A Study of Daridorexant in Chinese Patients With Insomnia Disorder

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.

2. Male or female aged ≥ 18 years old, ≤75 years old.

3. Insomnia disorder according to diagnostic and statistical Manual of Mental Disorder,Fifth Edition (DSM-5®) criteria, as follows:

3.1 The predominant complaint is dissatisfaction with sleep quantity or quality,associated with one (or more) of the following symptoms:

• Difficulty initiating sleep

• Difficulty maintaining sleep, characterized by frequent awakenings or problemsreturning to sleep after awakenings.

• Early-morning awakening with inability to return to sleep. 3.2 The sleepdisturbance causes clinically significant distress or impairment in social,occupational, educational, academic, behavioral, or other important areas offunctioning.

3.3 The sleep difficulty occurs despite adequate opportunity for sleep. 3.4 Theinsomnia is not better explained by another sleep-wake disorder (e.g., narcolepsy, abreathing-related sleep disorder, a circadian rhythm sleep-wake disorder, aparasomnia).

3.5 The insomnia is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) 3.6 Coexisting mental disorders and medicalconditions do not adequately explain the predominant complaint of insomnia.

3.7 Self-reported history of all the following on at least 3 nights per week and forat least 3 months prior to Visit 1: 3.7.1 ≥30 min to fall asleep, and 3.7.2 Waketime during sleep ≥ 30 min, and 3.7.3 Subjective Total Sleep Time (sTST)≤6.5 h

4. Insomnia Severity Index© score≥15

5. Ability to communicate well with the investigator, to understand the studyrequirements and independently complete the study, as judged by the investigator, tobe alert and oriented to person, place, time, and situation.

6. Meeting all the following sleep parameters on at least 3 nights out of 7 nights onthe eDiary completed at home between Visit 3 and Visit 4:

6.1 ≥ 30 min to fall asleep, and 6.2 Wake time during sleep ≥ 30 min, and 6.3 sTSTof ≤ 6.5 h

7. Usual bedtime between 20:30 and 00:30 as reported on sleep diary completed betweenVisit 3 and Visit 4.

8. Regular time in bed between 6 and 9 h as reported on sleep diary completed betweenVisit 3 and Visit 4.

9. Meeting all the following sleep parameters on the 2 PSG nights at Visit 4:

9.1 Mean Latency to Persistent Sleep (LPS) ≥ 20 min (with neither of the two nights < 15 min), and 9.2 Mean Wake After Sleep Onset (WASO) ≥ 30 min (with neither of thetwo nights < 20 min), and 9.3 Mean Total Sleep Time (TST) < 420 min

10. For women of childbearing potential, the following are required:

• Negative serum pregnancy test (Visit 1).

• Negative urine pregnancy test (Visit 3, Visit 5).

11. Female and male subjects agree to use the contraception scheme as required by theprotocol from Screening visit up to at least 30 days after last D B study treatmentintake, and have no plans to become pregnant, planned parenthood or sperm/eggdonation plans, unless they have been sterilization surgically (with surgery atleast 1 month before dosing), or female are postmenopausal (female subjects withnatural menopause ≥12 months, ≥ 50 years old, can be considered postmenopausal afterexclusion of pregnancy and other disorders that may cause amenorrhea; If age <50years by follicle stimulating hormone level confirmed).

Exclusion Criteria:

1. Chronic obstructive pulmonary disease, or any lifetime history of sleep-relatedbreathing disorderlike sleep apnea.

2. Cognitive behavioral therapy (CBT) for any indication is allowed only if the CBTstarted at least 1 month prior to Visit 4 and the subject agrees to continue thisCBT throughout the study.

3. Self-reported usual daytime napping ≥ 1 h per day, and ≥ 3 days per week.

4. Acute or unstable psychiatric conditions (including but not restricted to anxietydisorder, major depression, bipolar disorder, schizophrenia, obsessive compulsivedisorder, or depression) that are diagnosed by the Mini InternationalNeuropsychiatric Interview© or that require pharmacological treatment for thesedisorders. N.B.: subjects with a history of major depressive disorder currentlywithout any symptoms and not requiring treatment are eligible.

