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

Sponsor
Eisai Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02783729
Collaborator
(none)
1,006
Enrollment
102
Locations
4
Arms
20
Actual Duration (Months)
9.9
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will be conducted to demonstrate, using polysomnography, that lemborexant 10 milligrams (mg) and 5 mg is superior to placebo on objective sleep onset as assessed by latency to persistent to sleep (LPS) after the last 2 nights of 1 month of treatment in participants 55 years and older with insomnia disorder.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
1006 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Parallel-Group Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1)
Actual Study Start Date :
May 31, 2016
Actual Primary Completion Date :
Jan 30, 2018
Actual Study Completion Date :
Jan 30, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Lemborexant 5 milligrams (mg)

Participants will receive one lemborexant 5 mg tablet and one zolpidem-matched placebo tablet each night

Drug: Lemborexant
Lemborexant 5 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.
Other Names:
  • E2006

    • Drug: Zolpidem-matched placebo
    Zolpidem-matched placebo will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.
    Experimental: Lemborexant 10 mg

    Participants will receive one lemborexant 10 mg tablet and one zolpidem-matched placebo tablet each night

    Drug: Lemborexant
    Lemborexant 10 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.
    Other Names:
  • E2006

    • Drug: Zolpidem-matched placebo
    Zolpidem-matched placebo will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.
    Active Comparator: Zolpidem tartrate

    Participants will receive one zolpidem 6.25 mg tablet and one lemborexant-matched placebo tablet each night

    Drug: Lemborexant-matched placebo
    Lemborexant-matched placebo be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.

    Drug: Zolpidem tartrate
    Zolpidem tartrate extended release 6.25 mg will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.
    Other Names:
  • Ambien CR

    		•
    Placebo Comparator: Placebo

    Participants will receive one zolpidem-matched placebo tablet and one lemborexant-matched placebo tablet each night

    Drug: Lemborexant-matched placebo
    Lemborexant-matched placebo be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.

    Drug: Zolpidem-matched placebo
    Zolpidem-matched placebo will be administered orally in tablet form at home each night, immediately before the time the participant intends to try to sleep.

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Mean Latency to Persistent Sleep (LPS) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 [Baseline, Days 29/30]

      LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non- wakefulness as measured by PSG. Change from baseline to average LPS on Day 29 and 30 was reported.

    Secondary Outcome Measures

    1. Change From Baseline in Mean Sleep Efficiency (SE) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 [Baseline, Days 29/30]

      SE is defined as percentage of time spent in bed asleep, calculated as total sleep time (TST) divided by interval from lights off until lights on as measured by PSG, multiplied by 100. Change from baseline to average SE on Day 29 and 30 was reported.

    2. Change From Baseline in Mean Wake After Sleep Onset (WASO) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 [Baseline, Days 29/30]

      WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. Change from baseline to average WASO on Days 29 and 30 was reported.

    3. Change From Baseline in WASO in the Second Half of the Night (WASO2H) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30 [Baseline, Days 29/30]

      WASO2H is defined as time in minutes of wake during the interval from 240 minutes after lights off until lights on as measured by PSG. Change from baseline to average WASO2H on Days 29 and 30 was reported.

    Other Outcome Measures

    1. Change From Baseline in Mean Body Sway Upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3 [Baseline, Days 2/3]

      Body sway is detected through a cable around the participant's waist by the ataxia meter. Body sway is measured in units of one-third degree of the angle of arc. For ease in reporting, these are called arbitrary units, with a higher number indicating more body sway (less postural stability). Change from baseline in mean body sway on Days 2 and 3 was reported.

    2. Change From Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30 [Baseline, Days 1/2, and Days 29/30]

      LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness as measured by the PSG. WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. TST is defined as the amount of sleep in minutes from LPS until terminal awakening as measured by PSG. Change from baseline to average LPS, WASO, and TST on Days 1 and 2, and Days 29 and 30 were reported.

