Clinical trial NCT02952820: Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Insomnia Disorder
Keywords: insomnia
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2016-11-02
Enrollment: 971
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6
timeFrame: Baseline and Month 6
Secondary outcomes:
measure: 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
timeFrame: Baseline, (mean of 7 nights [approximately Week 1]), Months 1 and 3
measure: 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
timeFrame: Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
measure: 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
timeFrame: Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
measure: 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
timeFrame: Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
measure: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6
timeFrame: Month 6
measure: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12
timeFrame: Month 12
measure: Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6
timeFrame: Baseline, Months 1, 3, and 6
measure: Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and 6
timeFrame: Baseline, Months 1, 3 and 6
measure: 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
timeFrame: Baseline, (mean of 7 nights [approximately Week 1]) in placebo-controlled period, Month 1, 3, 6
measure: 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)
timeFrame: Baseline, First 7 nights (approximately Week 1) in active treatment period
measure: 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
timeFrame: Screening, First and second 7 mornings in follow-up period (Week 52 to 54)
measure: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12
timeFrame: Baseline, Months 1, 3, 6, 9 and 12
measure: Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period
timeFrame: First 3 nights, first and Last 7 nights of the follow up period (Week 52 to 54)
measure: Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period
timeFrame: First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)
measure: 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
timeFrame: First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)
measure: 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
timeFrame: First 3 nights, First and Last 7 nights of the follow up period (Week 52 to 54)
measure: Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1
timeFrame: Baseline, Month 1, 3, 6, 9, 12
measure: Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1
timeFrame: Baseline, Months 1, 3, 6, 9, and 12
measure: 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
timeFrame: Baseline, Month 7, 9, 12
measure: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7
timeFrame: Baseline, Month 7, 9, 12
measure: 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
timeFrame: Baseline, Month 1, 3, 6
measure: 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
timeFrame: Baseline, Month 1, 3, 6
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Facility # 1
state: Arizona
city: Chandler
country: United States
facility: Facility # 2
state: Arizona
city: Rogers
country: United States
facility: Facility # 1
state: Arkansas
city: Beverly Hills
country: United States
facility: Facility # 1
state: California
city: Los Angeles
country: United States
facility: Facility # 2
state: California
city: Los Angeles
country: United States
facility: Facility # 1
state: California
city: Redlands
country: United States
facility: Facility # 1
state: California
city: Sacramento
country: United States
facility: Facility # 1
state: California
city: Santa Monica
country: United States
facility: Facility # 1
state: California
city: Torrance
country: United States
facility: Facility # 1
state: California
city: Colorado Springs
country: United States
facility: Facility # 1
state: Colorado
city: Celebration
country: United States
facility: Facility # 1
state: Florida
city: Hialeah
country: United States
facility: Facility # 1
state: Florida
city: Homestead
country: United States
facility: Facility # 1
state: Florida
city: Jacksonville
country: United States
facility: Facility # 1
state: Florida
city: Lauderhill
country: United States
facility: Facility # 1
state: Florida
city: Maitland
country: United States
facility: Facility # 1
state: Florida
city: Miami