5. Mini Mental State Examination© score < 25 in subjects ≥ 50 years.

6. Shift work within 2 weeks prior to the screening visit, or planned shift work duringthe study.

7. Travel across ≥ 3 time zones within 2 weeks prior to the screening visit, or plannedtravel across ≥ 3 time zones during the study.

8. Treatment with central nervous system-active drugs, including over-the- countermedication and herbal medicines, are prohibited by this protocol within 5 half-livesof the respective drug (or 2 weeks, whichever is longer) prior to Visit 1, and until 24 h after the end of treatment (the end of the run-out period).

9. Diagnosis of alcohol or substance use disorder within 2 years prior to the screeningvisit or inability to refrain from drinking alcohol for at least 3 consecutive days.

10. Heavy tobacco use (at least one pack of cigarettes a day or inability to refrainfrom smoking during the night).

11. Caffeine consumption ≥ 600 mg per day or any caffeine consumption after 4 pm

12. Use of traditional Chinese medicine as prophylaxis or treatment of sleep disturbancewithin 4 weeks prior to Visit 1 and during the treatment phase.

13. Treatment with another investigational drug within 3 months prior to Visit 1,previous treatment with daridorexant or other orexin receptor antagonists (i.e.lemborexant, YZJ-1139) or previous randomization in any trial involving daridorexant

14. Known hypersensitivity or contraindication to drugs of the same class as the studytreatment or to any excipients of the study drug formulation.

15. Not able or willing to stop treatment with moderate or strong cytochrome P450 (CYP)3A4 inhibitors, or treatment with moderate or strong CYP3A4 inducers, within atleast 1 week prior to Visit 3, until the end of treatment (the end of the run-outperiod).

16. Not able or willing to stop consumption of grapefruit, Seville (bitter) oranges orjuices from those fruits within at least 1 week prior to Visit 3, and until the endof treatment (the end of placebo run-out period).

17. A prolonged QTc interval calculated using Fridericia's formula (QTcF) interval (QTcFgreater than 450 ms). If the QTcF is greater than 450 ms on the first single 12-leadECG, 2 additional 12-lead ECGs will be performed (at least after 30 min) and themean of the 3 QTcF values will be calculated. (QTcF alculation formula seen in 11.5Appendix)

18. Periodic limb movement disorder with arousal index (PLMAI)

≥ 15/h (assessed on the 1st PSG night), restless legs syndrome, circadian rhythmdisorder, rapid eye movement (REM) behavior disorder, or narcolepsy.

19. Apnea/hypopnea index ≥ 15/h according to American Academy of Sleep Medicine criteriaor event associated with blood oxygen saturation level by pulse oximetry (SpO2) < 80%, as assessed on the 1st PSG night

20. A history of moderate to severe hepatic impairment (eg, Child-Pugh Class B or C). (details in 11.6 Appendix)

21. Sleep diary completed less than 70% between Visit 3 to Visit 4, or at least 3 daysout of the 7 days immediately preceding the first PSG of visit 4.

22. Subjects who took placebo tablets less than 80% of days in from Visit 3 to Visit 4. Criteria assessed at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5

23. Any of the following conditions related to suicidality:

• Any suicidal ideation with intent, with or without a plan, at screening, i.e.,answering "Yes" to questions 4 or 5 on the suicidal ideation section of thelifetime (Visit 1) and visit (Visit 2, Visit 3, Visit 4, Visit 5) version ofthe Columbia Suicide Severity Rating Scale© (C-SSRS©).

• History of suicide attempt on the suicidal behavioral section of the lifetimeversion of the C-SSRS© (Visit 1).

24. Coronavirus Disease 2019 (COVID-19) positive subjects, supported by Antigen test orNucleic acid detection.

25. For female subjects: pregnant, lactating or planning to become pregnant duringprojected duration of the study.

26. Positive urine drug test or presence of alcohol in exhaled breath as detected bybreathalyzer test.

27. Unstable medical condition, significant medical disorder or acute illness, ECG,hematology or biochemistry test, thyroid function or coagulation test results within 1 month prior to the screening visit, which, in the opinion of the investigator,could affect the subject's safety or interfere with the study assessments.