Insomnia Disorder

Primary Objective Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in subjects with insomnia disorder Key Secondary Objectives  Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective sleep efficiency (sSE) after 6 months of treatment in subjects with insomnia disorder  Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective wake after sleep onset (sWASO) after 6 months of treatment in subjects with insomnia disorder Additional Secondary Objectives  Determine the efficacy of LEM5 and LEM10 compared to PBO on sSOL, sSE, sWASO, and subjective total sleep time (sTST): - over the 1st 7 nights of treatment - after 1 month of treatment - after 3 months of treatment  Determine the efficacy of LEM5 and LEM10 compared to PBO on sTST at 6 months  Evaluate the proportions of sleep onset and sleep maintenance responders to LEM5 and LEM10 compared to PBO as defined by response on sSOL or sWASO at 6 months and 12 months

Lemborexant (E2006)

(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl) cycl

5、10

Screening Assessments (administered only at the 1st screening visit)
Sleep Disorders Screening Battery (SDSB)
The SDSB will include the following, to be administered by trained site personnel:
 STOPBang: a list of 8 questions to be answered Yes or No, which screens subjects for
obstructive sleep apnea
 IRLS: a subjective scale comprising 10 questions, which measures disease severity of restless
legs syndrome
 ESS: a questionnaire that rates the probability of falling asleep, on a scale of increasing
probability from 0 to 3 for eight different situations that most people engage in during their
daily lives, which assesses the severity of daytime sleepiness
 Adapted version of the MUPS: a scale comprising 21 questions asking whether the subject
has experienced phenomena related to International Classification of Sleep Disorders,
Version 2 (ICSD-2) classified parasomnias (eg, enuresis, sleepwalking, sleep paralysis) along
with a time frame for occurrence of these experiences ranging from within past month to
lifetime, and frequency within the time frame ranging from occasionally to almost every
night

1. Male or female, age 18 years or older at the time of informed consent
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for Insomnia Disorder, as follows:
 Complains of dissatisfaction with nighttime sleep in the form of difficulty getting to sleep,
difficulty staying asleep and/or awakening earlier in the morning than desired despite
adequate opportunity for sleep
 Frequency of complaint ≥3 times per week
 Duration of complaint ≥3 months
 Associated with complaint of daytime impairment
3. At Screening: History of sSOL ≥30 minutes on at least 3 nights per week in the previous 4 weeks
AND sWASO ≥60 minutes on at least 3 nights per week in the previous 4 weeks
4. At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours
5. At Screening: Reports regular bedtime, defined as the time the subject attempts to sleep, between
21:00 and 24:00 and regular waketime, defined as the time the subject gets out of bed for the day, between 05:00 and 09:00
6. At Screening and Study Baseline: ISI score ≥15
7. At the 2nd Screening Visit (Visit 2a): Confirmation of current insomnia symptoms as determined
from responses on the Sleep Diary completed on at least 7 consecutive mornings (minimum 5 of
7 for eligibility), such that sSOL ≥30 minutes on at least 3 of the 7 nights and sWASO ≥60
minutes on at least 3 of the 7 nights
8. At 2nd Screening Visit (Visit 2a): Confirmation of regular bedtimes and waketimes, as
determined from responses on the Sleep Diary completed on a minimum of 7 consecutive
mornings between the 1st and 2nd screening visit, such that neither bedtime (defined as the time
the subject attempts to try to sleep), nor waketime (defined as the time the subject gets out of bed
for the day) deviates more than 1 hour on more than 2 nights from the calculated median habitual
bedtime or median habitual waketime, respectively, from the Screening Sleep Diary entries
9. At the 2nd Screening Visit (Visit 2a): Confirmation of sufficient duration of time in bed (TIB),
as determined from responses on the Sleep Diary completed on 7 mornings between the 1st and
2nd screening visit, such that there are not more than 2 nights with TIB duration <7 hours or
>9 hours
10. At Baseline (Visit 3a): Reconfirmation of insomnia symptoms, as determined from responses on
the Sleep Diary for the final 7 nights of the Run-in Period, such that sSOL ≥30 minutes on at
least 3 of the 7 nights and sWASO ≥60 minutes on at least 3 of the 7 nights
11. At Baseline (Visit 3a): Reconfirmation of regular bedtimes and waketimes as defined in
Inclusion Criterion 8, for the final 7 nights of the Run-In Period
12. At Baseline (Visit 3a): Reconfirmation of sufficient duration of TIB (as defined in Inclusion
Criterion 9) for the final 7 nights of the Run-In period
13. Willing and able to comply with all aspects of the protocol, including TIB of at least 7 hours each night
14. Willing to not start a behavioral or other treatment program for insomnia during the subject’s participation in the study