    3. Change From Baseline in Subjective Sleep Onset Latency (sSOL), Subjective Wake After Sleep Onset (sWASO) and Subjective Total Sleep Time (sTST) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER [First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)]

      sSOL: estimated minutes from time attempted to sleep to sleep onset. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. sSOL, sWASO, sTST were analyzed with diary handling rules (DHR) on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.

    4. Change From Baseline in Subjective Sleep Efficiency (sSE) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER [First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)]

      sSE: percentage of sTST per subjective time spent in bed asleep, calculated as the interval from the time attempted to sleep to time stopped trying to sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sSE was analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.

    5. Change From Baseline in Mean LPS, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2 [Baseline, Days 1/2]

      LPS: amount of time in minutes from lights off to first epoch of 20 consecutive epochs of non-wakefulness. WASO: amount of time in minutes of wake from the onset of persistent sleep until lights. WASO2H: amount of time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST: amount of time in minutes of sleep from sleep onset until terminal awakening. LPS, WASO, WASO2H, and TST were measured by PSG. Change from baseline to average LPS, WASO, WASO2H, and TST on Day 1 and 2 were reported.

    6. Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2 [Baseline, Days 1/2]

      SE is defined as percentage of time spent in bed asleep, calculated as TST divided by interval from lights off until lights on as measured by PSG, multiplied by 100. Change from baseline to average SE on Day 1 and 2 were reported.

    7. Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 [Baseline, Days 29/30]

      WASO2H is defined as the time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST is defined as the amount of sleep in minutes from sleep onset until terminal awakening. WASO and TST were measured by PSG. Change from baseline to average WASO and TST on Day 29 and 30 were reported.

    8. Change From Baseline in Mean sSOL, sWASO, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo [First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)]

      sSOL: estimated minutes from time attempted to sleep to sleep onset. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. sSOL, sWASO, sTST were analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.

    9. Change From Baseline in Mean sSE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo [First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)]

      sSE: percentage of sTST per subjective time spent in bed asleep, calculated as the interval from the time attempted to sleep to time stopped trying to sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sSE was analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.

    10. Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response [Days 1/2, Days 29/30, first 7 night (approximately Week 1), and Last seven nights (approximately Week 4)]

      Objective sleep onset response: LPS less than or equal to (<=) 20 minutes (mins) provided baseline LPS was greater than (>) 30 mins. Subjective sleep onset response: sSOL <=20 mins provided mean baseline sSOL was >30 mins. Objective sleep maintenance response: WASO <=60 minutes provided baseline WASO was >60 mins and was reduced by >10 mins compared to baseline. Subjective sleep maintenance response: sWASO <=60 mins provided mean WASO was >60 mins and was reduced by >10 mins compared to baseline. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals. Average data for Days 1 and 2, Days 29 and 30, and first and last 7 nights of treatment period was reported.

    11. Change From Baseline in Score From Items 4 to 7 on the Insomnia Severity Index (ISI) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31 [Baseline and Day 31]

      The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: severity of sleep onset; sleep maintenance; early morning awakening problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning; noticeability of the sleep problems by others; and 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) yielding a total score from 0 to 28.

    12. Change From Baseline in Fatigue Severity Scale (FSS) Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31 [Baseline and Day 31]

      The FSS is a self-report scale on which participants are instructed to choose a number from 1 to 7 that indicates their degree of agreement with each of 9 statements about their fatigue where "1" indicates strongly disagree, and "7" indicates strongly agree. The FSS total score was the sum of all responses to the 9 questions. The FSS average item score was the average of the score for each item. Higher total scores and higher average item scores indicated greater fatigue.

    13. Change From Baseline in Mean Power of Attention (POA) and Speed of Memory Retrieval (SOMT) on Days 2/3 [Baseline, Days 2/3]

      POA reflects the ability to focus attention and process information. POA is calculated from the sum of simple reaction time, choice reaction time and digit vigilance. SOMT reflects time taken to retrieve information from working and episodic memory. SOMT is a composite score created by combining numerical working memory and spatial working memory and word recognition and picture recognition. Cognitive performance assessment was done by a computerized performance assessment battery (PAB) which was administered on a laptop computer. A positive change from baseline reflects impairment and a lower value of decrease from baseline indicates better performance. Change from baseline to average POA and SOMT on Days 2 and 3 was reported.

