Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1)

The study is a multicenter, randomized, double-blind, placebo-controlled, active comparator, parallel-group study of 2 dose levels of lemborexant for 30 nights in approximately 950 participants, 55 years or older with insomnia disorder. Participants will be males 65 years or older or females 55 years or older. Approximately 60% of the participants will be age 65 years or older. The study will have 2 phases: The Prerandomization Phase and the Randomization Phase. Including both phases, the study will last for a minimum of 65 and a maximum of 81 days per participant.

Inclusion criteria

• Male age 65 years or older or female age 55 years or older at the time of informed consent
• Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for Insomnia Disorder, as follows:

• Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep and/or awakening earlier in the morning than desired despite adequate opportunity for sleep (Note that if the complaint is limited to difficulty initiating sleep, the participant is not eligible)
• Frequency of complaint ≥ 3 times per week
• Duration of complaint ≥ 3 months
• Associated with complaint of daytime impairment
• History of subjective wake after sleep onset (sWASO) typically ≥ 60 minutes on at least 3 nights per week in the previous 4 weeks
• Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours
• Reports habitual bedtime, defined as the time the participant attempts to sleep, between 21:00 and 24:00 and habitual waketime between 05:00 and 09:00
• Insomnia Severity Index (ISI) score ≥ 13
• Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary before the second screening visit
• Confirmation of regular bedtime and waketime as determined from responses on the Sleep Diary
• Confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary
• Objective (polysomnography [PSG]) evidence of insomnia as follows:

a) Wake after sleep onset (WASO) average ≥ 60 minutes on the 2 consecutive PSGs, with neither night < 45 minutes

• Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours each night
• Willing not to start a behavioral or other treatment program for the treatment of insomnia during the participant's participation in the study

Exclusion criteria

• 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 screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia as follows:

• STOPBang score ≥5
• International Restless Legs Scale score ≥16
• Epworth Sleepiness Scale score >15 (scores of 11 to 15 require excessive daytime sleepiness to be recorded in participant's Medical History)
• Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy
• On the Munich Parasomnia Scale (MUPS), endorsed the item that corresponds to a history of sleep-eating or reports a history of sleep-related violent behavior, sleep-driving, or symptoms of another parasomnia that in the investigator's opinion make the participant unsuitable for the study
• Apnea-Hypopnea Index > 15 or Periodic Limb Movement with Arousal Index >15 as measured on the PSG at the second screening visit
• Beck Depression Inventory - II (BDI-II) score >19 at Screening
• Beck Anxiety Index (BAI) score >15 at Screening
• Habitually naps during the day more than 3 times per week
• Is a female of childbearing potential Note: All females will be considered to be of childbearing potential unless they are postmenopausal (defined as amenorrheic for at least 12 consecutive months, and are postmenopausal without other known or suspected cause), or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
• Excessive caffeine use that in the opinion of the investigator contributes to the participant'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.
• History of drug or alcohol dependency or abuse within approximately the previous 2 years
• 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 no more than 2 drinks per day or forego having alcohol within the 3 hours before bedtime for the duration of his/her participation in the study
• Known to be positive for human immunodeficiency virus
• Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
• A prolonged QT/QTcF interval (QTcF >450 milliseconds [ms]) as demonstrated by a repeated electrocardiogram (ECG) at Screening (repeated only if initial ECG indicates a QTcF interval >450 ms)
• Current evidence of clinically significant disease (e.g., cardiac; respiratory including chronic obstructive pulmonary disease, acute and/or severe respiratory depression; gastrointestinal; severe hepatic impairment; renal including severe renal impairment; neurological including myasthenia gravis; 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 participant's safety or interfere with the study assessments, including the ability to perform tasks on the cognitive performance assessment battery (PAB). Participants for whom a sedating drug would be contraindicated for safety reasons because of the participant's occupation or activities are also excluded.
• Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the night
• Any history of a medical or psychiatric condition that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessment, including the ability to perform the PAB.
• Any suicidal ideation with intent with or without a plan, at the time of or within 6 months before the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) administration during the Prerandomization Phase (i.e., answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the eC-SSRS)
• Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the eC-SSRS)
• Scheduled for surgery during the study
• Used any prohibited prescription or over-the-counter concomitant medications within 1 week or 5 half lives, whichever is longer, before the first dose of study medication (Run-in Period).
• 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 first dose of study medication (Run-in Period)
• Failed treatment with suvorexant (Belsomra®) (efficacy and/or safety) following treatment with an appropriate dose and of adequate duration in the opinion of the investigator
• Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between Screening and Baseline, or plans to travel across more than 3 time zones during the study
• A positive drug test at Screening, Run-In, or Baseline, or unwilling to refrain from use of recreational drugs during the study
• Hypersensitivity to lemborexant or zolpidem or to their excipients
• Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5× the half-life, whichever is longer preceding informed consent
• Previously participated in any clinical trial of lemborexant