and Timing of Dose for Each Subject..........................................31
9.4.6
Blinding........................................................................................................31
9.4.7
Prior and Concomitant Therapy...................................................................31
9.4.8
Prohibitions and Restrictions during Study Period......................................32
9.4.8.1
Food and Water....................................................................................32
9.4.8.2
Beverage and Other Restrictions .........................................................33
9.4.8.3
Physical Activity Restrictions..............................................................33
9.4.9
Treatment Compliance.................................................................................33
9.4.10
Drug Supplies and Accountability...............................................................33
9.5
Study Assessments.................................................................................................35
9.5.1
Assessments.................................................................................................35
9.5.1.1
Demography.........................................................................................35
9.5.1.2
Baseline Assessments ..........................................................................35
9.5.1.2.1
Medical History .............................................................................35
9.5.1.2.2
Height and Weight Measurements.................................................35
9.5.1.3
Efficacy Assessments...........................................................................35
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................35
9.5.1.4.1
Pharmacokinetic Assessments .......................................................35
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments...................................................................................36
9.5.1.5
Safety Assessments..............................................................................36
9.5.1.5.1
Adverse Events ..............................................................................36
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................38
9.5.1.5.3
Laboratory Measurements .............................................................39
9.5.1.5.4
Vital Signs and Weight Measurements..........................................40
9.5.1.5.5
Physical Examinations...................................................................40
9.5.1.5.6
Electrocardiograms ........................................................................40
9.5.1.5.7
Viral Tests......................................................................................41
9.5.1.5.8
Pregnancy Test...............................................................................41
9.5.1.5.9
Urine Drug Test .............................................................................41
9.5.1.5.10
Breath Alcohol Test .......................................................................41
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9.5.2
Schedule of Procedures/Assessments ..........................................................41
9.5.2.1
Schedule of Procedures/Assessments ..................................................41
9.5.2.2
Total Volume of Blood Sampling........................................................44
9.5.3
Appropriateness of Measurements...............................................................45
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................45
9.5.4.1
Reporting of Serious Adverse Events..................................................45
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................46
9.5.4.3
Reporting of Events Association with Special Situations....................46
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................46
9.5.4.4
Expedited Reporting ............................................................................47
9.5.4.5
Breaking the Blind...............................................................................47
9.5.4.6
Regulatory Reporting of Adverse Events ............................................47
9.5.5
Completion/Discontinuation of Subjects.....................................................47
9.5.6
Confirmation of Medical Care by Another Physician (for Hepatic 
Impairment Subjects):..................................................................................48
9.6
Data Quality Assurance .........................................................................................48
9.6.1
Data Collection ............................................................................................48
9.6.2
Clinical Data Management ..........................................................................48
9.7
Statistical Methods.................................................................................................48
9.7.1
Statistical and Analytical Plans....................................................................49
9.7.1.1
Study Endpoints...................................................................................49
9.7.1.2
Definitions of Analysis Sets.................................................................49
9.7.1.3
Subject Disposition..............................................................................50
9.7.1.4
Demographic and Other Baseline Characteristics ...............................50
9.7.1.5
Prior and Concomitant Therapy...........................................................50
9.7.1.6
Efficacy Analyses ................................................................................50
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................50
9.7.1.7.1
Pharmacokinetic Analyses.............................................................50
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................51
9.7.1.8
Safety Analyses....................................................................................51
9.7.1.8.1
Extent of Exposure.........................................................................51
9.7.1.8.2
Adverse Events ..............................................................................51
9.7.1.8.3
Laboratory Values..........................................................................52
9.7.1.8.4
Vital Signs......................................................................................52
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9.7.1.8.5
Electrocardiograms ........................................................................52
9.7.2
Determination of Sample Size .....................................................................52
9.7.3
Interim Analysis...........................................................................................53
9.7.4
Other Statistical/Analytical Issues ...............................................................53
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................53
10
REFERENCE LIST .........................................................................................................54
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......55
11.1
Adherence to the Protocol......................................................................................55
11.2
Monitoring Procedures...........................................................................................55
11.3
Recording of Data..................................................................................................56
11.4
Identification of Source Data.................................................................................56
11.5
Retention of Records..............................................................................................56
11.6
Auditing Procedures and Inspection......................................................................57
11.7
Handling of Study Drug.........................................................................................57
11.8
Publication of Results ............................................................................................57
11.9
Disclosure and Confidentiality ..............................................................................58
11.10 Discontinuation of Study .......................................................................................58
11.11 Subject Insurance and Indemnity...........................................................................58
12
APPENDICES .................................................................................................................59
LIST OF IN-TEXT TABLES
Table 1
Criteria for Child-Pugh Classification .......................................................26
Table 2
Child-Pugh Classification Scoring.............................................................26
Table 3
Clinical Laboratory Tests...........................................................................39
Table 4
Schedule of Procedures/Assessments in E2006-A001-104.......................42
Table 5
Blood Sampling Schedule for Pharmacokinetic Assessments...................44
Table 6
Summary of Blood Sample Volumes ........................................................44
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................60
Appendix 2
List of Prohibited Concomitant Medications.............................................62
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under plasma concentration vs. time curve
AUC(0-8h)
area under plasma concentration vs. time curve from time = 0 to 8 hours 
postdose
AUC(0-96h)
area under plasma concentration vs. time curve from time = 0 
to 96 hours postdose 
AUC(0-t)
area under plasma concentration vs. time curve from time = 0 
to time of last quantifiable concentration 
AUCinf
area under plasma concentration vs. time curve from time = 0 
to infinity
AUCu
AUC(0-inf) values adjusted by unbound fraction in plasma 
BA
bioavailability
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CA
competent authority
CFR
Code of Federal Regulations
CI
confidence interval
CLIA
Clinical Laboratory Improvement Amendments
CLu/F
Apparent clearance relative to the unbound plasma concentration 
based on AUCu 
Cmax
maximum drug concentration
CRA
clinical research associate
CRF
case report form
CRO
clinical research organization
CSR
clinical study report
CYP
cytochrome P450
DORA
dual orexin receptor antagonist 
ECG
electrocardiogram
EDTA
ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
fu
Plasma protein unbound fraction
GCP
Good Clinical Practice
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HBsAg
hepatitis B surface antigen 
HCVAb
hepatitis C antibody
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISWRD
Irregular Sleep-Wake Rhythm Disorder 
LC-MS-MS
liquid chromatography with tandem mass spectrometry
LLT
lower level term
LNH
low-normal-high
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model of end stage liver disease 
MHRA
Medicines and Healthcare products Regulatory Agency
OTC
over-the-counter
P-gp
P-glycoprotein
PT
preferred term
RBC
red blood cell
SAD
single ascending dose 
SAE
serious adverse event
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
t1/2
terminal phase plasma half-life
TEAE
treatment-emergent adverse event
tmax
time to reach maximum drug concentration
US
United States
Vz/F
Apparent volume of distribution
WBC
white blood cell 
WCT
Worldwide Clinical Trials
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for
Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) E6 
(Good Clinical Practice), Section 3, and any local regulations.  Any protocol amendment or 
revision to the ICF will be resubmitted to the IRB/IEC for review and approval, except for 
changes involving only logistical or administrative aspects of the study (eg, change in clinical 
research associate [CRA], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC 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.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and competent authority (CA) within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures 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 revised version 
Fortaleza 2013)
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
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•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator or designee must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF 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/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations (eg, Federal Regulations, 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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at up to 4 investigational sites in the United States (US).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are provided to the sites.
7
INTRODUCTION
7.1
Indication
Lemborexant (E2006) is part of the dual orexin receptor antagonist (DORA) class of drugs 
and it is being developed as a treatment of insomnia disorder and for Irregular Sleep-Wake 
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Rhythm Disorder (ISWRD).  Phase 1 and 2 studies in the lemborexant clinical program have 
provided evidence for pharmacological efficacy at safe and well-tolerated doses. 
7.1.1
Lemborexant
The proposed study is an open-label, parallel-group study to evaluate the pharmacokinetics 
(PK) of lemborexant and its metabolites in subjects with normal hepatic function and 
subjects with mild and moderate hepatic impairment.
7.1.1.1
Therapeutic Pathway
Lemborexant (E2006), a dual orexin receptor antagonist, is an Eisai in-house discovered and 
developed small molecule which inhibits orexin by binding competitively to two subtypes of 
orexin receptors (orexin receptor 1 and 2). In individuals with insomnia, it is possible that the 
orexin system, which regulates sleep and wakefulness, is not functioning normally. During 
normal periods of sleep, orexin system activity is suppressed, suggesting it is possible to 
purposefully counteract inappropriate wakefulness and facilitate the initiation and 
maintenance of sleep by interfering with orexin neurotransmission. 
7.1.1.2
Clinical Experience With Lemborexant
To date, a total of 9 Phase 1 studies have been completed, with healthy subjects treated with 
either single or multiple once daily doses for 14 days, and subjects with insomnia disorder 
who were administered single doses of lemborexant.  In addition, a Phase 2 dose-finding 
study in adult and elderly subjects with insomnia disorder demonstrated efficacy and safety 
over a dose range from 1 mg to 25 mg to enable lemborexant to proceed into Phase 3 studies. 
Relevant to the currently proposed study, the tolerability data from the first human study 
suggest that single doses up to 200 mg have been generally well tolerated in healthy adult 
subjects.
Following single oral dose administration, lemborexant generally exhibited linear PK within 
the dose range studied (1 mg to 200 mg), but at doses of 50 mg and above, the increase in the 
maximum drug concentration (Cmax) was less than dose proportional.  Lemborexant exhibits 
approximate dose proportional (based on Cmax and the area under the plasma concentration 
versus time curve [AUC]) PK at steady state on Day 14 following multiple dose 
administrations between 2.5 mg and 75 mg of lemborexant administered once daily.  Oral 
absorption of lemborexant was rapid with peak plasma concentration around 1 to 3 hours 
postdose. 
The terminal half-life was ~45 to 55 hours over a comparable dose range 
following single and multiple dose administration of lemborexant.  Accumulation of 
lemborexant following multiple dosing was lower than predicted by terminal half-life, with 
mean Cmax ranging from 1.21 to 2.39 and an area under the concentration-time curve from 
zero time to 96 hours postdose (AUC[0-96h]) of 1.67 to 3.26 over the dose range. Based on the 
overall drug accumulation, effective half-life of lemborexant ranged from 16.9 to 39.3 hours 
over the dose range.  Exposure (AUC[0-96h]) of the main inactive metabolites (M4, M9, M10) 
relative to lemborexant was 19.9% to 57.5% following multiple dosing at 25 mg for 14 days.  
Additionally, lemborexant exposures were similar between healthy volunteers administered 
lemborexant in the morning compared to otherwise healthy subjects with primary insomnia 
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administered lemborexant in the evening, suggesting that the time of dosing does not affect 
the PK.
Based on in vitro data, lemborexant and its main metabolites (M4, M9, and M10) were 
metabolized via CYP3A as the primary pathway. Coadministration of a single oral dose of 
lemborexant 10 mg and oral itraconazole 200 mg administered once daily (QD) under steady 
state conditions in healthy volunteers resulted in a moderate interaction as evidenced by 
approximately 36% and 3.7-fold increases in lemborexant Cmax and area under the plasma 
concentration versus time curve from time 0 to infinity (AUC[0-inf]), respectively; the effect 
on lemborexant exposure during the 8 hours postdose was weak, as the with mean Cmax 
ranging from 1.21 to 2.39 and an area under the concentration-time curve from zero time to 
8 hours postdose (AUC[0-8h]) increased by approximately 1.75-fold.  The terminal half-life of 
lemborexant was extended from ~54 hours (lemborexant treatment only) to 118 hours 
following coadministration of itraconazole.  Exposure of the main metabolites of 
lemborexant, ie, M4, M9, and M10 decreased between 32 - 87% (Cmax) whereas AUC(0-inf)  
remained unchanged (M4), increased 2.4-fold (M9) and decreased by approximately 37% 
(M10) compared with the administration of lemborexant alone.  Terminal half-lives of the 
metabolites increased approximately 2- to 3- fold (terminal phase plasma half-life [t1/2] of 
~108 to 150 hours) compared to administration of lemborexant alone (t1/2 ~48 to 53 hours).  
Coadministration of a single 10-mg oral dose of lemborexant and oral rifampin 600 mg QD 
at steady state resulted in decreases in lemborexant Cmax, and AUC(0-inf) by approximately 
92% and 97%, respectively, as compared with administration of lemborexant alone.  In vitro 
data also showed lemborexant to exhibit some inhibitory potential on CYP3A and CYP2B6.  
The effects of steady state dosing of lemborexant (10 mg) on a combined single oral dose of 
midazolam (a sensitive CYP3A substrate, 2 mg) and bupropion (a sensitive 2B6 substrate, 
75 mg) in healthy subjects showed no effect on the PK for midazolam but a weak effect on 
the PK of bupropion based on approximately ~50% decreased exposure (Cmax and AUC [0-inf]
for bupropion and the [S,S]-hydroxylated metabolite of bupropion).  These findings showed 
that the observed PK for midazolam and bupropion in this study were similar to reported 
values in literature, which confirms that there were no apparent effects on the PK of either 
drug when coadministered (Heizmann, et al., 1983; Lai and Schroeder, 1983).  In summary, 
these findings suggest that no clinically meaningful interaction can be expected when 
lemborexant is administered concomitantly with other sensitive CYP3A or CYP2B6 
substrates.  However, lemborexant exposure may considerably increase or decrease when 
coadministered with either a strong CPY3A inhibitor or inducer respectively.
Regulatory guidelines related to assessing PK in hepatic impaired subjects recommend that 
the effect of hepatic impairment on the PK of the drug and its main metabolites should be 
evaluated if hepatic metabolism accounts for at least 20% of elimination of the drug (FDA, 
2003).  In the case of lemborexant, the data from a radiolabeled 14C-human mass balance 
study indicate that lemborexant is extensively metabolized since only less than 13% of 
administered dose was recovered unchanged in feces only.  Urinary excretion of unchanged 
lemborexant was not detectable indicating renal clearance is negligible.  The proposed 
metabolic pathways of lemborexant involve primarily oxidation of dimethylpyrimidine 
moiety of lemborexant to the M4, M9, and M10 metabolites. These metabolites accounted 
for 6.6%, 6.3%, and 12.5% of the total drug-related AUC(0-96h), respectively.  In vitro studies 
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also identified these human in vivo metabolites and indicated CYP3A-mediated metabolism
as the predominant clearance pathway for lemborexant.  Overall, these results indicate that 
lemborexant meets regulatory standards requiring assessment of the impact of hepatic 
impairment on PK.
7.2
Study Rationale
This study is being conducted to assess whether mild or moderate hepatic impairment 
influences the PK and metabolism of lemborexant, with the findings of this study anticipated 
to guide future dosing recommendations in patients with various degrees of hepatic 
impairment.  Based on data from drug interaction with itraconazole as well as 
CYP3A-mediated metabolism being the predominant clearance pathway for lemborexant, it 
is anticipated that a strong effect will be observed in severe hepatic impaired subjects, which 
will impact the PK of lemborexant, thus leading to contraindications in this subgroup of 
hepatic impairment subjects.  To mitigate the anticipated effect of hepatic function on 
lemborexant disposition, ongoing Phase 3 studies do not include subjects with severe hepatic 
disease, however, they do allow for enrollment of subjects with mild and moderate 
impairment, which likely reflects the anticipated insomnia patient population  Therefore, the 
proposed study limits the population to mild and moderate impaired subjects only.  
Furthermore, a population PK analysis applied to data from phase 2 and 3 studies will also be 
utilized to formulate a comprehensive dosing recommendation relevant to the mild and 
moderate hepatic-impaired subjects.
7.2.1
Study Design
The overall study design proposed, including the dose, regimen, number of healthy control 
subjects, endpoints, and analyses follows the recommendations from the latest guidelines by 
FDA and EMA on evaluation of PK in subjects with hepatic impairment (FDA, 2003; EMA, 
2005). 
The proposed study design includes the enrollment of patients with mild and moderate liver 
impairment (Child-Pugh class A and B respectively).  Subjects with severe hepatic 
impairment (Child-Pugh class C) will be excluded from the study as outlined above. 
The regulatory guidelines include a provision for use of a reduced, sequential study design, to 
evaluate the group of subjects with higher severity of liver impairment first (such as 
moderate liver impairment), and if no effect on PK is demonstrated, then these results could 
be extrapolated to the subjects with liver impairment of lesser severity.  In the case of 
lemborexant, the reduced study design is considered to be unsuitable since a large effect in 
the moderate hepatic impaired subjects is expected based on the current disposition profile 
for lemborexant.  This design would require subsequent investigation in mild hepatic 
impaired subjects to ensure clarity regarding lemborexant labeling.   
The proposed study design includes 8 subjects per cohort of mild and moderate hepatic 
impairment and 8 matched control subjects, and will utilize an estimation-based approach to 
calculate the ratios of the geometric means rather than powering the study to test for a 
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specific difference in exposure between subjects with hepatic impairment and healthy 
controls.  In addition, 90% CIs for the slope parameter of the relationship between 
Child-Pugh score and apparent clearance of lemborexant may provide additional indication
of any effect (or lack of) on lemborexant PK.  This analysis will take into account all 
subjects’ data (N=24), thereby increasing the possibility to detect a relationship between 
severity of liver impairment and lemborexant PK. 
7.2.2
Assessment of Severity of Liver Impairment 
As proposed for the study, both guidelines (FDA, 2003; EMA, 2005) recommend use of 
Child-Pugh Classification Score as a marker of degree of liver impairment.  The EU 
guidelines also recommend obtaining the adequate range of decreases in serum albumin and 
increases in bilirubin and prothrombin times.  Unlike serum creatinine or creatinine 
clearance, which have been used to assess the degree of renal impairment, there is no single 
measure or group of measures that has gained widespread clinical use to estimate the degree 
of liver impairment.  As the Child-Pugh classification system is based on laboratory-based 
parameters (serum albumin, bilirubin and prothrombin time) and also 2 clinical features 
(encephalopathy and ascites), the total score relies on the subjective assessments of these 
features, and hence is associated with variability in estimation of the degree of impairment.  
Among other models that have been increasingly used as a measure of liver impairment, the 
model of end stage liver disease (MELD) score, relies only on the laboratory parameters, and 
thus, is more likely to be consistent between different clinical centers for grading a particular 
patient for degree of liver impairment.  In addition, published reports have indicated a good 
correlation between the MELD scores and Child-Pugh Scores (Albarmawi et al 2013).  
Therefore, as per the regulatory guidelines, although the proposed study will use the Child-
Pugh Classification as a primary approach for characterizing degree of liver impairment, an 
exploratory assessment of the correlation between the lemborexant PK and the MELD score 
will be included to aid clinical guidance.  Nonetheless, in agreement with the guidelines, the 
overall conclusions and dosing recommendations will be based on analysis using the Child-
Pugh Scores and their relationship with lemborexant PK.
7.2.3
Choice of Dose, Regimen, and PK Assessments 
A single-dose study design is proposed based on the following PK characteristics of 
lemborexant and is in agreement with regulatory guidelines.  Following single-dose 
administration in healthy volunteers, lemborexant was safe and well tolerated up to 200 mg 
and demonstrated approximate dose-proportional PK up to 75 mg with no time-dependency 
in plasma exposures upon multiple dosing.  The main metabolites, including M4, M9, and 
M10, are pharmacologically active in vitro but are also P-glycoprotein (P-gp) substrates; 
therefore the likelihood to penetrate into the central nervous system (CNS) would be low.  
The half-lives of the M4, M9, and M10 metabolites were similar to lemborexant accounting 
for 6.3%, 6.6%, and 12.5% of the total plasma exposure (AUC0-96h.  In addition, the AUC 
metabolite to parent ratios at steady state was approximately 19.9% to 57.5% for a 2.5-fold 
higher dose (ie, 25 mg) than the current planned dose level of 10 mg lemborexant.  Taken 
together, these findings support the conclusion that using a single dose of lemborexant is 
appropriate and translatable to the effect at steady state.
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The choice of the 10-mg dose is based on the fact that it is the highest dose being studied in 
the ongoing Phase 3 studies, and is also likely to be the selected dose for final registration.  
Taking into consideration the safety and tolerability of lemborexant in healthy volunteers 
from single ascending doses up to 200 mg, the predicted exposure and safety margins for 
lemborexant at 10 mg in the hepatic impaired subjects are well covered. 
With lemborexant as the only pharmacologically active moiety, the primary PK endpoints for 
the study will be the total Cmax and AUC parameters for lemborexant, whereas the PK 
comparisons for the metabolites will be secondary endpoints.  In order to account for 
potential prolongation of the half-life of lemborexant or metabolites in subjects with liver 
impairment, the PK samples will be collected up to Day 14 after dosing.  One of the key 
assessments stipulated in all regulatory guidelines for special population studies (ie, renal and 
hepatic impairment) is the evaluation of any change in the unbound fraction of the 
pharmacologically active moieties in vivo and assessment of the relationship between the 
unbound plasma exposures (AUCu) and apparent clearance with measures of liver 
impairment, where binding of the drug to plasma proteins is high (eg, >90%).  With 
lemborexant and its main metabolites (M4, M9, and M10), plasma protein binding based on 
in vitro studies is approximately 88%, 74%, 86%, and 92% bound to human plasma, 
respectively, and linear over the clinically observed concentrations.  Due to the marginally 
high plasma protein binding of lemborexant and its metabolites in the current study, 2 blood 
samples will be collected, one at the maximum plasma exposure time and one at trough level.  
The respective unbound PK parameters for lemborexant will be derived by applying the 
unbound ratio to the PK parameters calculated using total plasma concentrations of 
lemborexant.  Plasma protein binding of metabolites will be assessed to compare these results 
to in vitro data and assess any difference between hepatic impaired subjects and healthy 
volunteers that is currently not anticipated.  The analysis of the unbound PK parameters 
(lemborexant only) between subjects with liver impairment and normal controls will be 
considered as secondary PK parameter endpoints only.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective is to assess the effect of mild and moderate hepatic impairment on the 
PK of lemborexant after a single dose administration.
8.2
Secondary Objectives
The secondary objectives are:

