Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2)

Study Overview
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Brief Summary
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The key objectives of this study are to determine, using sleep diaries, whether lemborexant at the doses 5 milligrams (mg) and 10 mg is superior to placebo on subjective sleep onset, subjective sleep efficiency, and subjective sleep maintenance in participants with insomnia disorder.

Detailed Description
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This is a long-term (approximately 1 year), multicenter, randomized, controlled, double-blind, parallel group study of two doses of lemborexant and placebo in approximately 900 male or female participants with insomnia disorder. Approximately 40% of participants will be age 65 years or older. The study will last a maximum of 60 weeks, and will include a Screening Period, an approximately 54-week Treatment Period (during which study medication will be administered), and a 2-week Follow-up Period. All participants will receive lemborexant for at least 6 months and will receive placebo at some point during the study. Participants will not know which medication they receive (lemborexant or placebo) until the study has been completed, and will not know the timings at which the medication will change.

Official Title
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A Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel Group Study of the Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder (SUNRISE 2)

Conditions
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Insomnia Disorder

Intervention / Treatment
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* Drug: lemborexant
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 years or older at the time of informed consent 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 History of (Subjective Sleep Onset Latency) sSOL ≥30 minutes on at least 3 nights per week in the previous 4 weeks and/or subjective Wake after Sleep Onset (sWASO) ≥60 minutes on at least 3 nights per week in the previous 4 weeks History of regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours Regular bedtime, between 21:00 and 01:00 and regular wake time, the time the participant gets out of bed for the day, between 05:00 and 10:00 Insomnia Severity Index (ISI) score ≥15 Confirmation of current insomnia symptoms as determined from 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/or sWASO ≥60 minutes on at least 3 of the 7 nights Confirmation of time spent in bed, as determined from on the Sleep Diary completed on 7 mornings between the first and second screening visit, such that there are not more than 2 nights with duration of time spent in bed 7 hours and 10 hours Confirmation of regular bedtimes and wake times such that the participant has a regular time spent in bed, either sleeping or trying to sleep, between 7 and 10 hours for the final 7 nights of the before visit 3. Confirmation of regular bedtime between 21:00 and 01:00 and time of getting out of bed for the day between 05:00 and 10:00 for the final 7 nights of the before visit 3. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours each night Willing to not start a behavioral or other treatment program for insomnia during the participants participation in the study Exclusion Criteria: A current diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia. STOPBang score greater than or equal to (>=) 5 International Restless Legs Scale (IRLS) score >=16 Epworth Sleepiness Scale (ESS) score >15 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 Reports a history of sleep-related violent behavior, or sleep driving, or any other complex sleep-related behavior, eg, making phone calls, or preparing and eating food while asleep For participants who underwent polysomnography (PSG) within the previous year: 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 Beck Depression Inventory - II (BDI II) score >19 at Screening Beck Anxiety Inventory (BAI) score >15 at Screening Habitually naps more than 3 times per week Females who are breastfeeding or pregnant at Screening or Study Baseline Females of childbearing potential who are not practicing acceptable pregnancy prevention methods (NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically.) 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 A prolonged QT/QT interval corrected by Fridericia's formula (QTcF >450 ms) as demonstrated by a repeated electro cardiogram(ECG) at Screening (repeated only if initial ECG indicates a QTcF interval >450 ms) Current evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal, neurological [including participants who lack capacity and/or whose cognitive decline indicates disorientation to person/place/time and/or situation], or psychiatric disease or malignancy other than 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 Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the night Scheduled for major surgery during the study Used any prohibited prescription or over-the-counter concomitant medications within 1 week before the first dose of study medication Used any modality of treatment for insomnia, including cognitive behavioral therapy or marijuana within 2 weeks before Screening 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 Study Baseline Previously participated in any clinical trial of lemborexant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lemborexant 5 milligrams (mg)<br>Lemborexant 5 mg will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep. | Drug: lemborexant<br> <br> |
| Experimental: lemborexant 10 mg<br>Lemborexant 10 mg will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep. | Drug: lemborexant<br> <br> |
| Placebo Comparator: Placebo matched to lemborexant<br>Lemborexant-matched placebo will be taken orally in tablet form at home each night immediately before the time the participant intends to try to sleep. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6 | sSOL was defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3 | sSOL was defined as estimated minutes from time attempted to sleep to sleep onset. | Baseline, (mean of 7 nights [approximately Week 1]), Months 1 and 3 | 
| Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6 | sSE was defined as percentage of subjective total sleep time (sTST) divided by subjective time spent in bed, calculated as the interval from the time the participant reported attempting to sleep until the time participant stopped trying to sleep for the night (operationalized as the time the participant got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. | Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6 | 
| Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6 | sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. | Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6 | 
| Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6 | sTST was defined as minutes of sleep from sleep onset to time stopped trying to sleep for the night. | Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6 | 
| Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6 | Sleep onset responder was defined as follows: sSOL at study Baseline was greater than or equal to (>=) 30 minutes and mean sSOL at 6 months was less than or equal to (<=) 20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of greater than (>)10 minutes compared to Study Baseline. | Month 6 | 
| Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12 | Sleep onset responder was defined as follows: sSOL at study Baseline was >=30 minutes and mean sSOL at 6 months was <=20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of > 10 minutes compared to study Baseline. | Month 12 | 
| Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6 | The ISI is a 4-7 item, self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: 1. severity of sleep onset; 2. sleep maintenance; 3. early morning awakening problems; 4. sleep dissatisfaction; 5. interference of sleep difficulties with daytime functioning; 6. noticeability of the sleep problems by others; and 7. distress caused by the sleep difficulties. A 5-point Likert scale was used to rate each item (from 0=no problem to 4=very severe problem). Daytime functioning score (sum of items 4 to 7) were analyzed. Higher score indicated severe insomnia problem. The total score range for sum of items is 0-16. | Baseline, Months 1, 3, and 6 | 
| Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and 6 | The FSS is a self-reported scale on which participants were instructed to choose a number from 1 to 7 that indicated their degree of agreement with 9 statements about their fatigue where 1 indicates strongly disagree and 7, strongly agree. The FSS total score was the sum of all responses to the 9 questions. Higher total scores and average item scores indicated greater fatigue. Total score range is 9 to 63. | Baseline, Months 1, 3 and 6 | 
| Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6 | The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: How sleepy/alert do you feel this morning? Participants rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. | Baseline, (mean of 7 nights [approximately Week 1]) in placebo-controlled period, Month 1, 3, 6 | 
| Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period) |  | Baseline, First 7 nights (approximately Week 1) in active treatment period | 
| Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period | The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: How sleepy/alert do you feel this morning? Participants rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. | Screening, First and second 7 mornings in follow-up period (Week 52 to 54) | 
| Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12 | The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: How sleepy/alert do you feel this morning? Participants rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. | Baseline, Months 1, 3, 6, 9 and 12 | 
| Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period | Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sSOL was defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. | First 3 nights, first and Last 7 nights of the follow up period (Week 52 to 54) | 
| Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period | Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. | First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54) | 
| Rebound Insomnia: Percentage of Participants Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period | Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sSOL was defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. | First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54) | 
| Rebound Insomnia: Percentage of Participants Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period | Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. | First 3 nights, First and Last 7 nights of the follow up period (Week 52 to 54) | 
| Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1 | sSOL was defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. At each month beyond Month 1, the change from Baseline was compared to either the lower bound of the 95% CI (for sTST) or the upper bound of the 95% CI (for sSOL and sWASO) at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sTST and below the upper bound of the 95% CI at Month 1 for sSOL and sWASO. | Baseline, Month 1, 3, 6, 9, 12 | 
| Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1 | sSE was defined as percentage of sTST per subjective time spent in bed, calculated as the interval from the time the participant reports attempting to sleep until the time the participant stopped trying to sleep for the night (operationalized as the time the participant got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 1, the change from Baseline was compared to the lower bound of the 95% CI at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sSE. | Baseline, Months 1, 3, 6, 9, and 12 | 
| Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7 | sSOL is defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. sWASO: sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. At each month beyond Month 7, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sTST and below the upper bound of the 95% CI at Month 7 for sSOL and sWASO. | Baseline, Month 7, 9, 12 | 
| Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7 | sSE: percentage of sTST per subjective time spent in bed, calculated as the interval from the time the participant reports attempting to sleep until the time the participant stopped trying to sleep for the night (operationalized as the time the subject got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 7, the change from Baseline was compared to the lower bound of the 95% CI for sSE at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sSE. | Baseline, Month 7, 9, 12 | 
| Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1 | sSOL was defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. sWASO: sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. At 3 and 6 months of exposure, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sTST and below the upper bound of the 95% CI at 1 month of exposure for sSOL and sWASO. | Baseline, Month 1, 3, 6 | 
| Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1 | sSE was defined as percentage of sTST per subjective time spent in bed, calculated as the interval from the time the participant reports attempting to sleep until the time the participant stopped trying to sleep for the night (operationalized as the time the participant got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At 3 and 6 months of exposure, the change from Baseline was compared to the lower bound of the 95% CI for sSE at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sSE. | Baseline, Month 1, 3, 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insomnia