country: United States
facility: Innovative Clinical Research Inc
state: Florida
city: Ocala
country: United States
facility: Facility # 1
state: Florida
city: Orlando
country: United States
facility: Facility # 1
state: Florida
city: Oviedo
country: United States
facility: Facility # 1
state: Florida
city: Pinellas Park
country: United States
facility: Facility # 1
state: Florida
city: Tampa
country: United States
facility: Facility # 1
state: Florida
city: The Villages
country: United States
facility: Facility # 1
state: Florida
city: Evansville
country: United States
facility: Facility # 1
state: Indiana
city: Elkridge
country: United States
facility: Facility # 1
state: Maryland
city: Quincy
country: United States
facility: Facility # 1
state: Massachusetts
city: Kansas City
country: United States
facility: Facility # 1
state: Missouri
city: Albuquerque
country: United States
facility: Facility # 1
state: New Mexico
city: Brooklyn
country: United States
facility: Facility # 1
state: New York
city: Hickory
country: United States
facility: Facility # 1
state: North Carolina
city: Dayton
country: United States
facility: Facility # 1
state: Ohio
city: Oklahoma City
country: United States
facility: Facility # 2
state: Oklahoma
city: Oklahoma City
country: United States
facility: Facility # 1
state: Oklahoma
city: Portland
country: United States
facility: Facility # 1
state: Oregon
city: Lincoln
country: United States
facility: Facility # 1
state: Rhode Island
city: Memphis
country: United States
facility: Facility # 1
state: Tennessee
city: Austin
country: United States
facility: Facility # 1
state: Texas
city: Austin
country: United States
facility: Facility # 2
state: Texas
city: Fort Worth
country: United States
facility: Facility # 1
state: Texas
city: San Angelo
country: United States
facility: Facility # 1
state: Texas
city: Seattle
country: United States
facility: Facility # 1
state: Washington
city: Kelowna
country: Canada
facility: Facility # 1
state: British Columbia
city: Toronto
country: Canada
facility: Facility # 1
state: Ontario
city: Point-Claire
country: Canada
facility: Facility # 1
state: Quebec
city: Sherbrooke
country: Canada
facility: Facility # 1
state: Quebec
city: Oulu
country: Finland
facility: Facility # 1
state: Oulun Laani
city: Helsinki
country: Finland
facility: Facility # 1
city: Kuopio
country: Finland
facility: Facility # 1
city: Tampere
country: Finland
facility: Facility # 1
city: Turku
country: Finland
facility: Facility # 1
city: Turku
country: Finland
facility: Facility # 2
city: Bochum
country: Germany
facility: Facility # 1
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: Facility # 1
state: Sachsen
city: Berlin
country: Germany
facility: Facility # 1
city: Berlin
country: Germany
facility: Facility # 2
city: Berlin
country: Germany
facility: Facility # 3
city: Hamburg
country: Germany
facility: Facility # 1
city: Hannover
country: Germany
facility: Facility # 1
city: Milano
country: Italy
facility: Facility # 1
state: Lombardia
city: Siena
country: Italy
facility: Facility # 1
state: Toscana
city: Roma
country: Italy
facility: Facility # 1
city: Maebashi
country: Japan
facility: Eisai Trail Site 1
state: Gunma
city: Sapporo
country: Japan
facility: Eisai Trail Site 1
state: Hokkaido
city: Sapporo
country: Japan
facility: Eisai Trail Site 2
state: Hokkaido
city: Sapporo
country: Japan
facility: Eisai Trail Site 3
state: Hokkaido
city: Sapporo
country: Japan
facility: Eisai Trail Site 4
state: Hokkaido
city: Sagamihara
country: Japan
facility: Eisai Trail Site 1
state: Kanagawa
city: Yokohama
country: Japan
facility: Eisai Trial Site 1
state: Kanagawa
city: Yokohama
country: Japan
facility: Eisai Trial Site 2
state: Kanagawa
city: Yokohama
country: Japan
facility: Eisai Trial Site 3
state: Kanagawa
city: Tokorozawa
country: Japan
facility: Eisai Trail Site 1
state: Saitama
city: Arakawa
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Katsushika
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Minato
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Minato
country: Japan
facility: Eisai Trail Site 2
state: Tokyo
city: Musashino
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Ota
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Ota
country: Japan
facility: Eisai Trail Site 2
state: Tokyo
city: Ota
country: Japan