To evaluate the effects of hepatic impairment on the PK of lemborexant metabolites M4, 
M9, and M10.

To evaluate the relationship between the PK parameters of lemborexant and its 
metabolites and the Child-Pugh Classification score, serum albumin, total bilirubin, and 
prothrombin time.
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
To assess safety and tolerability of lemborexant following a single dose administration in 
subjects with mild and moderate hepatic impairment and healthy subjects.
8.3
Exploratory Objectives
The exploratory objectives are:

To explore the relationship between the PK parameters of lemborexant and its 
metabolites and the model of end stage liver disease (MELD) score.
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E2006-A001-104 is a multicenter, single dose, open-label, parallel-group study in subjects 
with mild and moderate hepatic impairment and matched (with regard to age [±10 years], 
sex, and body mass index [BMI, ±20%]) healthy control subjects. The study will enroll a 
total of 24 subjects, including 16 subjects with impaired hepatic function; 8 subjects each in 
Child-Pugh class A (mild) and B (moderate).  At least 8 healthy subjects will be dosed as one 
control cohort to match (1:1) to the subjects with hepatic impairment in each Child-Pugh 
class with regard to age, sex, and BMI. 
The study will consist of 2 phases: Prerandomization and Treatment.  The Prerandomization
Phase will include 2 study periods; Screening and Baseline (Day -1).  The subjects will be 
admitted to the clinical facility on Day -1, remain confined to the clinic until Day 8, and then 
return to the clinical facility for additional PK sampling as outpatients until Day 14.  In the 
event of early discontinuation of the subjects, the subjects with Child Pugh Class A and B 
(Cohorts A and B) and the matched controls (Cohort C) may be replaced.
On Day 1, the subjects will be administered a single 10-mg dose of lemborexant with 
approximately 240 mL of water in the morning after an overnight fast.  The blood samples 
for PK assessments will be collected at prespecified intervals up to 312 hours postdose
administration.  The subjects will be discharged on Day 14 of the study.  In addition, the 
blood samples for plasma protein binding assessments of lemborexant will be collected from 
each subject at 2 time points; approximately 1 hour and 24 hours postdose.
The end of the study will be the date of the last study visit for the last subject.
9.1.1
Prerandomization Phase
The Prerandomization Phase will include a Screening Period and a Baseline Period.
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9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.  Screening period assessments and timing thereof are shown in Section 9.5.2.
9.1.1.2
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility and to obtain baseline 
data for assessment.  Subjects who complete the Baseline Period and meet the criteria for 
inclusion/exclusion (Section 9.3.1 and Section 9.3.2) will begin the Treatment Phase.  
Baseline assessments and timing thereof are shown in Section 9.5.2. 
9.1.2
Treatment Phase
The Treatment Phase will consist of 1 study period of 14 days.  The Treatment Phase
assessments and timing thereof are shown in Section 9.5.2.
9.2
Discussion of Study Design, Including Choice of Control Groups
This single dose, parallel-group study aims to investigate the effects of mild and moderate 
hepatic impairment on the PK of lemborexant and its main metabolites (M4, M9, and M10).
At least 24 subjects will be enrolled, and 16 of these subjects will have impaired (mild or 
moderate) hepatic function.  The other approximately 8 subjects will be healthy and will 
serve as the control group.  Healthy subjects will be matched (1:1) with the 8 subjects with
mild hepatic impairment and the 8 subjects with moderate hepatic impairment according to
age (±10 years), sex, and BMI (±20%).  
The data from this study will help guide specific dosing recommendations in insomnia 
disorder and/or ISWRD patients with impaired hepatic function and establish labeling 
recommendations for this new chemical entity.
Adjudication Committee (revised per Amendment 01)
An independent Adjudication Committee will be employed at intervals to review, in a
blinded manner, AEs that could potentially be considered cataplexy or seizure. A set of
preferred terms constituting a customized Medical Dictionary for Regulatory Activities
(MedDRA) query for cataplexy or seizure will be used to identify events for adjudication
(including cataplexy, muscle fatigue, muscular weakness, muscle tone disorder, hypotonia,
drop attacks, slurred speech, diplopia, falls, convulsions [standardized MedDRA query
(SMQ) narrow and broad], atypical migraine, loss of consciousness, decreased
consciousness, myoclonus, syncope, transient global amnesia, lipothymia, [faintness] and
transient ischemic attack). To assist in the preparation of narratives about such events and to
support the committee’s adjudication process, investigators and site staff will be instructed to
query subjects who report any of the above events for supplemental information using a
questionnaire for events potentially related to cataplexy and the serious adverse event (SAE)
form for any of the above events considered serious.
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9.3
Selection of Study Population
A total of 24 subjects will be enrolled in each of the following 3 cohorts:
Cohort A:  8 subjects with mild hepatic impairment (Child Pugh Class A)
Cohort B: 8 subjects with moderate hepatic impairment (Child Pugh Class B)
Cohort C: At least 8 healthy subjects (control) matched to subjects in Cohorts A and B
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
Inclusion Criteria for All Subjects
Subjects who meet all of the following inclusion criteria will be eligible for participation in 
the study.
1. Male or female subjects, ages 18 to 79, inclusive, at the time of informed consent.
2. BMI between 18 and 40 kg/m2, inclusive, at Screening.
3. Voluntary agreement to provide written informed consent, and the willingness and 
ability to comply with all aspects of the protocol.
4. Nonsmokers or smokers who smoke 20 cigarettes or less per day.
5. For Cohorts A and B:  stable (without any change in disease status for at least 60 days 
prior to study screening) hepatic impairment conforming to Child-Pugh classification 
A or B, respectively (see Table 1 and Table 2), and documented by medical history 
and a physical examination. 
6. For Cohort C: healthy subjects matched to subjects with hepatic impairment with 
regard to age (±10 years), sex, and BMI (±20%), and as determined by no clinically 
significant deviation from normal in medical history, physical examination, 
electrocardiogram (ECG), and clinical laboratory determinations.
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Table 1
Criteria for Child-Pugh Classification 
Points Scored for Observed Findings
Clinical or Biochemical 
Assessments
1
2
3
Albumin (g/dL)
>3.5
2.8 – 3.5
<2.8
Bilirubin (mg/dL)
<2
2 – 3
>3
PT (seconds prolonged)
<4
4 – 6
>6
    or INR
<1.7
1.7 – 2.3
>2.3
Ascites
None
Mild/Moderate 
(diuretic-responsive)
Tense 
(diuretic-refractory)
Encephalopathya
None
1 or 2 ( or precipitant-induced)
3 or 4 (chronic)
      cps=cycle per second; INR=international normalized ratio; PT=prothrombin time
a:  Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram;  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, and 5 cps waves;  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves;  Grade 3: 
somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves;  Grade 4: 
unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
Table 2
Child-Pugh Classification Scoring
Total Points
Child-Pugh Class
5 – 6
A
7 – 9
B
9.3.2
Exclusion Criteria
Exclusion Criteria for All Subjects
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG] test with a minimum 
sensitivity of 25 IU/L or equivalent units of ß-hCG).  A separate baseline assessment 
is required if a negative screening pregnancy test was obtained more than 72 hours 
before the dose of study drug.
2. Females of childbearing potential who did not use a highly effective method of 
contraception (as described below) within 28 days before study entry, or who do not 
agree to use an approved method of contraception from 28 days before study entry, 
throughout the entire study period, and for 28 days after study drug discontinuation.  
Approved (highly effective) methods of contraception for this study include at least 
one of the following:

Total abstinence (if it is their preferred and usual lifestyle)

An intrauterine device or intrauterine hormone-releasing system (IUS)

A double-barrier method of contraception such as condom plus diaphragm with 
spermicide

A contraceptive implant
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
An oral contraceptive (with additional barrier method). 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. 