1. A current diagnosis of sleep-related breathing disorder, including obstructive sleep apnea (with or without continuous positive airway pressure [CPAP] treatment), periodic limb movement
disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy, or an exclusionary score on the SDSB as follows:
 STOPBang score ≥5
 IRLS score ≥16
 ESS score >10
2. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator indicate the need for referral for a diagnostic evaluation for the presence of narcolepsy.
3. On the MUPS, (a) a history of symptoms of Rapid Eye Movement (REM) Behavior Disorder, sleep-related violent behavior, sleep-driving, or sleep-eating, or (b) symptoms of another parasomnia that in the investigator's opinion make the subject unsuitable for the study
4. For subjects who underwent diagnostic polysomnography (PSG) within 1 year before informed
consent:
 Age 18 to 64 years: Apnea-Hypopnea Index ≥10, or Periodic Limb Movements with Arousal
Index ≥10
 Age ≥65 years: Apnea-Hypopnea Index >15, or Periodic Limb Movements with Arousal
Index >15
5. Beck Depression Inventory – II (BDI-II) score >19 at Screening
6. Beck Anxiety Inventory (BAI) score >15 at Screening
7. Habitually naps more than 3 times per week
8. Females who are breastfeeding or pregnant at Screening or Study Baseline (as documented by a
positive serum beta-human chorionic gonadotropin [ß-hCG]). A separate baseline assessment is
required if a negative screening pregnancy test was obtained more than 72 hours before the 1st
dose of study drug.
9. Females of childbearing potential who:
 Had unprotected sexual intercourse within 30 days before study entry and who do not agree
to use a highly effective method of contraception (eg, total abstinence, an intrauterine device,
a contraceptive implant, injectable contraceptives, an oral contraceptive, or have a
vasectomized partner with confirmed azoospermia) throughout the entire study period or for
28 days after study drug discontinuation. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception. (revised per Amendments 01 and 02)
 Are currently abstinent, and do not agree to use a highly effective method (as described
above) or refrain from sexual activity during the study period and for 28 days after study drug
discontinuation. (revised per Amendment 02)
 Are using hormonal contraceptives but are not on a stable dose of the same hormonal
contraceptive product for at least 4 weeks before dosing and who do not agree to use the
same contraceptive during the study and for 28 days after study drug discontinuation.
(NOTES: All females will be considered to be of childbearing 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].
For sites outside of the EU, it is permissible that if a highly effective method of contraception is
not appropriate or acceptable to the subject, the subject must agree to use a medically acceptable
method of contraception, ie, double-barrier methods of contraception such as condom plus
diaphragm or cervical/vault cap with spermicide.) (revised per Amendment 02)
10. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s
insomnia, or habitually consumes caffeine-containing beverages after 18:00 and is unwilling to
forego caffeine after 18:00 for the duration of his/her participation in the study. Subjects are
excluded if, in the previous 3 months, they had symptoms that would meet DSM-5 criteria for
caffeine intoxication, which includes consumption of a high dose of caffeine (significantly in
excess of 250 mg) and ≥5 of the following symptoms: restlessness, nervousness, excitement,
insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of
thought and speech, tachycardia or cardiac arrhythmia, periods of high energy, or psychomotor
agitation. To be exclusionary, those symptoms must cause distress or impairment in social,occupational and other forms of functioning, and not be associated with other substance, mental
disorder or medical condition. (revised per Amendment 01)
11. History of drug or alcohol dependency or abuse within approximately the previous 2 years
12. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or
more than 21 drinks containing alcohol per week (males), or unwilling to limit alcohol intake to 2
or fewer drinks per day or forego having alcohol within 3 hours before bedtime for the duration
of his/her participation in the study
13. Known to be human immunodeficiency virus (HIV) positive
14. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
15. A prolonged QT/QT interval (QTc >450 ms) as demonstrated by a repeated ECG at Screening
(repeated only if initial ECG indicates a QT interval corrected by Fridericia’s formula [QTcF]
>450 ms)
16. Current evidence of clinically significant disease (eg, cardiac; respiratory including chronic
obstructive pulmonary disease, acute and/or severe respiratory depression; severe hepatic
insufficiency; gastrointestinal; renal including severe renal impairment; neurological [including
subjects who lack capacity and/or whose cognitive decline indicates disorientation to
person/place/time and/or situation] or psychiatric disease or malignancy within the past 5 years
[other than adequately treated basal cell carcinoma]) or chronic pain that in the opinion of the
investigator(s) could affect the subject’s safety or interfere with the study assessments. Subjects
for whom a sedating drug would be contraindicated for safety reasons because of the subject’s
occupation or activities are also excluded. (revised per Amendment 01)
17. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the
night
18. Any history of a medical or psychiatric condition that in the opinion of the investigator(s) could
affect the subject’s safety or interfere with the study assessments
19. Any suicidal ideation with intent with or without a plan at Screening or Study Baseline or within
6 months of Study Baseline (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation
section of the eC-SSRS)
20. Any lifetime suicidal behavior (per the Suicidal Behavior section of the eC-SSRS)
21. Scheduled for surgery during the study
22. Used any prohibited prescription or over-the-counter medications within 1 week or 5 half lives,
whichever is longer, before the 1st dose of study medication (Run-In Period). (A list of
prohibited or limited concomitant medications is presented in Appendix 3 of the protocol.)
23. Used any modality of treatment for insomnia, including cognitive behavioral therapy or
marijuana, within 1 week or 5 half lives, whichever is longer, before the 1st dose of study
medication (Run-In Period)
24. Failed treatment with suvorexant (efficacy or safety) following treatment with an appropriate
dose and of adequate duration in the opinion of the investigator
25. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between
Screening and Study Baseline
26. A positive drug test at Screening, Run-In, or Baseline or unwilling to refrain from use of recreational drugs during the study
27. Hypersensitivity to the study drug or any of the excipients
28. Currently enrolled in another clinical trial or used any investigational drug or device within
30 days or 5 times the half-life, whichever is longer preceding informed consent
29. Previously participated in any clinical trial of lemborexant