facility: Eisai Trail Site 3
state: Tokyo
city: Shibuya
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Shinagawa
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Shinagawa
country: Japan
facility: Eisai Trail Site 2
state: Tokyo
city: Shinjuku
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Shinjuku
country: Japan
facility: Eisai Trail Site 2
state: Tokyo
city: Toshima
country: Japan
facility: Eisai Trail Site 1
state: Tokyo
city: Seongnam-si
country: Korea, Republic of
facility: Facility # 1
state: Gyeonggido
city: Suwon
country: Korea, Republic of
facility: Facility # 1
state: Gyeonggido
city: Daegu
country: Korea, Republic of
facility: Facility # 1
city: Seoul
country: Korea, Republic of
facility: Facility # 1
city: Seoul
country: Korea, Republic of
facility: Facility # 3
city: Monterrey
country: Mexico
facility: Facility # 1
state: Nuevo Leon
city: Wellington
country: New Zealand
facility: Facility # 1
state: North Island
city: Christchurch
country: New Zealand
facility: Facility # 1
state: South Island
city: Dunedin
country: New Zealand
facility: Facility # 1
state: South Island
city: Auckland
country: New Zealand
facility: Facility # 1
city: Rotorua
country: New Zealand
facility: Facility # 1
city: Tarnow
country: Poland
facility: Facility # 1
state: Malopolskie
city: Warszawa
country: Poland
facility: Facility # 1
state: Mazowieckie
city: Gdansk
country: Poland
facility: Facility # 1
city: Katowice
country: Poland
facility: Facility # 1
city: Ostroda
country: Poland
facility: Facility # 1
city: Warszawa
country: Poland
facility: Facility # 2
city: Warszawa
country: Poland
facility: Facility # 3
city: Brasov
country: Romania
facility: Facility # 1
city: Bucharest
country: Romania
facility: Facility # 1
city: Constanta
country: Romania
facility: Facility # 1
city: Sibiu
country: Romania
facility: Facility # 1
city: Targu Mures
country: Romania
facility: Facility # 1
city: Palma de Mallorca
country: Spain
facility: Facility # 1
state: Baleares
city: Torrejon de Ardoz
country: Spain
facility: Facility # 1
state: Madrid
city: Quart de Poblet
country: Spain
facility: Facility # 1
state: Valencia
city: Barcelona
country: Spain
facility: Facility # 1
city: Valencia
country: Spain
facility: Facility # 1
Study officials:
affiliation: Eisai Inc.
name: Eisai Medical Information
role: STUDY_DIRECTOR
References:
citation: Dash A, Pinner K, Inoue Y, Hayashida K, Lim SC, Yun CH, Lan TH, Huang CL, Yardley J, Kubota N, Moline M. Efficacy and safety of lemborexant over 12 months in Asian adults with insomnia disorder. Sleep Med X. 2022 Mar 24;4:100044. doi: 10.1016/j.sleepx.2022.100044. eCollection 2022 Dec.
citation: Chepke C, Jain R, Rosenberg R, Moline M, Yardley J, Pinner K, Kumar D, Perdomo C, Filippov G, Atkins N, Malhotra M. Improvement in fatigue and sleep measures with the dual orexin receptor antagonist lemborexant in adults with insomnia disorder. Postgrad Med. 2022 Apr;134(3):316-325. doi: 10.1080/00325481.2022.2049553. Epub 2022 Mar 20.
citation: Roth T, Rosenberg R, Morin CM, Yardley J, Pinner K, Perdomo C, Atkins N Jr, Pappadopulos E, Malhotra M, Moline M. Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder. Sleep Med. 2022 Feb;90:249-257. doi: 10.1016/j.sleep.2022.01.024. Epub 2022 Feb 8.
citation: Citrome L, Juday T, Frech F, Atkins N Jr. Lemborexant for the Treatment of Insomnia: Direct and Indirect Comparisons With Other Hypnotics Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed. J Clin Psychiatry. 2021 Jun 1;82:20m13795. doi: 10.4088/JCP.20m13795.
citation: Yardley J, Karppa M, Inoue Y, Pinner K, Perdomo C, Ishikawa K, Filippov G, Kubota N, Moline M. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021 Apr;80:333-342. doi: 10.1016/j.sleep.2021.01.048. Epub 2021 Feb 1.
citation: Inoue Y, Watanabe T, Takashima S, Takase T, Ishikawa K, Kubota N, Yardley J, Moline M. Efficacy and safety of lemborexant in adults with insomnia: comparing Japanese and non-Japanese subgroups from the global, phase 3, randomized, double-blind, placebo-controlled SUNRISE 2 study. J Clin Sleep Med. 2021 May 1;17(5):1067-1074. doi: 10.5664/jcsm.9148.
citation: Karppa M, Yardley J, Pinner K, Filippov G, Zammit G, Moline M, Perdomo C, Inoue Y, Ishikawa K, Kubota N. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020 Sep 14;43(9):zsaa123. doi: 10.1093/sleep/zsaa123.