Have a vasectomized partner with confirmed azoospermia.
(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. Known to be positive for human immunodeficiency virus (HIV).
4. Currently enrolled in another clinical study or used any investigational drug or device 
within 4 weeks, or 5 times the half-life of the investigational drug (whichever is 
longer), preceding informed consent.
5. Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or 
donation of plasma within 1 week of dosing until study discharge.
6. Intake of herbal preparations containing St. John’s Wort within 4 weeks prior to 
dosing until study discharge.
7. Intake of nutritional supplements (including herbal preparations), foods or beverages 
that may affect CYP3A
enzyme (eg, alcohol, grapefruit, grapefruit juice, 
grapefruit-containing beverages, apple or orange juice, vegetables from the mustard 
green family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels 
sprouts, mustard] and charbroiled meats) within 1 week before dosing until study 
discharge.
8. Intake of beverages, food, or other products that contain caffeine from 24 hours 
before until 48 hours after dosing with lemborexant. 
9. Engagement in strenuous exercise (eg, moving large bulky items, bodybuilding) 
within 2 weeks prior to check-in until study discharge.
10. History of clinically significant drug or food allergies, or is presently experiencing 
significant seasonal allergies.
11. A prolonged QT/QTc interval (QTc >480 ms) demonstrated on ECG at Screening or 
Baseline (Day -1).
12. Any major surgery within 4 weeks of study drug administration.
13. Any history of abdominal surgery that may affect PK of lemborexant
(eg, hepatectomy, nephrectomy, digestive organ resection). 
14. Inability to tolerate oral medication.
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15. Inability to tolerate venous access and/or venipuncture. 
16. Unwilling to abide by the study requirements, or in the opinion of the investigator, is 
not likely to complete the study.
Additional Exclusion Criteria for Hepatically Impaired Subjects (Cohorts A and B)
In addition to the Exclusion Criteria above for All Subjects, other standard exclusion criteria 
for subjects with hepatic impairment will be used. These include:
17. Any significant acute medical illness (such as new conditions or exacerbation of 
pre-existing conditions) within 8 weeks of dosing.
18. Medical conditions which are not adequately and stably controlled on stable doses of 
medications or which, in the clinical opinion of the Principal Investigator, may 
interfere with study procedures or subject safety within 4 weeks before dosing (eg, 
psychiatric disorders and disorders of the gastrointestinal tract, kidney, respiratory 
system, endocrine system, hematological system, neurological system, or 
cardiovascular system, or subjects who have a congenital abnormality in metabolism).
19. History of esophageal and gastric variceal bleeding within the past 6 months unless 
the subject has completed a course of endoscopic therapy with the appropriate 
documentation (eg, endoscopy report) of successful ablation of esophageal varices; 
subjects with esophageal varices may be included if not bleeding within the past 6 
months or have been treated adequately by ablation therapy, as specified above.
20. Spontaneous bacterial peritonitis within 3 months of dosing.
21. Treatment with plasmapheresis within 6 months of dosing.
22. Primarily cholestatic liver diseases (eg, primary biliary cirrhosis or primary sclerosing 
cholangitis).
23. Current or recent (within 3 months prior to screening) history of significant 
gastrointestinal disease other than that secondary to hepatic impairment.
24. Autoimmune liver disease.
25. Active alcoholic hepatitis determined either clinically or by histology.
26. History of hepatoma or metastatic disease of the liver.
27. Presence of severe ascites or edema.
28. Presence of hepatopulmonary syndrome or hydrothorax, or hepatorenal syndrome.
29. Known significant bleeding diathesis that could preclude multiple venipunctures 
(INR >2.5).
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30. Creatinine clearance <60 mL/min at Screening or Baseline as calculated using 
Cockroft and Gault Equation. 
31. The subject’s standard therapy/concomitant medication for diseases related to 
cirrhosis has not remained stable/unchanged for at least 14 days before the first dose 
of study drug.
32. History of drug or alcohol dependency or abuse within 4 weeks prior to Screening, or 
those who have a positive urine drug test or breath alcohol test at Screening or 
Baseline unless a prescribed medication for the underlying condition is the cause of 
the positive urine screen.
Additional Exclusion Criteria for Healthy Subjects (Cohort C)
In addition to the Exclusion Criteria for All Subjects, other standard exclusion criteria for 
healthy subjects in Phase 1 studies will be used. These include:
33. Presence of active liver disease, or acute liver injury, as indicated by (1) an abnormal 
liver function test, or (2) clinical or laboratory signs of active viral hepatitis 
(including B and C, as demonstrated by positive serology at Screening).   
34. Clinically significant illness, within 4 weeks prior to dosing, that requires medical 
treatment or  may influence the outcome of the study; eg, psychiatric disorders and 
disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine 
system, hematological system, neurological system, or cardiovascular system, or 
subjects who have a congenital abnormality in metabolism.
35. Any abnormal finding based on physical examination, assessment of vital signs, 
ECG, or laboratory test results that require treatment or clinical follow-up based on 
the investigator’s opinion.
36. History of drug or alcohol use disorder within the 2 years prior to Screening, or those 
who have a positive urine drug test or breathalyzer alcohol test at Screening or 
Baseline.
37. Use of any prescription drugs within 4 weeks prior to dosing until study discharge.
38. Intake of any over-the-counter (OTC) medications within 2 weeks prior to dosing 
until study discharge.
9.4
Treatments
Test drug: lemborexant (E2006)
Comparator Drug: Not applicable
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9.4.1
Treatments Administered
All subjects enrolled in the study will receive a single 10-mg dose (1 × 10 mg lemborexant 
tablet) in the morning after an overnight fast.
9.4.2
Identity of Investigational Product
Test drug will be supplied by the sponsor in labeled containers.
9.4.2.1
Chemical Name, Structural Formula of E2006
•
Test drug code: E2006
•
Generic name:  Lemborexant tablet
•
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 (molar mass):  410.42 g/mol
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Lemborexant will be labeled in English with text that is in full compliance with US 
regulations.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to 1 of 3 cohorts: subjects with mild hepatic impairment (Child 
Pugh Class A) will be in Cohort A, subjects with moderate hepatic impairment (Child Pugh 
Class B) will be in Cohort B, and healthy (control) subjects will be in Cohort C. To qualify 
for Cohort A or B, the subject must have stable (ie, without any change in disease status for 
at least 60 days prior to study screening) hepatic impairment conforming to Child-Pugh 
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classification A or B, respectively (see Table 1 and Table 2), documented by medical history 
and a physical examination. To qualify for Cohort C, the healthy subject must match a
subject with hepatic impairment with regard to age (±10 years), sex, and BMI (±20%), and as 
determined by no clinically significant deviation from normal in medical history, physical 
examination, ECG, and clinical laboratory determinations.
9.4.4
Selection of Doses in the Study
Lemborexant 10 mg proposed in this study is consistent with the highest dose being tested in 
Phase 3 clinical trials for insomnia disorder. 
9.4.5
Selection and Timing of Dose for Each Subject
Following an overnight fast of at least 10 hours, subjects will be administered the study drug 
product in the morning with 240 mL (8 fluid ounces) of water. No food will be allowed for 
at least 4 hours postdose. Water will be allowed as desired except for 1 hour before and after 
drug administration.
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter [OTC] medications) or therapy administered to 
the subject within 30 days prior to Screening until the end of study participation will be 
recorded on the Prior and
Concomitant Medication case report form (CRF) or 
Non-Pharmacological Procedures CRF.  The investigator will record on the Adverse Event 
CRF any AE for which the concomitant medication/therapy was administered. 
The following prior and concomitant therapies are prohibited for all subjects:

Nutritional supplements, juice, and herbal preparations or other foods or beverages that 
may affect the various drug metabolizing enzymes and transporters (eg, alcohol, 
grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, 
vegetables from the mustard green family [eg, kale, broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, mustard], and charbroiled meats) within 1 week before dosing 
until study discharge.

Herbal preparations containing St. John’s Wort within 4 weeks before dosing until study 
discharge.
The following prior and concomitant therapies are prohibited for healthy subjects:

Use of prescription drugs is prohibited from at least 4 weeks before dosing until study 
discharge.
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
Use of over-the-counter (OTC) medications is prohibited from at least 2 weeks before 
dosing until study discharge.
Subjects with hepatic impairment may receive standard therapy approved by the Medical 
Monitor for diseases related to cirrhosis; however, the following restrictions apply:

All such standard therapy concomitant medications should remain unchanged for at 
least 14 days before dosing with study drug and for the duration of the study. 

Standard therapy concomitant medication may not be administered at least 4 hours 
before or after study drug administration on Day 1.  

Standard therapy concomitant therapy of any agent known to induce or inhibit drug 
metabolizing enzymes is prohibited within 2 weeks before dosing and until study 
discharge.  
See Appendix 2 for a full list of prohibited concomitant medications.
9.4.8
Prohibitions and Restrictions during Study Period
9.4.8.1
Food and Water
Menus will be standardized while subjects are inpatients in the study unit.  The menus will be 
the same for all subjects; however, the menus for each inpatient day need not be identical. 
Subjects must consume only the food given to them while in the unit.  Food and water will be 
restricted as follows:
Day -1 (Baseline)
•
Subjects will be given an evening snack following check-in to the study unit on the day 
before dosing.  They will fast (only water is permitted) for at least 10 hours prior to 
dosing.
Day 1 (day of dose administration)
•
Subjects will fast (only water is permitted) for at least 4 hours after dosing.  Fluid will be 
restricted (240 mL water at time of oral dosing) from 1 hour before dosing until 1 hour 
after dosing.  
•
A low-fat lunch (<30% fat), an afternoon snack, dinner, and an evening snack will be 
provided at appropriately scheduled times.
Days 2 through 7
•
A similar schedule and menu for meals/snacks will be followed on each day after dosing 
until clinic discharge. There will be free access to drinking water throughout each day.
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9.4.8.2
Beverage and Other Restrictions

Intake of beverages, food, or other products that contain caffeine from at least 24 hours 
before until at least 48 hours after dosing with lemborexant. 
Intake of nutritional supplements, juice, herbal preparations, or other foods or beverages 
that may affect CYP3A enzyme or transporters (eg, alcohol, grapefruit, grapefruit juice, 
grapefruit-containing beverages, apple or orange juice, vegetables from the mustard green 
family [eg, kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, mustard]
and charbroiled meats) within 1 week before dosing until study discharge.

Smokers must not smoke more than 20 cigarettes per day.
9.4.8.3
Physical Activity Restrictions

Engagement in strenuous exercise is prohibited within 2 weeks before check-in on Day -1 
and until study discharge.