    14. Change From Baseline in Mean Quality of Memory (QOM) and Continuity of Attention (COA) on Days 2/3 [Baseline, Days 2/3]

      QOM represents the ability to store information in memory and subsequently retrieve it. It is a composite score created by combining accuracy measures from 2 sets of working memory and 4 sets of episodic memory. Two sets of working memory were included: numerical and spatial working memory, and ranges from -2 to 2. Four sets of episodic memory were included: immediate and delayed word recall, and word and picture recognition, and ranges from -200 to 400. COA is the ability to sustain attention. Number of correct responses (out of 50) for choice reaction time was added to total number of targets correctly identified (out of 45) digit vigilance minus number of false alarms (total score of -45 to 95). Higher values were better. Change from baseline to average QOM and COA on Days 2 and 3 was reported.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    55 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    1. Male age 65 years or older or female age 55 years or older at the time of informed consent

    2. 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

    1. History of subjective wake after sleep onset (sWASO) typically ≥ 60 minutes on at least 3 nights per week in the previous 4 weeks

    2. Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours

    3. 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

    4. Insomnia Severity Index (ISI) score ≥ 13

    5. Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary before the second screening visit

    6. Confirmation of regular bedtime and waketime as determined from responses on the Sleep Diary

    7. Confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary

    8. Objective (polysomnography [PSG]) evidence of insomnia as follows:

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

    1. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours each night

    2. 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

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

    2. STOPBang score ≥5

    3. International Restless Legs Scale score ≥16

    4. Epworth Sleepiness Scale score >15 (scores of 11 to 15 require excessive daytime sleepiness to be recorded in participant's Medical History)

    5. 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

    6. 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

    7. Apnea-Hypopnea Index > 15 or Periodic Limb Movement with Arousal Index >15 as measured on the PSG at the second screening visit

    8. Beck Depression Inventory - II (BDI-II) score >19 at Screening

    9. Beck Anxiety Index (BAI) score >15 at Screening

    10. Habitually naps during the day more than 3 times per week

    11. 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).

    12. 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.

    13. History of drug or alcohol dependency or abuse within approximately the previous 2 years

    14. 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

    15. Known to be positive for human immunodeficiency virus

    16. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening

    17. 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)

    18. 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.

    19. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the night

    20. 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.

    21. 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)

    22. Any suicidal behavior in the past 10 years (per the Suicidal Behavior section of the eC-SSRS)

    23. Scheduled for surgery during the study

    24. 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).

    25. 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)

    26. 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

    27. 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

    28. A positive drug test at Screening, Run-In, or Baseline, or unwilling to refrain from use of recreational drugs during the study