Subjects should maintain an upright (greater than 45angle) position for at least 4 hours 
following administration of study drug, except for AEs or study-related procedures 
requiring a different position.
9.4.9
Treatment Compliance
All doses will be administered by qualified research site personnel ensuring compliance to 
the protocol-specified dosing regimens. Each subject’s dose will be administered at the 
designated dosing time and documented in the source documents maintained on site.  At the 
end of each tablet dose, a hand and mouth check will be performed to ensure that the entire 
dose of study drug has been properly consumed.
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.10
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
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•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
•
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable
•
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable
•
A signed and dated curriculum 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/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to Good Clinical Practice (GCP) guidelines as well as local or 
regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies 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/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, (e) 
documentation of returns to the sponsor, and (f) certificates of destruction for any destruction 
of study drugs/study supplies that occurs at the site.  All forms will be provided by the 
sponsor.  Any comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs/study supplies 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, MHRA).  As applicable, all unused study drugs/study supplies and 
empty and partially empty containers from used study drugs/study supplies are to be returned 
to the investigator by the subject and together with unused study drugs/study supplies 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/study supplies 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/study supplies to the central or local depot(s).  
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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/study supplies that 
are to be returned to the sponsor’s designated central or local depot(s) must be boxed and 
sealed and shipped back to the central or local depot(s) following all local regulatory 
requirements.  In some regions, study drugs/study supplies may be removed from the site and 
hand delivered to the central or local depot by sponsor representatives.  Where study 
drugs/study supplies 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 includes date of birth (or age), sex, race/ethnicity, and BMI.
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All clinically significant medical and surgical history must be noted in the Medical 
History and Current Medical Conditions CRF.
9.5.1.2.2
HEIGHT AND WEIGHT MEASUREMENTS
Height (cm) and weight (kg) will be recorded and BMI will be determined at the Screening 
Visit. Subjects will have their weight (kg) measured again on Day -1.
9.5.1.3
Efficacy Assessments
Not applicable.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Plasma concentration of Lemborexant
Blood samples (4 mL each) will be collected as specified in
the Schedule of 
Procedures/Assessments (Table 4).  A separate lab manual will be provided for a description 
of collection, handling, and shipping procedures of the plasma samples for PK analysis.  In 
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addition, blood samples for protein binding (12 mL per time point) of lemborexant will be 
collected at 1 and 24 hours postdose matching the PK sample collection at those time points.
Total plasma concentrations of lemborexant and its metabolites (M4, M9, and M10) will be 
measured by validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) 
methods.  The unbound concentrations of lemborexant, M4, M9, and M10 will also be 
measured using a similar validated LC-MS/MS method following equilibrium dialysis.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Not applicable.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital 
signs and ECGs; and performance of physical examinations as detailed in Table 4.
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. 
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 non-protocol required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit in the Treatment Phase and for 28 days after 
the subject’s last dose.  Serious AEs will also be collected for 28 days after the last dose 
(or 5 times the half-life, whichever is longer).
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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.
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 AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care 
•
Planned hospitalizations required by the protocol
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
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•
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 PK analysis should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection and are to be fasting for at least 4 hours before blood is drawn for clinical 
laboratory measurements.  The Schedule of Procedures/Assessments (Table 4) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.
Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, red blood cell (RBC)
count, and white blood cell (WBC) count with differential
(bands, basophils, eosinophils, lymphocytes, monocytes,
neutrophils)
Coagulation Panel
Prothrombin time (PT), activated partial thromboplastin 
time (aPTT), and international normalized ratio (INR)
Chemistry
Electrolytes
Chloride, potassium, sodium, calcium
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate
aminotransferase,
gamma
glutamyl
transpeptidase,
direct
bilirubin, total bilirubin
Other
Total protein, globulin, albumin, cholesterol, triglycerides,
glucose, lactate dehydrogenase, uric acid, and creatinine
(revised per Amendment 01)
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones,
occult blood, pH, protein, RBCs, specific gravity, WBCs
Virology
Hepatitis B surface antigen (HBsAg) and hepatitis C antibody 
(HCVAb)
Clinical laboratory tests during the study will be performed by a Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory. All blood and urine samples will be 
collected and sent to the central laboratory on the day of collection unless otherwise 
instructed.
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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.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained as designated in the Schedule of Procedures/Assessments (Table 4) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been in 
supine position for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed prior to drawing blood samples in order to maximize 
the accuracy of blood sampling times while minimizing the potential effects of blood 
drawing on recordings obtained during safety assessments.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Comprehensive and abbreviated physical examinations will be performed as designated in
the Schedule of Procedures/Assessments (Table 4).  Documentation of the physical 
examination will be included in the source documentation at the site.  Significant findings at 
the Screening Visit will be recorded on the Medical History and Current Medical Conditions 
CRF.  Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the Adverse Events CRF.
Comprehensive Physical Examination
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well. 
Abbreviated/Routine Physical Examination
Health status will be assessed by brief evaluation of the chest (including heart and lungs), 
abdomen and limbs, and other physical conditions of note.  The subject must be queried 
regarding changes in physical status since the last examination.
9.5.1.5.6
ELECTROCARDIOGRAMS
Twelve-lead electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 4). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
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9.5.1.5.7
VIRAL TESTS
An 8.5 mL sample of blood will be taken for hepatitis B surface antigen (HBsAg) and hepatitis C 
antibody (HCVAb) at Screening.
9.5.1.5.8
PREGNANCY TEST
At Screening, a serum pregnancy (β-hCG test) will be performed for all premenopausal 
women and postmenopausal women who have been amenorrheic for less than 12 months 
using the 8.5 mL blood sample taken for clinical laboratory tests.  These women will have a 
urine pregnancy test after Screening at the designated time points specified in the Schedule of 
Procedures/Assessments (Table 4).
9.5.1.5.9
URINE DRUG TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 4).  This sample will be tested for common 
drugs of use/abuse: eg, cocaine, cannabinoids, PCP, opioids (as a group), benzodiazepines, 
barbiturates, and amphetamines.
9.5.1.5.10
BREATH ALCOHOL TEST
The breath alcohol test will be performed according to the investigational site’s SOP at 
designated time points as specified in the Schedule of Procedures/Assessments (Table 4).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 
4
presents 
the 
schedule 
of 
procedures/assessments 
for 
the 
study.
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Table 4
Schedule of Procedures/Assessments in E2006-A001-104
Study Phase
Prerandomization
Treatment
Period
Screening
Baseline
Visit
1
2
3
4
5/Early Discontinuation
Day(s)
-21  to -2
-1
1
2
3, 4, 5, 6, 7
8
10
12
Day 14/ET
Assessment
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History and Demographics
X
Comprehensive Physical Exam
X
Abbreviated/Routine Physical Exam
X
X
X
Height, Weight, and BMI
X
  X a:
Vital Signs b:
X
X
X
X
X
X
X
X
12-lead ECG c:
X
X
X
X
X
Viral Screen (hepatitis B and C)
X
Urine Drug Test
X
X
Alcohol Breathalyzer
X
X
Serum β-hCG Pregnancy Test d:
X
Urine Pregnancy Test d:
X
X
Clinical Lab Tests (Hematology, Clinical 
Chemistry, and Urinalysis) e:
X
X
X
X
PT, aPTT, and INR
X
X
X
X
PK Blood Sample f:
X
X
X
X
X
X
X
Blood Sample for Protein Binding 
Assessment g:
X
X
Administer Lemborexant h:
X
Admission to Clinic
X
Release from Clinic i:
X
Discharge from Study j:
X
Adverse Events
------------------------------------------------------------------------------------------------------------------------------------
Prior/Concomitant Medications
------------------------------------------------------------------------------------------------------------------------------------
aPTT=activated partial thromboplastin time; β-hCG= beta-human chorionic gonadotropin; BMI=body mass index; ECG = electrocardiogram; ET= early 
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termination; INR= international normalized ratio; PK=pharmacokinetic; PT=prothrombin time
a:
Only weight will be recorded at Baseline (Day -1). 
b:
Single measurements of vital signs (blood pressure, heart rate, body temperature, and respiratory rate) after at least 5 minutes of supine rest will be recorded 
at Screening, clinic check-in on Day -1, predose on Day 1, Day 2, prior to clinic discharge on Day 8, on Days 10 and 12, and at end-of study (Day 14 or 
early termination).
c:
Single ECG will be recorded at Screening, Baseline (Day -1), Day 1 (predose and 3 hours postdose), Day 2 (24 hours postdose), and Day 14 (312 hours
postdose). A variance of ±15 minutes is allowed.  Before excluding a subject with QTcF > 480 at Screening, ECG should be repeated once to confirm.
d:
Females of childbearing potential only.  
e:
Subjects will fast for at least 4 hours before blood is drawn for clinical laboratory assessments. Measurement of serum albumin and creatinine will be part of 
the central laboratory tests. (revised per Amendment 01)
f:
Blood samples (4 mL per time point) for PK assessments will be collected on Day 1 (predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12  hours  postdose), Days 2 
(24 hours postdose), 3 (48 hours postdose), 4 (72 hours postdose), 5 (96 hours postdose), 6 (120 hours postdose), 7 (144 hours postdose), 8 (168 hours
postdose), 10 (216 hours postdose), 12 (264 hours postdose) and 14 (312 hours postdose). If a subject is early terminated, he or she will not have a blood 
sample collected for PK unless early termination coincides with a scheduled PK time point.  A variance of ±5 minutes (up to the first 2 hours postdose),   
±10 minutes for time points up to, and including, Day 8 (168 hours postdose) and ±2 hours for Day 10 (216 hours postdose) to Day 14 (312 hours postdose) 
is allowed.
g:
Blood samples (12 mL per time point) for plasma protein binding will be collected at approximately 1 and 24 hours postdose, matching with the time 
collection for PK samples for lemborexant and its main metabolite, M4, M9 and M10. 
h:
A single 10-mg dose of lemborexant as 1 × 10 mg tablet will be administered with 240 mL of water following an overnight fast. Dosing will be in the 
morning followed by a 4-hour postdose fast. Water will be allowed ad libitum except for the interval from 1 hour before to 1 hour after study drug 
administration.
i:
Subjects will be released from the clinic after completing the Day 8 procedures and then return to the clinic for outpatient visits on Days 10, 12, and 14.
j:
Subject will be released from the study after completion of Day 14 (end-of-study) procedures or early termination.
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Table 5 presents the blood sampling schedule for PK assessments.
Table 5
Blood Sampling Schedule for Pharmacokinetic Assessments
Study day
Time (on each day)
Acceptable time-window
Day 1
Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
and 12 hours postdose
Predose; -1 hour
Postdose (up to first 2 hours postdose); ±5 minutes 
Postdose (after 2 hours postdose); ±10 minutes
Day 2
24 hours postdose
±10 minutes
Day 3
48 hours postdose
Day 4
72 hours postdose
Day 5
96 hours postdose
Day 6
120 hours postdose
Day 7
144 hours postdose
Day 8
168 hours postdose
Day 10
216 hours postdose
±2 hours
Day 12
264 hours postdose
Day 14
312 hours postdose
9.5.2.2
Total Volume of Blood Sampling
Table 6 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 6
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
8.5
Screening (including pregnancy 
testing):  1
Baseline (Day -1): 1
Day 2: 1
Day 14 or early termination: 1
8.54=34
Viral test
8.5
Screening: 1
8.51=8.5
PK blood sampling
4
20
420=80
Blood sampling for plasma 
protein binding
12
2
212=24
Total
146.5
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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in bioavailability 
studies.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, must 
be reported on a completed SAE form by email or fax as soon as possible but no later than 
24 hours from the date the investigator becomes aware of the event (revised per Amendment 
01).
SAEs, regardless of causality assessment, must be collected through the last visit in the 
Treatment Phase and for 28 days after the subject’s last dose.  All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator 
to be related to the study treatment or any protocol-required procedure should be reported to 
the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator 
Study File.
For urgent safety issues call:  
 (24/7 number). 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt. (revised per Amendment 01)  If the follow-up information changes the investigator’s 
assessment of causality, this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
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The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
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 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. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
AEs 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
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Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse 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.
9.5.4.4
Expedited Reporting
The sponsor must inform investigator 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
9.5.4.6
Regulatory Reporting of Adverse Events
AEs 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 local and regional requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects who discontinue the study are to complete the study’s early 
discontinuation procedures indicated in the Schedule of Procedures/Assessments (Table 4).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate 1 
or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
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A subject removed from the study for any reason may be replaced.
9.5.6
Confirmation of Medical Care by Another Physician (for Hepatic Impairment 
Subjects):
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may 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 after the study is completed and the database is 
locked and released. Statistical analyses will be performed using WinNonlin and SAS 
software or other validated statistical software as required.  Details of the statistical analyses 
will be included in a separate statistical analysis plan (SAP).
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9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
The endpoints include the following PK parameters derived by non-compartmental analysis 
using the plasma concentration-time data of lemborexant and its metabolites:
Cmax
Maximum plasma concentration
tmax
Time to reach maximum plasma concentration
AUC(0-t)
Area under plasma concentration vs. time curve from time = 0 
to time of last quantifiable concentration 
AUC(0-inf)
Area under plasma concentration vs. time curve from time = 0 
to infinity
t1/2
Terminal phase plasma half-life
CL/F
Apparent total body clearance ( for lemborexant only)
Vz/F
Apparent volume of distribution (for lemborexant only)
AUC Metabolite 
Ratio
Ratio of AUC(0-inf) of individual metabolite to AUC(0-inf) of 
lemborexant, corrected for molecular weights
fu
Plasma protein unbound fraction
AUCu
AUC(0-inf) values adjusted by unbound fraction in plasma 
(for lemborexant only)
CLu/F
Apparent clearance relative to the unbound plasma concentration 
based on AUCu (for lemborexant only)
The Cmax, AUC(0-t), and AUC(0-inf) based on total exposures of lemborexant will be the 
primary PK endpoints.  The rest of the parameters, including the PK parameters of the 
metabolites, will be secondary endpoints.
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who dosed with the test drug and had at least 
1 postdose safety assessment.
The Pharmacokinetic Analysis Set is the group of subjects who dosed with the test drug and 
had sufficient PK data to derive at least 1 PK parameter.
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9.7.1.3
Subject Disposition
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the safety analysis set will be summarized 
for each treatment group using descriptive statistics.  Continuous demographic and baseline 
variables include age, weight, height, BMI, and for subjects with hepatic impairment: MELD 
score and Child-Pugh classification; categorical variables include sex, ethnicity, and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD, March 2017).  Prior 
medications will be defined as medications that stopped before the dose of study drug.  Any 
medication (including OTC medications) or therapy administered to the subject during the 
study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication CRF or Non-Pharmacological Procedures CRF. All medications 
will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
Not applicable.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for individual plasma concentration listings.  The PK 
Analysis Set will be used for summaries of plasma concentrations and for analyses, 
summaries, and listings of PK parameters.
The effect of hepatic impairment on the PK of lemborexant, the primary PK parameters 
based on total Cmax, AUC(0-t), and AUC(0-inf) will be compared between the cohort of healthy 
normal controls and the cohorts of subjects with mild and moderate hepatic impairment as 
defined by Child-Pugh classes A or B.
A general linear model of logarithmically 
transformed values with hepatic function class as a fixed effect will be utilized to estimate 
the geometric mean ratio (and two-sided 90% confidence intervals) of subjects with 
mild/normal and moderate/normal hepatic function.  Similar statistical analyses will be 
conducted for the PK parameters of the metabolites and unbound lemborexant as secondary 
endpoints. Protein binding will be calculated for metabolites without any assessment of PK 
parameters.
Scatter plots of PK parameters of lemborexant and its metabolites versus Child-Pugh Score 
will be provided.  The association between the primary PK parameters and Child-Pugh Score 
will be evaluated by regression analysis (the PK parameter as a dependent variable and 
Child-Pugh Score as an independent variable).  Similar analyses will be performed for 
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MELD score, serum albumin, total bilirubin, and PT.  Additionally, association between the 
PK parameters and liver transaminase levels will be performed, if deemed necessary. 
Summary statistics will be generated for each of the PK parameters for each Child-Pugh class 
and healthy controls. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Not applicable. 
9.7.1.8
Safety Analyses
An evaluation of safety will be performed on the Safety Analysis Set.  Safety data that will 
be evaluated include AEs, clinical laboratory results, vital signs, and ECGs.
Treatment-emergent adverse events (TEAEs) will be summarized for each Child-Pugh class
and healthy controls. Descriptive summary statistics (eg, mean, standard deviation [SD], 
median, minimum, maximum for continuous variables, and number and percent for 
categorical variables) including shift tables of the laboratory, vital signs, ECG parameters. 
Changes from Baseline for the clinical laboratory, vital signs and ECG parameters will be 
evaluated for each Child-Pugh class and healthy controls by time point.
9.7.1.8.1
EXTENT OF EXPOSURE
All subjects enrolled in the study will receive a single 10-mg dose (1 × 10 mg lemborexant 
tablet) in the morning after an overnight fast.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 20.1 or higher) lower level term 
(LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by group.  The incidence of TEAEs will be reported as the 
number (percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted 
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only once within a SOC and PT, even if the subject experienced more than 1 TEAE within a 
specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
Subject data listings of AEs, TEAEs leading to death, SAEs, and AEs leading to withdrawal 
will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and group using descriptive statistics.  
Qualitative parameters listed in Section 9.5.1.5.3 will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline to each postbaseline visit 
and to end of treatment will be reported using shift tables.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results.
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-group 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.  
Clinical laboratory results post baseline will be evaluated for markedly abnormal values.
Appendix 1 presents the Sponsor’s grading for laboratory values that will be used to identify 
subjects with markedly abnormal laboratory values.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by day 
and time after dosing and group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
9.7.2
Determination of Sample Size
A sample size of 8 subjects per each cohort of mild and moderate hepatic impairment, as
defined by Child-Pugh classes A or B, is based on the recommendations in regulatory 
guidelines for a minimum number of subjects to be enrolled for moderate liver impairment 
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cohort (FDA, 2003).  Additionally, from single-dose studies of the 10-mg tablet 
(E2006-A001-004, E2006-A001-005, and E2006-A001-008), the pooled between-subject 
standard deviations of logarithmically transformed Cmax and AUC(0-inf) of lemborexant were 
0.334 and 0.391 respectively. With a sample size of 8 subjects in each Child-Pugh category 
and at least 8 matched controls, a 2-sided 90% confidence interval (CI) for the ratio for 
AUC(0-inf) will extend 0.322 from the observed mean difference on the log scale.
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
1. Albarmawi A, Czock D, Gauss A, Ehehalt R, Bermejo JL, Burhenne J, Ganten T, 
Sauer P, and Haefeli W.  CYP3A activity in severe liver cirrhosis correlates with 
Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin 
Pharmacol, 2013;77(1),160-169.
2. Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of 
midazolam in man. Br J Clin Pharmacol. 1983;16 (Suppl 1):43S–49S.
3. Lai AA and Schroeder DH. Clinical pharmacokinetics of bupropion: a review. J Clin 
Psychiatry.1983;44(5 Pt 2):82–4.
4. Food and Drug Administration Guidance for Industry: Pharmacokinetics in Patients 
with Impaired Hepatic Function- Study Design, Data Analysis, and Impact on Dosing 
and Labeling [updated May 2003; cited 12 Dec 2017]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/gui
dances/ucm072123.pdf.
5. European Medicines Agency. Guideline on the Evaluation of the Pharmacokinetics of 
Medicinal Products in Patients with Impaired Hepatic Function. 17 Feb 2005.  
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
09/WC500003122.pdf.
Accessed on 28 Dec 2017.
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11 PROCEDURES 
AND 
INSTRUCTIONS 
(ADMINISTRATIVE 
PROCEDURES)
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 additional approval by the applicable IRBs/IECs.  These requirements should in 
no way prevent any immediate action from being taken by the investigator, or by the sponsor, 
in the interest of preserving the safety of all subjects included in the study.  If the investigator 
determines that an immediate change to or deviation from the protocol is necessary for safety 
reasons to eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and 
the IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC 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.
11.1
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.2
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals. These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and IRB/IEC 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 which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, CT scans, magnetic resonance images, radioactive images, 
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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 and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.3
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as source document.  Any correction to entries made 
on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.4
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.
11.5
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).  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.
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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.
11.6
Auditing Procedures and Inspection
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations. If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.7
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor or designee.  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 designee, when approval is given by the sponsor, the investigator (or 
a designated pharmacist) will destroy supplies and containers at the site.
11.8
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.
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11.9
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.
11.10 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.11 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
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12 APPENDICES
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Page 61 of 66
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN 
–
10 
mg/dL 
≤0.59 
mmol/L 
with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Page 62 of 66
Appendix 2
List of Prohibited Concomitant Medications
If a medication is not presented in the list below, but does fit into a class of medications
noted in the list, the medical monitor must be consulted to determine whether it is
permitted.
Category
Medication
Anticholinergics(centrally-acting)
-
Anticonvulsants with known sedating effects
Barbiturates
Benzodiazepines
GABA analogues
Hydantoins
Phenyltriazines
Antihistamines (centrally-acting H1, including over-the-counter)

DiphenhydramineHCl

Carbinoxamine

Doxylamine

Dimenhyrinate

Triprolidine

Bromopheniramine

Chlorphemamine

Hydroxazine
Antihistamines with known sedating effects

Non-sedating, eg, loratadine is not
prohibited
Anxiolytics with known sedating effects

Lorazepam

Alprazolam

Buspirone
Strong CYP3A inhibitors
Amiodarone
Boceprevir
Clarithomycin
Cobicistat
Conivaptan
Danoprevir
Eltegravir
Fluvoxamine
Idelalisib
Indinavir
Itraconazole
Ketoconazole
Lopinavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
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Page 63 of 66
Category
Medication
Moderate CYP3A inhibitors
Amprenavir
Aprepitant
Atazanavir
Casopitant
Cimetidine
Ciprofloxacin
Crizotinib
Cyclosporine
Darunavir
Diltiazem
Dronedarone
Erythromycin
Faldaprevir
Fluconazole
Imatinib
Netupitant
Verampamil
CYP3A inducers
Avasimibe
Carbamazepine
Enzalutamide
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St John’s Wort Extract
Bosentan
Efavirenz
Etravirine
Lersivirine
Modafinil
Nafcillin
Talviraline
Thioridazine
Hypnotics
Melatonin
Prescribed or OTC
Herbal preparations with sedating effects
-
MAOIs
-
Opioid Analgesics
-
Muscle relaxants (centrally-acting) with known
GABA analogues
Hydantoins
Phenyltriazines
sedating effects
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Page 64 of 66
Category
Medication
Stimulants
Amphetamines
Modafinil
Armodafinil
Methylphenidate
Other
Warfarin, heparin, ticlopidine
Non-stimulant diet pills
Systemic isoretinoin
Systemicglucocorticoids
Tryptophan
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E2006-A001-104
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Confidential
Page 65 of 66
PROTOCOL SPONSOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-104
Study Protocol Title:
An Open-label, Parallel-Group Study to Evaluate the 
Pharmacokinetics of Lemborexant 
(E2006) and its 
Metabolites in Subjects with Mild and Moderate Hepatic 
Impairment Compared to Healthy Subjects
Investigational Product Name:
E2006/Lemborexant
IND Number:
111871
SIGNATURES
Authors:
 
Medical Development Center
Eisai Inc.
Neurology Business Group 
Eisai Inc.
Neurology Business Group
Eisai Inc.
 
Medical Development Center
Eisai Inc.
Date
Date
Date
Date
Page 66 of 133
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Page 66 of 66
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2006-A001-104
Study Protocol Title:
An Open-label, Parallel-Group Study to Evaluate the 
Pharmacokinetics of Lemborexant (E2006) and its Metabolites 
in Subjects with Mild and Moderate Hepatic Impairment 
Compared to Healthy Subjects
Investigational Product 
Name:
E2006/Lemborexant
IND Number:
111871
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
Page 67 of 133

SAP_003.pdf: 
 
 
Eisai, Inc. 
 
E2006-A001-104 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Issue Date 11-MAY-2018 
 
Template: WCT-TP-ST-005-003 
 
Page 1 of 29 
Effective Date: 05-SEP-2017 
 
Confidential 
 
 
 
Statistical Analysis Plan 
An Open-label, Parallel-Group Study to Evaluate the 
Pharmacokinetics of Lemborexant and its Metabolites in Subjects 
with Mild and Moderate Hepatic Impairment Compared to 
Healthy Subjects 
Protocol Number: E2006-A001-104 
 
Version 1.0 
Issue Date: 11-MAY-2018 
Authors: 
 
  
 
 
 
Previous Versions 
Not Applicable 
 
 
PPD
PPD


 
 
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SAP Amendments before database lock 
 
Version  Issue Date 
Section 
Revision/Addition 
Rationale 
 
 
 
 
 
 
 
 


 
 
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Table of Contents 
1 
INTRODUCTION ............................................................................................... 5 
2 
STUDY OBJECTIVES ....................................................................................... 5 
2.1 
Primary Objective ........................................................................................................... 5 
2.2 
Secondary Objectives...................................................................................................... 5 
2.3 
Exploratory Objectives ................................................................................................... 6 
3 
ENDPOINTS ....................................................................................................... 6 
3.1 
Pharmacokinetic Endpoints ............................................................................................ 6 
3.2 
Safety Endpoints ............................................................................................................. 7 
4 
SAMPLE SIZE .................................................................................................... 7 
5 
RANDOMIZATION ........................................................................................... 7 
6 
PLANNED ANALYSES ..................................................................................... 7 
6.1 
Analysis Sets ................................................................................................................... 7 
6.1.1 
Enrolled Subjects ...................................................................................................... 7 
6.1.2 
Pharmacokinetic Analysis Set................................................................................... 7 
6.1.3 
Safety Analysis Set ................................................................................................... 8 
6.2 
Derived Data ................................................................................................................... 8 
6.2.1 
Race........................................................................................................................... 8 
6.2.2 
MELD Score ............................................................................................................. 8 
6.2.3 
Pharmacokinetic Parameters ..................................................................................... 9 
6.2.4 
Baseline ................................................................................................................... 11 
6.2.5 
Duration/Study Day/Time ....................................................................................... 11 
6.2.6 
Conventions for Missing and Partial Dates ............................................................ 11 
6.2.7 
Unscheduled Visits ................................................................................................. 11 
6.2.8 
Potential Cataplexy AEs ......................................................................................... 11 
6.3 
Conventions .................................................................................................................. 12 
6.3.1 
Decimal Places ........................................................................................................ 13 
6.4 
Subject Disposition ....................................................................................................... 13 
6.5 
Protocol Deviations ....................................................................................................... 13 
6.6 
Inclusion and Exclusion Criteria ................................................................................... 14 
6.7 
Baseline Assessments ................................................................................................... 14 
6.8 
Medical History ............................................................................................................ 14 
6.9 
Prior and Concomitant Medications ............................................................................. 14 
6.10 
Viral Serology ............................................................................................................... 15 


 
 
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6.11 
Urine drug and alcohol screening ................................................................................. 15 
6.12 
Pregnancy Test .............................................................................................................. 15 
6.13 
Exposure to Study Drug ................................................................................................ 15 
6.14 
Efficacy Analyses ......................................................................................................... 15 
6.15 
Pharmacokinetic Analysis ............................................................................................. 15 
6.16 
Pharmacogenomic Analysis .......................................................................................... 17 
6.17 
Safety Analyses ............................................................................................................. 17 
6.17.1 
Adverse Events ....................................................................................................... 17 
6.17.2 
Laboratory Data ...................................................................................................... 18 
6.17.3 
Vital Signs ............................................................................................................... 19 
6.17.4 
Electrocardiogram Data .......................................................................................... 19 
6.17.5 
Physical Examination.............................................................................................. 19 
7 
INTERIM ANALYSIS ......................................................................................19 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................19 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................20 
10 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ................20 
10.1 
Pharmacokinetic Data Handling ................................................................................... 20 
10.1.1 
Lower Limit of Quantification of Plasma Concentration ....................................... 20 
11 REFERENCES ..................................................................................................21 
12 LIST OF TABLES, FIGURES AND LISTINGS .............................................22 
 
 
 


 
 
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1 INTRODUCTION 
This document details the planned statistical analyses for Eisai protocol E2006-A001-104. 
The proposed analyses are based on the contents of V2.0 of the protocol (dated 28-Feb-2018). 
This is a multicenter, single dose, open-label, parallel-group study in subjects with mild and 
moderate hepatic impairment and healthy control subjects matched with regard to age [±10 
years], sex, and body mass index [BMI, ±20%]. The study will enroll a total of 24 subjects, 
including 16 subjects with impaired hepatic function; 8 subjects each in of Child-Pugh class A 
(mild) and B (moderate). At least 8 healthy subjects will be dosed as one control cohort to match 
(1:1) to the subjects with hepatic impairment in each Child-Pugh class with regard to age, sex, 
and BMI. 
The study will consist of 2 phases: Prerandomization and Treatment. The Prerandomization 
Phase will include 2 study periods; Screening and Baseline (Day -1). The subjects will be 
admitted to the clinical facility on Day -1, remain confined to the clinic until Day 8, and then 
return to the clinical facility for additional pharmacokinetic (PK) sampling as outpatients until 
Day 14. In the event of early discontinuation of the subjects, the subjects with Child Pugh Class 
A and B (Cohorts A and B) and the matched controls (Cohort C) may be replaced. On Day 1, the 
subjects will be administered a single 10-mg dose of lemborexant with approximately 240 mL of 
water in the morning after an overnight fast. The blood samples for PK assessments will be 
collected at prespecified intervals up to 312 hours postdose administration. The subjects will be 
discharged on Day 14 of the study. In addition, the blood samples for plasma protein binding 
assessments of lemborexant will be collected from each subject at 2 time points; approximately 1 
hour and 24 hours postdose.  
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to assess the effect of mild and moderate hepatic impairment on the 
PK of lemborexant after a single dose administration. 
2.2 Secondary Objectives 
• To evaluate the effects of hepatic impairment on the PK of lemborexant metabolites M4, M9, 
and M10. 
• To evaluate the relationship between the PK parameters of lemborexant and its metabolites 
and the Child-Pugh Classification score, serum albumin, total bilirubin, and prothrombin 
time. 


 
 
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• To assess safety and tolerability of lemborexant following a single dose administration in 
subjects with mild and moderate hepatic impairment and healthy subjects. 
2.3 Exploratory Objectives 
To explore the relationship between the PK parameters of lemborexant and its metabolites and 
the model of end stage liver disease (MELD) score. 
3 ENDPOINTS 
3.1 
Pharmacokinetic Endpoints 
The endpoints are PK parameters derived by noncompartmental analysis using plasma 
concentrations of lemborexant and its metabolites. These parameters include, but are not limited 
to: 
Cmax 
maximum observed concentration 
tmax 
time at which the highest drug concentration occurs 
AUC(0-72) 
area under the concentration-time curve from zero time to 72 hours 
postdose 
AUC(0-t) 
area under the concentration-time curve from zero time to time of last 
quantifiable concentration 
AUC(0-inf) 
area under the concentration-time curve from zero time extrapolated to 
infinite time 
AUCex 
the percentage of AUC(0-inf) based on extrapolation 
t1/2 
terminal elimination phase half-life 
CL/F 
apparent total body clearance (lemborexant only) 
Vz/F 
apparent volume of distribution (lemborexant only) 
MPR AUC(0-inf) 
ratio of AUC(0-inf) of individual metabolite to AUC(0-inf) of lemborexant, 
corrected for molecular weights 
fu 
Plasma protein fraction unbound 
AUCu 
AUC(0-inf) values adjusted by unbound fraction in plasma (for lemborexant 
only) 
CLu/F 
Apparent clearance relative to the unbound plasma concentration based on 
AUCu (for lemborexant only) 
Lemborexant and its metabolites plasma concentrations will be listed and tabulated.   