    29. Hypersensitivity to lemborexant or zolpidem or to their excipients

    30. 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

    31. Previously participated in any clinical trial of lemborexant

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Jasper Summit Research LLC Jasper Alabama United States 35501
    2 PACT Glendale Arizona United States 85306
    3 Preferred Research Partners Little Rock Arkansas United States 72211
    4 Carlsbad California United States 92011
    5 Southern California Research Fountain Valley California United States 92708
    6 Pacific Sleep Medicine Services Oceanside California United States 92054
    7 Research Center of Southern California Oceanside California United States 92056
    8 Orange County Neuropsychiatric Research Center, LLC Orange California United States 92868
    9 SDS Clinical Trials, Inc. Orange California United States 92868
    10 Artemis Institute For Clinical Research LLC San Diego California United States 92103
    11 Pacific Research Network Inc San Diego California United States 92103
    12 Artemis Institute For Clinical Research San Marcos California United States 92078
    13 Santa Monica Clinical Trials Santa Monica California United States 90404
    14 Empire Clinical Research Upland California United States 91786
    15 PAB Clinical Research Brandon Florida United States 33511
    16 Saint Francis Sleep Allergy and Lung Institute Clearwater Florida United States 33765
    17 Fleming Island Center For Clinical Research Fleming Island Florida United States 32003
    18 Sarkis Clinical Trials Gainesville Florida United States 32607
    19 MD Clinical Hallandale Beach Florida United States 33009
    20 QPS MRA Hollywood Florida United States 33024
    21 Quest Pharmaceutical Services-Miami Research Associates, LLC (QPS MRA) Miami Florida United States 33143
    22 Research Centers of America Oakland Park Florida United States
    23 Compass Research LLC Orlando Florida United States 32806
    24 NeuroMedical Research Institute Panama City Florida United States 32405
    25 Clinical Research Group of St Petersburg Inc Saint Petersburg Florida United States 33707
    26 NeuroTrials Research Inc. Atlanta Georgia United States 30342
    27 SleepCare Research Institute Inc Stockbridge Georgia United States 30281
    28 Northwestern University Chicago Illinois United States 60611
    29 Chicago Research Center Inc Chicago Illinois United States 60634
    30 Helene A Emsellem MD PC Chevy Chase Maryland United States 20815
    31 Sleep Disorders Center of the Mid-Atlantic Glen Burnie Maryland United States 21061
    32 Neurocare Inc Newton Massachusetts United States 02459
    33 University of Michigan Ann Arbor Michigan United States 48109
    34 Henry Ford Hospital Novi Michigan United States 48377
    35 Clinical Neurophysiology Services Sterling Heights Michigan United States 48314
    36 St. Louis Clinical Trials Saint Louis Missouri United States 63141
    37 Clayton Sleep Institute Saint Louis Missouri United States 63143
    38 Clinical Research Center of Nevada Las Vegas Nevada United States 89104
    39 Hassman Research Institute Berlin New Jersey United States 08009
    40 CLINiLABS, Inc. Eatontown New Jersey United States 07724
    41 Winthrop University Hospital Garden City New York United States 11530
    42 Clinical Research Unit New York New York United States 10019
    43 University of Rochester Rochester New York United States 14642
    44 Richmond Behavioral Associates Staten Island New York United States 10312
    45 Sleep Medicine Centers of Western New York West Seneca New York United States 14224
    46 Wake Research Associates, LLC Raleigh North Carolina United States 27612
    47 Wilmington Health Associates Wilmington North Carolina United States 28401
    48 Cincinnati Ohio United States 45212
    49 Intrepid Research Cincinnati Ohio United States 45245
    50 CTI Clinical Research Center Cincinnati Ohio United States 45255
    51 Ohio Sleep Medicine Institute Dublin Ohio United States 43017
    52 Cleveland Sleep Research Center Middleburg Heights Ohio United States 44130
    53 Lynn Health Science Institute Oklahoma City Oklahoma United States 73112
    54 University of Pennsylvania Philadelphia Pennsylvania United States 19104-3309
    55 Medical University of South Carolina - PPDS Charleston South Carolina United States 29425
    56 Sleepmed of South Carolina Columbia South Carolina United States 29201
    57 Pioneer Research Solutions Houston Texas United States 77099
    58 Sleep Disorders Center of the Mid-Atlantic Vienna Virginia United States 22182
    59 Seattle Washington United States 98101
    60 Swedish Medical Center Seattle Washington United States 98122
    61 Sleep and Fatigue Institute Calgary Alberta Canada
    62 Medical Arts Health Research Group Kelowna British Columbia Canada
    63 Markham Ontario Canada L3R 1A3
    64 Somni Research Inc. Markham Ontario Canada
    65 Tri Hospital Sleep West Mississauga Ontario Canada
    66 Sleep Wake Disorders Clinic Scarborough Ontario Canada
    67 Toronto Ontario Canada M4P 1P2
    68 Toronto Sleep Institute Toronto Ontario Canada
    69 Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin Bordeaux France
    70 Hopital Gabriel Montpied Clermont-ferrand France
    71 CHU Dijon Bourgogne Dijon Cedex France
    72 Hôtel Dieu de Paris Hospital Paris France
    73 Hopital Civil Strasbourg France
    74 Zentralinstitut für Seelische Gesundheit Mannheim Baden-Württemberg Germany
    75 Universitätsklinikum Schleswig-Holstein Lübeck Schleswig-Holstein Germany
    76 Advanced Sleep Research GmbH Berlin Germany
    77 Emovis GmbH Berlin Germany
    78 Studienzentrum Wilhelmshöhe Kassel Germany
    79 Klinikum rechts der Isar der Technischen Universität München München Germany
    80 Universitätsklinikum Münster Münster Germany
    81 Somni Bene Institut für Medizinische Forschung und Schlafmedizin Schwerin GmbH Schwerin Germany
    82 Ospedale Bellaria Bologna Emilia-Romagna Italy
    83 Ospedale San Raffaele S.r.l. - PPDS Milan Lombardia Italy
    84 Azienda Ospedaliero Universitaria di Parma Parma Italy
    85 ASST di Pavia - Fondazione Istituto Neurologico Mondino IRCCS Pavia Italy
    86 Azienda Ospedaliero Universitaria Pisana Pisa Italy
    87 Fondazione PTV Policlinico Tor Vergata Roma Italy
    88 Azienda Ospedaliera Città della Salute e della Scienza di Torino Torino Italy
    89 Clinica Universidad de Navarra Pamplona Navarra Spain
    90 Hospital Clinic de Barcelona Badalona Spain
    91 Barcelona Spain 08025
    92 Clinica del Son Estivill Barcelona Spain
    93 Hospital de La Santa Creu i Sant Pau Barcelona Spain
    94 Hospital San Rafael La Coruña Spain
    95 Hospital Universitario Fundacion Jimenez Diaz Madrid Spain
    96 Hospital Universitario La Paz Madrid Spain
    97 Instituto de Investigaciones del Sueño Madrid Spain
    98 Hospital Universitario Araba - Txagorritxu Vitória Spain
    99 Papworth Hospital Cambridge Cambridge Shire United Kingdom
    100 University of Surrey Guildford Surrey United Kingdom
    101 Guys Hospital London United Kingdom
    102 Royal Stoke University Hospital Stoke on Trent United Kingdom