 
 
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AUC(0-t), AUC(0-inf), and Cmax of lemborexant are the primary PK parameters. The rest of the 
parameters, including the PK parameters of the metabolites, are secondary endpoints.  
3.2 
Safety Endpoints 
Safety will be assessed by monitoring and recording all adverse events (AEs) and serious adverse 
events (SAEs), regular monitoring of hematology and blood chemistry, regular measurement of 
vital signs, Electrocardiogram (ECG) and the performance of physical examinations. 
4 SAMPLE SIZE 
A sample size of 8 subjects per each cohort of mild and moderate hepatic impairment, as defined 
by Child-Pugh classes A or B, is based on the recommendations in regulatory guidelines for a 
minimum number of subjects to be enrolled for moderate liver impairment cohort (FDA, 2003). 
Additionally, from single-dose studies of the 10-mg tablet (E2006-A001-004, E2006-A001-005, 
and E2006-A001-008), the pooled between-subject standard deviations of logarithmically 
transformed Cmax and AUC(0-inf) of lemborexant were 0.334 and 0.391 respectively. With a 
sample size of 8 subjects in each Child-Pugh category and at least 8 matched controls, a 2-sided 
90% confidence interval (CI) for the ratio for AUC(0-inf) will extend 0.322 from the observed 
mean difference on the log scale. 
5 RANDOMIZATION 
Not Applicable. 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive 
and the final clinical study report (CSR) may contain additional tables or statistical tests if 
warranted by the data obtained.  The justification for any such additional analyses will be fully 
documented in the final CSR. 
6.1 Analysis Sets 
6.1.1 Enrolled Subjects 
A subject is considered to be enrolled in the study if he/she has provided informed consent. 
6.1.2 Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set is the group of subjects who dosed with the test drug and 
had sufficient PK data to derive at least 1 PK parameter. 


 
 
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6.1.3 
Safety Analysis Set 
The Safety Analysis Set is the group of subjects who dosed with the test drug and had at least 
1 postdose safety assessment. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 MELD Score 
The MELD score at Screening for each subject (in each of the three cohorts) will be calculated as 
follows per the OPTN policy, January 2016 (pages 4-5)2: 
First the initial MELD score will be calculated: 
MELD(i) = [0.957 × loge(Creatinine)] + [0.378 × loge (bilirubin)] + [1.120 × loge (INR)] + 
0.643 
This value will be rounded to two decimal places and multiplied by 10. 
If calculated value for MELD(i) is > 11, the additional MELD calculation will be performed: 
MELD = MELD(i) + [1.32 × (137 – Serum Sodium)] – [ 0.033 × MELD(i) × (137 – Serum 
Sodium) ] 
This recalculated MELD value will be rounded to the nearest integer. If MELD(i) ≤ 11 then the 
recalculated MELD value will equal the initial MELD value. 
The following scheduled screening values are used: 
• Creatinine in mg/dL 
• Bilirubin in mg/dL 
• INR  
• Sodium in mmol/L 
Where the scheduled screening value is missing the first non-missing repeat scheduled value will 
be used. 


 
 
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The following additional rules will be followed: 
• If the Bilirubin, Creatinine, or INR value is <1.0 a value of 1.0 will be used in the 
calculation.  
• If Creatinine>4.0 mg/dL, a value of 4.0 will be used in the calculation 
• If Sodium <125 mmol/L, a value of 125 will be used in the calculation. 
• If Sodium >137 mmol/L a value of 137 will be used in the calculation. 
The maximum MELD score is 40. 
 
 
6.2.3 Pharmacokinetic Parameters  
Concentration time data for lemborexant and its metabolites will be provided following database 
lock and will be analyzed by non-compartmental methods using Phoenix™ WinNonlin® 
(Version 6.3 or later, Pharsight Corporation), in accordance with Eisai 302-104.00-MNL Non-
Compartmental Pharmacokinetic Analysis (effective date 08 Jun 2016). 
Concentrations that are below the limit of quantification (BLQ) will be treated in accordance 
with Section 2.5.1 of Eisai 302-104.00-MNL. During the pharmacokinetic analysis, BLQ values 
at predose up to the first quantifiable concentration will be set to zero; BLQ values between 2 
quantifiable concentrations will be set to “missing”; and quantifiable concentrations preceded by 
2 or more consecutive BLQ values in the terminal phase will be set to missing. 
The following PK parameters will be calculated for lemborexant and its metabolites (as data 
permit): 
Cmax 
Maximum plasma concentration determined directly from individual 
concentration-time data, reported to 3 significant figures 
tmax 
Time to reach maximum plasma concentration determined directly from 
individual concentration-time data, reported to 2 decimal places 
AUC(0-72) 
Area under the plasma concentration–time curve from time zero to 
72 hours postdose; calculated using the linear-log trapezoidal rule (linear-
up log-down), reported to 3 significant figures 
AUC(0-t) 
Area under the plasma concentration–time curve from time zero to the 
time of the last quantifiable concentration; calculated using the linear-log 
trapezoidal rule (linear-up log-down), reported to 3 significant figures 


 
 
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AUC(0-inf) 
Area under the plasma concentration–time curve extrapolated to infinity, 
reported to 3 significant figures and calculated as:  
AUC(0-inf) = AUC(0-t) + Clast/λz 
AUCex 
The percentage of AUC0-inf based on extrapolation, reported to 3 
significant figures and calculated as:  
%AUCex=(AUC(0-inf) – AUC(0-t))/AUC(0-inf)*100 
t½ 
 
 
The observed terminal elimination half-life, calculated as:  
t½= ln(2)/λz; see additional criteria below, reported to 3 significant figures 
λz 
The observed elimination rate constant; estimated by linear regression 
through at least three data points (not including tmax) in the terminal phase 
of the log concentration-time profile; see additional criteria below, 
reported to 3 significant figures 
CL/F 
Apparent body clearance, reported to 3 significant figures and calculated 
as:  CL/F = Dose/AUC(0-inf); calculated for lemborexant only 
Vz/F 
Apparent volume of distribution based on the terminal phase, reported to 
3 significant figures and calculated as: Dose/(λz×AUC(0-inf)); calculated for 
lemborexant only 
MPR AUC(0-inf) 
Ratio of AUC(0-inf) of individual metabolite to AUC(0-inf) of lemborexant, 
corrected for molecular weights, reported to 3 significant figures 
fu 
 
 
plasma protein unbound fraction, reported to 3 significant figures 
AUCu 
AUC(0-inf) values adjusted by unbound fraction in plasma, reported to 
3 significant figures; calculated for lemborexant only 
CLu/F 
Apparent clearance relative to the unbound plasma concentration based on 
AUCu, reported to 3 significant figures (for lemborexant only) 
 
At least 3 time points with quantifiable plasma concentrations will be required for the calculation 
of AUC(0-t).  Individual AUC(0-inf) values for which AUCex >20% will be retained in the end of 
text tables and will not be included in the summary statistics. Individual AUC(0-inf) values for 
which AUCex >20% may be included in the summary statistics if approved by the Sponsor. 
At least 3 time points (of which the first time point must be greater than tmax) with quantifiable 
plasma concentrations will be required for the calculation of λz.   


 
 
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No value for λz and other λz-related parameters (AUC(0-inf), t1/2, CL/F, etc.) will be reported for 
lemborexant and its metabolites if the PK Analyst or the Sponsor decides a reliable estimate of λz 
is not possible after considering the following factors: 
1) 
The duration of time over which λz is estimated (λz range) is less than twice the 
subsequently estimated terminal elimination phase half-life (t½).  
2) 
The adjusted regression coefficient (R2 adj) is not ≥ 0.90; and 
3) 
The concentration profiles do not exhibit a terminal elimination phase in the 
concentration versus time profile. 
4)  
If the % extrapolation is > 20, related parameters AUC(0-inf), CL/F, and Vz/F will 
be reported based on the pharmacokineticist’s judgment. 
6.2.4 Baseline 
Baseline for the safety variables is defined as the last non missing value (either scheduled, 
unscheduled or repeat) before the subject receives the dose of lemborexant on Day 1. For 
laboratory variables only results provided by the Worldwide Clinical Trials laboratory will be 
used as baseline values. 
6.2.5 Duration/Study Day/Time  
Study day will be calculated as the number of days from the dose of lemborexant on Day 1 using 
the following rules:  
• date of event – date of first dose + 1, for events on or after first dose  
• date of event – date of first dose, for events before first dose.   
6.2.6 Conventions for Missing and Partial Dates 
All dates presented in the individual subject listings will be as recorded on the electronic case 
report form (eCRF). 
6.2.7 Unscheduled Visits 
Only scheduled post baseline laboratory and vital signs values will be tabulated. Post baseline 
repeat/unscheduled assessments will be disregarded unless otherwise stated, although these post 
baseline assessments will be listed in Appendix 16.2.   
6.2.8 Potential Cataplexy AEs 
Potential AEs of Cataplexy are identified as those AEs with a verbatim term coded to one of the 
following MedDRA preferred terms: 


 
 
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Cataplexy 
Dysarthria 
Apallic syndrome 
Presyncope 
Muscle fatigue 
Slow speech 
Consciousness 
fluctuating 
Transient ischaemic 
attack 
Muscular weakness 
Heteronymous 
diplopia 
Depressed level of 
consciousness 
Amaurosis fugax 
Muscular tone disorder 
Homonymous diplopia 
Lethargy 
Capsular warning 
syndrome 
Hypotonia 
Eyelid myoclonus 
Loss of consciousness 
Reversible ischaemic 
neurological deficit 
Drop attack 
Myoclonus 
Sopor 
 
Slurred speech 
Opsoclonus myoclonus Stupor 
 
Diplopia 
Clonus 
Transient global 
amnesia 
 
Falls 
Altered state of 
consciousness 
Syncope 
 
 
Such AEs are identified on the eCRF by an answer of ‘Yes’ to the question ‘Potential Cataplexy 
AE?’. 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS1 version 
9.4 or higher or Phoenix™ WinNonlin® (Version 6.3 or later, Pharsight Corporation). 
Listings will be sorted in the following order: cohort (Child Pugh Class A, Child Pugh Class B, 
followed by Healthy Subject cohort), subject, parameter, and day, unless otherwise stated. All 
data will be listed.  
Continuous variables will be summarized by the number of non missing observations, mean, 
median, standard deviation (SD), and minimum and maximum. For all tabulations of changes 
from baseline data, the lower and upper 95% confidence limits for the mean for the individual 
treatments will be given. In addition PK parameter data will have the geometric mean and 
coefficient variation (CV%) presented. CV% will be calculated as sqrt(exp[SD2 of log 
transformed data]-1)*100. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  


 
 
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6.3.1 Decimal Places 
For pharmacokinetic data, when presenting individual/raw (raw, hereafter) values and summary 
statistics, the following rules will be applied:  for drug concentrations and concentration-
dependent pharmacokinetic parameters, all summary statistics (mean, median, geometric mean, 
SD, and CV%) will have 3 significant digits.  For tmax, raw values and summary statistics will be 
presented to 2 decimal places.  
The adjusted regression coefficient (R2 adj) will be presented to 3 significant digits. The number 
of time points used in the lambda-z estimates will be presented as an integer number. Lower and 
upper times of the lambda-z range will be presented to the same precision as the actual sampling 
time after dosing used for the calculation of PK parameters. 
For all other data, means, medians and percentiles will be displayed to one more decimal place 
than the data, dispersion statistics (e.g. standard deviation) will have two more decimal places, 
and the minimum and maximum will be displayed to the same number of decimal places as 
reported in the raw data. Percentages will be displayed with one decimal place.  
6.4 Subject Disposition 
Subject disposition will be listed and summarized as follows:  
• The number of subjects who are in each analysis set will be summarized for all enrolled 
subjects by cohort and overall. 
• The number of subjects who failed screening and the reasons for failure will be tabulated 
overall. 
• The number of subjects who complete the study will be tabulated for all enrolled subjects 
by cohort and overall. 
• The number of early terminations and the primary reasons for terminations will be 
tabulated for all enrolled subjects by cohort and overall. Secondary reasons for 
termination will be listed. 
• Disposition data for all subjects screened will be listed. 
6.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2. Protocol deviations will be 
categorized as either major or minor by Eisai prior to DB lock.   


 
 
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6.6 Inclusion and Exclusion Criteria 
A listing of violators of the inclusion and exclusion criteria will be provided within 
Appendix 16.2.  
6.7 Baseline Assessments 
Standard continuous or categorical variable summaries will be presented by cohort and overall 
for the following variables based on the Safety Analysis Set. 
• Demographic data, data for all screened subjects will be listed. 
• Weight at screening (kg) 
• Height at screening (cm) 
• BMI at screening (kg/m2) 
• Child Pugh Score 
• Recalculated MELD Score (Initial MELD score will be listed only) 
• Serum Albumin at Screening 
• Total Bilirubin at Screening 
• PT at Screening 
• INR at Screening 
• Creatinine at Screening 
6.8 Medical History 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit. Separate listings of previous and ongoing conditions at screening will be presented for the 
Safety Analysis Set. Conditions will be coded using the Medical Dictionary of Regulated 
Activities (MedDRA) primary system organ class and preferred term. 
6.9 Prior and Concomitant Medications  
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes. Non 
pharmacological procedures will be recorded in the CRF but not coded. Prior and concomitant 
medications will be listed. Prior medications will be defined as medications that stopped before 
the first dose of lemborexant. Concomitant medications will be defined as medications that 
started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or started after the date of the first dose of study drug. 


 
 
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6.10 Viral Serology 
A listing of viral serology results will be provided within Appendix 16.2. 
6.11 Urine drug and alcohol screening 
A listing of urine drug and alcohol screening results will be provided within Appendix 16.2. 
6.12 Pregnancy Test 
A listing of serum and urine pregnancy test results will be provided within Appendix 16.2. 
6.13 Exposure to Study Drug 
A listing of dosing information will be provided within Appendix 16.2. 
6.14 Efficacy Analyses 
Not Applicable 
6.15  Pharmacokinetic Analysis 
The Safety Analysis Set will be used for individual plasma concentration listings. The PK 
Analysis Set will be used for summaries of plasma concentrations and for analyses, summaries, 
and listings of PK parameters.  
Blood samples (4 mL each) for PK assessments of lemborexant and its metabolites (M4, M9, and 
M10) will be collected at predose (0 hour), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 
168, 216, 264, and 312 hours postdose. In addition, blood samples for protein binding (12 mL 
per time point) of lemborexant and metabolites will be collected at 1 and 24 hours postdose 
matching the PK sample collection at those time points.  
For presentation of the individual data, BLQ values prior to the first non-zero concentration will 
be set to zero in the linear plots; BLQ values after the first non-zero concentration will be set to 
missing in the linear plots; and all BLQ values will be set to missing in the semi-logarithmic 
plots. 
For calculation of mean concentrations, all BLQ values will be assigned as zero. If the 
proportion of values reported as BLQ is more than 50% or if the calculated mean is less than the 
lower limit of quantification (LLOQ) at a given sampling time, the mean will be treated as 
follows: zero for time points prior to the first non-zero mean concentrations in the linear plots; 
missing for time points after the first non-zero mean concentration in the linear plots; and 
missing for all BLQ values in the semi-logarithmic plots. 


 
 
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Plasma concentration data will be tabulated by nominal time and summarized by analyte and 
group using descriptive statistics [number of observations (n), arithmetic mean, standard 
deviation (SD), minimum (min), median and maximum (max)].  
Mean plasma concentration-time data (using linear and semi-logarithmic scales) will be 
presented graphically; mean data will be plotted using nominal sample times.   
PK parameters for lemborexant and its metabolites (M4, M9, and M10) will be calculated as 
described in section 6.2.3. 
The adjusted regression coefficient (R2 adj), number of time points used in the lambda-z 
estimates, and the lower and upper times of the lambda-z range will also be listed.  
PK parameters will be summarized overall by treatment and by treatment stratified by analyte 
and group using descriptive statistics (n, mean, SD, min, median, max, geometric mean, CV%, 
calculated as: sqrt(exp[std^2 of log transformed data]-1)*100]).  
The rules for presenting raw individual values and summary statistics for PK concentration and 
parameter data are provided in section 6.3.1. 
Protein Binding 
Blood samples for plasma protein binding for lemborexant will be collected for each subject at 2 
time points: 1 hour and 24 hours postdose. Protein binding data will be provided by the vendor to 
WCT as a percentage; if more than one value is available for either time point, the average of the 
protein binding values will be used in the calculations. Protein binding results will be presented 
as fractions and percentages. 
Protein binding will be calculated for metabolites without any assessment of PK parameters. 
Evaluation of the impact of hepatic impairment on drug exposure: 
The effect of hepatic impairment on the PK of lemborexant, the primary PK parameters based on 
total Cmax, AUC(0-72h), AUC(0-t), and AUC(0-inf) will be compared between the cohort of healthy 
normal controls and the cohorts of subjects with mild and moderate hepatic impairment as 
defined by Child-Pugh classes A or B. A general linear model of logarithmically transformed 
values with hepatic function class as a fixed effect will be utilized to estimate the geometric 
mean ratio (and two-sided 90% confidence intervals) of subjects with mild/normal and 
moderate/normal hepatic function. Similar statistical analyses will be conducted for the PK 
parameters of the metabolites and unbound lemborexant as secondary endpoints. Protein binding 
will be calculated for metabolites without any assessment of PK Parameters. Summary statistics 
will be generated for each of the PK parameters for each Child-Pugh class and healthy controls  


 
 
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Scatter plots of PK parameters (Cmax, AUC(0-72), AUC(0-t) and AUC(o-inf)) of lemborexant and its 
metabolites versus Child-Pugh Score at Screening will be provided. The association between the 
primary PK parameters and Child-Pugh Score will be evaluated by regression analysis (the PK 
parameter as a dependent variable and Child-Pugh Score as an independent variable). For 
subjects in the Healthy cohort the Child-Pugh score will be set to zero in the scatter plots and 
regression analysis.  Similar analyses will be performed for the following measurements at 
Screening: MELD score, serum albumin, total bilirubin, PT, and creatinine. Additionally, 
association between the PK parameters and liver transaminase levels at Screening (ALT and 
AST) will be performed, if deemed necessary. 
6.16 Pharmacogenomic Analysis 
Not Applicable. 
6.17 Safety Analyses 
The safety analyses will be presented by cohort for the Safety Analysis Set.  
6.17.1 Adverse Events 
A treatment-emergent adverse event (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. 
The following tables will be presented for AEs: 
• Overall incidence by cohort in the number of TEAEs, SAEs and events associated with 
special situations, AEs related to study treatment, SAEs that are related to study 
treatment, AEs leading to discontinuation and Potential Cataplexy AEs (as defined in 
Section 6.2.8).  
• TEAEs by system organ class and preferred term - incidence.  
• TEAEs by system organ class, preferred term and maximum severity -  incidence 
• Treatment-related TEAEs by system organ class and preferred term -.  
• SAEs and deaths by system organ class and preferred term – incidence overall and for 
those related to treatment. 


 
 
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• Treatment-emergent, non-serious AEs by system organ class and preferred term – 
incidence overall and for those related to treatment. 
A subject will only be counted once within a specific system organ class and preferred term, 
even if the subject experienced more than one TEAE within that specific system organ class and 
preferred term.  
Listings of adverse events will be provided in the following categories: 
• TEAEs 
• Non treatment-emergent AEs 
• Deaths  
• Serious TEAEs and events associated with special situations 
• AEs leading to discontinuation  
• Potential Cataplexy AEs 
If an AE has missing relationship it is assumed to be related to the study drug for the purpose of 
summarizing the data. For an AE with missing severity the severity will be reported as “missing” 
if the subject has not reported another AE within the same level of summarization (i.e. system 
organ class or preferred term). If the subject has reported more than one AE within the same 
level then the worst severity will be used in the tabulation.  
For Potential Cataplexy AEs data from the supplemental information questionnaire will be listed. 
6.17.2 Laboratory Data 
Laboratory data at Day -1 was analyzed by both a local laboratory and Worldwide Clinical Trials 
laboratory. Data from both laboratories will be listed but summary tables will only include data 
provided by Worldwide Clinical Trials. 
All laboratory data will be listed and summarized using the International System of Units (SI). 
For continuous variables descriptive statistics of the observed values and change from baseline 
will be presented by cohort at each scheduled assessment and Early Termination (if applicable) 
for each hematology, serum chemistry, urinalysis, and coagulation parameter. For categorical 
variables the number and percentage of subjects in each reported level will be presented. Each 
hematology, serum chemistry, and urinalysis measurement will be classed as below, within, or 
above normal range, based on ranges supplied by the laboratory used. Shift tables in relation to 
the normal range from baseline to each post baseline assessment and Early Termination (if 
applicable) will be presented. 


 
 
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A listing of any markedly abnormal laboratory measurements (defined as meeting the criteria for 
grade 2 or higher in the sponsors grading of laboratory values presented in Appendix 1 to the 
study protocol) that were recorded throughout the study will be presented. The incidence of 
markedly abnormal laboratory results over the course of the study will be listed. 
6.17.3 Vital Signs 
Descriptive statistics of the observed values and change from baseline will be presented by 
cohort and timepoint for the following: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm)  
• Respiration Rate (breaths/min) 
• Body Temperature (degrees Celsius) 
The incidence of subjects reporting an increase or decrease greater than 20mmHg in systolic or 
15 mmHg in diastolic blood pressure relative to baseline will be summarized at each post 
baseline assessment. 
Weight at Day -1 will be listed only. 
6.17.4 Electrocardiogram Data 
Shift tables in relation to the overall interpretation (Normal, Abnormal Not Clinically Significant 
[NCS], and Abnormal Clinically Significant [CS]) from baseline to each post baseline 
assessment will be presented by cohort and overall. 
6.17.5 Physical Examination 
Significant findings at the Screening physical examination will be recorded on the Medical 
History and Current Medical Conditions CRF page and changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse Events 
CRF, this data will be listed as described in the previous sections. 
7 INTERIM ANALYSIS 
No interim analyses are planned.  
8 DATA SAFETY MONITORING BOARD ANALYSIS 
There is no data safety monitoring board (DSMB) for this study. 


 
 
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9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
None. 
10 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING  
10.1 Pharmacokinetic Data Handling 
10.1.1 Lower Limit of Quantification of Plasma Concentration 
The LLOQ for lemborexant and its metabolites (M4, M9, and M10) is 0.0500 ng/mL in plasma 
 
 


 
 
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11 REFERENCES 
1 SAS Institute Inc.   Cary, NC, SAS Institute Inc 
2 https://optn.transplant.hrsa.gov/media/1575/policynotice_20151101.pdf 
 


 
 
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12 LIST OF TABLES, FIGURES AND LISTINGS 
Please note: Table, Listing, and Figure titles are subject to change upon final analysis. Tables, 
Listings, and Figures may be consolidated as necessary. 
Table 
Number 
Table Title 
14.1.1 
Subject Disposition 
14.1.1.1 
Subject Disposition 
Enrolled Subjects 
14.1.1.2 
Screening Failures 
14.1.3 
Demography, Baseline Characteristics, Treatment Compliance, and 
Analysis Populations 
14.1.3.1 
Datasets Analyzed 
Enrolled Subjects 
14.1.4.1.1 
Demography and Baseline Characteristics 
Safety Analysis Set 
14.2 
PK Analysis 
14.2.2.1 
Descriptive Statistics for Lemborexant and Metabolites Concentration-Time 
Data after Administration of Lemborexant 10 mg to Subjects with Mild 
Hepatic Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), 
or Normal Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.2.2 
Descriptive Statistics for Percent Bound and Unbound of Lemborexant and 
Metabolites in Plasma after Administration of Lemborexant 10 mg to 
Subjects with Mild Hepatic Impairment (Cohort A), Moderate Hepatic 
Impairment (Cohort B), or Normal Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.3.1 
Descriptive Statistics for Pharmacokinetic Parameters of Lemborexant after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.3.2 
Descriptive Statistics for Pharmacokinetic Parameters of M4 after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.3.3 
Descriptive Statistics for Pharmacokinetic Parameters of M9 after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 


 
 
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Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.3.4 
Descriptive Statistics for Pharmacokinetic Parameters of M10 after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.4.1 
Statistical Analysis of the Natural Log-Transformed Systemic Exposure 
Parameters of Lemborexant (Mild or Moderate Hepatic Impairment vs. 
Normal Hepatic Function) 
PK Analysis Set 
14.2.4.2 
Statistical Analysis of the Natural Log-Transformed Systemic Exposure 
Parameters of M4 (Mild or Moderate Hepatic Impairment vs. Normal Hepatic 
Function) 
PK Analysis Set 
14.2.4.3 
Statistical Analysis of the Natural Log-Transformed Systemic Exposure 
Parameters of M9 (Mild or Moderate Hepatic Impairment vs. Normal Hepatic 
Function) 
PK Analysis Set 
14.2.4.4 
Statistical Analysis of the Natural Log-Transformed Systemic Exposure 
Parameters of M10 (Mild or Moderate Hepatic Impairment vs. Normal 
Hepatic Function) 
PK Analysis Set 
14.3.1 
Safety - AEs 
14.3.1.2.1 
Summary of Treatment-Emergent Adverse Event Reporting 
Safety Analysis Set 
14.3.1.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term 
Safety Analysis Set 
14.3.1.3.2 
Serious Adverse Events and Deaths by Primary System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.1.4.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity 
Safety Analysis Set 
14.3.1.5.1 
MedDRA Summary of Treatment-Emergent Treatment-related Adverse 
Events by Primary System Organ Class and Preferred Term 
Safety Analysis Set 


 
 
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14.3.1.6.1 
Treatment-Emergent Non-serious Adverse Events by Primary System Organ 
Class and Preferred Term 
Safety Analysis Set 
14.3.2 
Safety – Other AEs 
14.3.2.1.1 
Listing of Deaths 
Safety Analysis Set 
14.3.2.2.1 
Listing of Serious Adverse EventsSafety Analysis Set 
14.3.2.3.1 
Listing of Adverse Events Leading to Study Drug Discontinuation 
 Safety Analysis Set 
14.3.2.4.1 
Listing of Potential Cataplexy Adverse Events 
 Safety Analysis Set 
14.3.2.4.2 
Listing of Supplemental Information Questionnaire for Potential Cataplexy 
Adverse Events 
Safety Analysis Set 
14.3.4 
Safety - Other 
14.3.4.1.1.1 Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment 
Safety Analysis Set 
14.3.4.1.2.1 Normal Range Shifts in Hematology from Baseline to each Follow-up 
Assessment 
Safety Analysis Set 
14.3.4.2.1.1 Summary Statistics for the Change from Baseline in Chemistry at each 
Follow-up Assessment 
Safety Analysis Set 
14.3.4.2.2.1 Normal Range Shifts in Chemistry from Baseline to each Follow-up 
Assessment 
Safety Analysis Set 
14.3.4.3.1.1 Summary Statistics for the Change from Baseline in Urinalysis at each 
Follow-up Assessment 
Safety Analysis Set 
14.3.4.3.2.1 Normal Range Shifts in Urinalysis from Baseline to each Follow-up 
Assessment 
Safety Analysis Set 
14.3.4.4.1.1 Summary Statistics for the Change from Baseline in Coagulation at each 
Follow-up Assessment 
Safety Analysis Set 
14.3.4.4.2.1 Listing of Markedly Abnormal Laboratory Results 
 Safety Analysis Set 
14.3.4.5.2.1 Summary Statistics for the Change from Baseline in Vital Signs at each 


 
 
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Follow-up Assessment 
Safety Analysis Set 
14.3.4.6.2.1 Change from Baseline in the ECG Interpretation at each Follow-up 
Assessment 
Safety Analysis Set 
 
 


 
 
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Figure 
Number 
Figure Title 
14.2 
PK Analysis 
14.2.2.1 
Mean Lemborexant and Metabolites Concentration-Time Profiles after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) on Linear and Semi-Logarithmic Scales  
PK Analysis Set 
14.2.2.2 
Lemborexant and Metabolites Concentration-Time Profiles for All Subjects 
after Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A) on Linear and Semi-Logarithmic Scales 
Safety Analysis Set 
14.2.2.3 
Lemborexant and Metabolites Concentration-Time Profiles for All Subjects 
after Administration of Lemborexant 10 mg to Subjects with Moderate 
Hepatic Impairment (Cohort B) on Linear and Semi-Logarithmic Scales 
Safety Analysis Set 
14.2.2.4 
Lemborexant and Metabolites Concentration-Time Profiles for All Subjects 
after Administration of Lemborexant 10 mg to Subjects with Normal Hepatic 
Function (Cohort C) on Linear and Semi-Logarithmic Scales 
Safety Analysis Set 
14.2.2.5 
Concentration-Time Profiles after Administration of Lemborexant and 
Metabolites with Linear Regression for Estimating the Terminal Elimination 
Rate  
Safety Analysis Set 
14.2.2.6 
Box Plot Comparing Lemborexant and Metabolites Cmax Values after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.2.7 
Box Plot Comparing Lemborexant and Metabolites AUC(0-72) Values after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.2.8 
Box Plot Comparing Lemborexant and Metabolites AUC(0-t) Values after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 


 
 
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E2006-A001-104 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Issue Date 11-MAY-2018 
 
Template: WCT-TP-ST-005-003 
 
Page 27 of 29 
Effective Date: 05-SEP-2017 
 
Confidential 
14.2.2.9 
Box Plot Comparing Lemborexant and Metabolites AUC(0-inf) Values after 
Administration of Lemborexant 10 mg to Subjects with Mild Hepatic 
Impairment (Cohort A), Moderate Hepatic Impairment (Cohort B), or Normal 
Hepatic Function (Cohort C) 
PK Analysis Set 
14.2.2.10 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Child-Pugh Score at Screening 
PK Analysis Set 
14.2.2.11 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus MELD Score at Screening 
PK Analysis Set 
14.2.2.12 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Serum Albumin at Screening 
PK Analysis Set 
14.2.2.13 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Total Bilirubin at Screening 
PK Analysis Set 
14.2.2.14 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Prothrombin Time at Screening 
PK Analysis Set 
14.2.2.15 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Creatinine at Screening 
PK Analysis Set 
14.2.2.16 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus ALT at Screening 
PK Analysis Set 
14.2.2.17 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus AST at Screening 
PK Analysis Set 
 
 


 
 
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E2006-A001-104 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Issue Date 11-MAY-2018 
 
Template: WCT-TP-ST-005-003 
 
Page 28 of 29 
Effective Date: 05-SEP-2017 
 
Confidential 
Listing 
Number 
Listing Title 
16.2.1 
Subject Disposition 
16.2.1.1 
Subjects Disposition 
Enrolled Subjects 
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations 
Safety Analysis Set 
16.2.2.2 
Inclusion/Exclusion Not Met 
16.2.3 
Demography, Baseline Characteristics, Treatment Compliance, and 
Analysis Populations 
16.2.3.1 
Analysis Populations 
Enrolled Subjects 
16.2.4.1 
Demographics 
Enrolled Subjects 
16.2.4.2 
Child Pugh Classification 
Safety Analysis Set 
16.2.4.3 
Previous Medical History 
Safety Analysis Set 
16.2.4.4 
Ongoing Medical History 
Safety Analysis Set 
16.2.4.5 
Prior Medications 
Safety Analysis Set 
16.2.4.6 
Concomitant Medications 
Safety Analysis Set 
16.2.5.1 
Dosing Information 
Safety Analysis Set 
16.2.6 
PK 
16.2.6.1 
Lemborexant and Metabolites Concentration-Time and Protein Binding Data 
Listing by Subject 
Safety Analysis Set 
16.2.6.2 
Lemborexant Pharmacokinetic Parameter Listing by Subject 
PK Analysis Set 
16.2.6.3 
M4, M9, and M10 Pharmacokinetic Parameter Listing by Subject 
PK Analysis Set 
16.2.6.4 
Terminal Elimination Rate of Lemborexant and Metabolites 
for Individual Subjects after Administration of Lemborexant 10 mg to 
Subjects with Mild Hepatic Impairment (Cohort A), Moderate Hepatic 


 
 
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E2006-A001-104 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Issue Date 11-MAY-2018 
 
Template: WCT-TP-ST-005-003 
 
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Effective Date: 05-SEP-2017 
 
Confidential 
Impairment (Cohort B), or Normal Hepatic Function (Cohort C) 
PK Analysis Set 
16.2.6.5 
PK Text Output 
16.2.6.6 
ANOVA SAS Output Text 
16.2.7 
Safety – AEs 
16.2.7.1 
Adverse Events 
Safety Analysis Set 
16.2.8 
Safety – Labs 
16.2.8.1 
Hematology 
Safety Analysis Set 
16.2.8.2 
Serum Chemistry 
Safety Analysis Set 
16.2.8.3 
Urinalysis 
Safety Analysis Set 
16.2.8.4 
Coagulation 
Safety Analysis Set 
16.2.8.5 
Viral Serology 
Safety Analysis Set 
16.2.8.6 
Drug and Alcohol Screen 
Safety Analysis Set 
16.2.8.7 
Pregnancy 
Safety Analysis Set 
16.2.8 
Safety – Other 
16.2.8.8 
Vital Signs Data 
Safety Analysis Set 
16.2.8.9 
ECG Data 
Safety Analysis Set 
16.2.8.10 
Height and Weight Data 
Safety Analysis Set 
 


 
 
 
 
Eisai, Inc. 
E2006-A001-104 
Post database lock SAP Addendum  
Version: 1.0 
Issue Date: 24-JUL-2018 
 
Template: WCT-TP-ST-008-01 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
POST DATABASE LOCK ADDENDUM 
 
An Open-label, Parallel-Group Study to Evaluate the Pharmacokinetics of Lemborexant and its 
Metabolites in Subjects with Mild and Moderate Hepatic Impairment Compared to Healthy 
Subjects 
 
Protocol Ref: E2006-A001-104 
Version: 1.0 
Date effective:  24-JUL-2018 
 
 
 
 
 


 
 
 
 
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E2006-A001-104 
Post database lock SAP Addendum  
Version: 1.0 
Issue Date: 24-JUL-2018 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
 
SUMMARY OF SECTIONS 
 
1 
INTRODUCTION 
 
 
 
 
 
 
 
 
2 
CHANGES/ADDITIONS TO EXISTING ANALYSIS PLAN 
 
 
 
 
 
 
 


 
 
 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
1. INTRODUCTION 
This document is a post database lock addendum to the statistical analysis plan dated 
11 May 2018 which details the planned statistical analyses for the Eisai protocol E2006-A001-
104.  
 
2. CHANGES/ADDITIONS TO EXISTING ANALYSIS PLAN 
Section 6.2.3 Pharmacokinetic Parameters 
The following parameter was added during the pharmacokinetic analysis, and included in 
subsequent comparisons across treatments. 
AUC(0-8) 
Area under the plasma concentration–time curve from time zero to 8 h 
post dose; calculated using the linear-log trapezoidal rule (linear-up 
log-down), reported to 3 significant figures 
 
Section 6.15 Pharmacokinetic Analysis 
Descriptive statistics for unbound fraction protein were added.  Additional figures; Scatterplots 
for Pharmacokinetic Parameters of Lemborexant and Metabolites versus Cohort, Scatterplots for 
Pharmacokinetic Parameters Adjusted by Unbound Fraction in Plasma, Protein binding box 
plots, AUC0-8 box plots comparing Lemborexant and Metabolites, and mean profiles truncated 
to 24 hours Postdose were added. 
Section 12, LIST OF TABLES, FIGURES AND LISTINGS: 
Minor updates were made to the order, numbering, and/or titles of the planned tables, listings, 
and figures containing pharmacokinetic data (concentration-time data, pharmacokinetic 
parameters, statistical analysis), and new outputs were added. 
The pharmacokinetic tables in Section 16 were updated as follows: 
Table added: 
Table  
Title 
14.2.2.3 
Descriptive Statistics for the Unbound Fraction (%) of Lemborexant 
and Metabolites in Plasma after Administration of Lemborexant 10 mg 
to Subjects with Mild Hepatic Impairment (Cohort A), Moderate 


 
 
 
 
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Version: 1.0 
Issue Date: 24-JUL-2018 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Hepatic Impairment (Cohort B), or Normal Hepatic Function (Cohort 
C) - PK Analysis Set 
14.2.2.4 
Descriptive Statistics for the Percent Unbound Fraction of 
Lemborexant and Metabolites in Plasma after Administration of 
Lemborexant 10 mg to Subjects with Mild Hepatic Impairment (Cohort 
A), Moderate Hepatic Impairment (Cohort B), or Normal Hepatic 
Function (Cohort C) with Averaged Time Points (1h and 24h) - PK 
Analysis Set 
14.2.2.5 
Descriptive Statistics for the Fraction Unbound Protein of 
Lemborexant and Metabolites in Plasma after Administration of 
Lemborexant 10 mg to Subjects with Mild Hepatic Impairment (Cohort 
A), Moderate Hepatic Impairment (Cohort B), or Normal Hepatic 
Function (Cohort C) with Averaged Time Points (1h and 24h) - PK 
Analysis Set 
14.2.3.5 
Descriptive Statistics for Pharmacokinetic Parameters of Lemborexant 
Adjusted by Unbound Fraction in Plasma after Administration of 
Lemborexant 10 mg to Subjects with Mild Hepatic Impairment (Cohort 
A), Moderate Hepatic Impairment (Cohort B), or Normal Hepatic 
Function (Cohort C) - PK Analysis Set 
 
The pharmacokinetic listings in Section 16 were updated as follows: 
Revised title: 
Listing 
Title 
16.2.6.6 
Lemborexant ANOVA SAS Output Text – PK Analysis Set 
 
New Listings: 
Listing 
Title 
16.2.6.7 
M4 ANOVA SAS Output Text – PK Analysis Set 
16.2.6.8 
M9 ANOVA SAS Output Text – PK Analysis Set 
16.2.6.9 
M10 ANOVA SAS Output Text – PK Analysis Set 
16.2.6.10 
Lemborexant and Metabolites Pharmacokinetic Parameters Adjusted 
by Unbound Fraction in Plasma by Subject - PK Analysis Set 
 
The pharmacokinetic figures in Section 14 were updated to the following: 


 
 
 
 
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E2006-A001-104 
Post database lock SAP Addendum  
Version: 1.0 
Issue Date: 24-JUL-2018 
 
Template: WCT-TP-ST-008-01 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Population changed: 
Figure 
Title 
14.2.2.5 
Concentration-Time Profiles after Administration of Lemborexant and 
Metabolites with Linear Regression for Estimating the Terminal 
Elimination Rate - PK Analysis Set 
 
Figure added: 
Figure 
Title 
14.2.2.7 
Box Plot Comparing Lemborexant and Metabolites AUC(0-8) Values 
after Administration of Lemborexant 10 mg to Subjects with Mild 
Hepatic Impairment (Cohort A), Moderate Hepatic Impairment (Cohort 
B), or Normal Hepatic Function (Cohort C) - PK Analysis Set 
 
Figures renumbered: 
Figure 
Title 
14.2.2.8 
Box Plot Comparing Lemborexant and Metabolites AUC(0-72) Values 
after Administration of Lemborexant 10 mg to Subjects with Mild 
Hepatic Impairment (Cohort A), Moderate Hepatic Impairment (Cohort 
B), or Normal Hepatic Function (Cohort C) - PK Analysis Set 
14.2.2.9 
Box Plot Comparing Lemborexant and Metabolites AUC(0-t) Values 
after Administration of Lemborexant 10 mg to Subjects with Mild 
Hepatic Impairment (Cohort A), Moderate Hepatic Impairment (Cohort 
B), or Normal Hepatic Function (Cohort C) - PK Analysis Set 
14.2.2.10 
Box Plot Comparing Lemborexant and Metabolites AUC(0-inf) Values 
after Administration of Lemborexant 10 mg to Subjects with Mild 
Hepatic Impairment (Cohort A), Moderate Hepatic Impairment (Cohort 
B), or Normal Hepatic Function (Cohort C) - PK Analysis Set 
 
Figures added: 
Figure 
Title 
14.2.2.11 
Protein Binding (Percent Bound) Box Plots Comparing PBE2006A, 
PBM4A, PBM9A and PBM10A Values after Administration of 


 
 
 
 
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E2006-A001-104 
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Version: 1.0 
Issue Date: 24-JUL-2018 
 
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PROPRIETARY AND CONFIDENTIAL 
 
 
Lemborexant 10 mg to Subjects with Mild Hepatic Impairment (Cohort 
A), Moderate Hepatic Impairment (Cohort B), or Normal Hepatic 
Function (Cohort C) for 1 and 24 hours  - PK Analysis Set 
14.2.2.12 
Scatterplots for Pharmacokinetic Parameters of Lemborexant and 
Metabolites versus Cohort - PK Analysis Set 
14.2.2.13 
Scatterplots for Pharmacokinetic Parameters Adjusted by Unbound 
Fraction in Plasma for Lemborexant and Metabolites versus Cohort - 
PK Analysis Set 
14.2.2.14 
Mean and Mean (SD) Lemborexant and Metabolites Concentration-
Time Profiles after Administration of Lemborexant 10 mg to Subjects 
with Mild Hepatic Impairment (Cohort A), Moderate Hepatic 
Impairment (Cohort B), or Normal Hepatic Function (Cohort C) 
Truncated to 24 hours Postdose on Linear and Semi-Logarithmic 
Scales - PK Analysis Set 
 
Figures renumbered: 
Figure 
Title 
14.2.2.15 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Child-Pugh Score at Screening 
PK Analysis Set 
14.2.2.16 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus MELD Score at Screening 
PK Analysis Set 
14.2.2.17 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Serum Albumin at Screening 
PK Analysis Set 
14.2.2.18 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Total Bilirubin at Screening 
PK Analysis Set 
14.2.2.19 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Prothrombin Time at Screening 
PK Analysis Set 
14.2.2.20 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus Creatinine at Screening 
PK Analysis Set 
14.2.2.21 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus ALT at Screening 


 
 
 
 
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E2006-A001-104 
Post database lock SAP Addendum  
Version: 1.0 
Issue Date: 24-JUL-2018 
 
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Effective: 14-Feb-13 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
PK Analysis Set 
14.2.2.22 
Scatterplot and Regression Analysis for Pharmacokinetic Parameters of 
Lemborexant and Metabolites versus AST at Screening 
PK Analysis Set 
 
 
 


PPD


PPD