    Sponsors and Collaborators

    • Eisai Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Eisai Inc.
    ClinicalTrials.gov Identifier:
    NCT02783729
    Other Study ID Numbers:
    • E2006-G000-304
    • 2015-004347-39
    First Posted:
    May 26, 2016
    Last Update Posted:
    Feb 11, 2020
    Last Verified:
    Mar 1, 2018
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Keywords provided by Eisai Inc.
    E2006
    Lemborexant
    zolpidem tartrate
    Ambien CR
    Insomnia
    Additional relevant MeSH terms:
    Sleep Initiation and Maintenance Disorders
    Zolpidem
    Lemborexant

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 67 investigative sites in the United States, Spain, Germany, Canada, United Kingdom, and Italy from 31 May 2016 to 30 January 2018.
    Pre-assignment Detail A total of 3537 participants were screened, of which 1006 participants were randomized to the treatment period. All participants who were subsequently randomized completed a Run-in Period before randomization to treatment period.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Period Title: Overall Study
    STARTED 208 263 266 269
    COMPLETED 198 246 258 260
    NOT COMPLETED 10 17 8 9

    Baseline Characteristics

    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg Total
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Total of all reporting groups
    Overall Participants 208 263 266 269 1006
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.4
    (6.36)
    64.3
    (7.12)
    63.7
    (6.78)
    64.2
    (6.88)
    63.9
    (6.81)
    Sex: Female, Male (Count of Participants)
    Female
    184
    88.5%
    226
    85.9%
    229
    86.1%
    230
    85.5%
    869
    86.4%
    Male
    24
    11.5%
    37
    14.1%
    37
    13.9%
    39
    14.5%
    137
    13.6%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    35
    16.8%
    32
    12.2%
    51
    19.2%
    47
    17.5%
    165
    16.4%
    Not Hispanic or Latino
    173
    83.2%
    231
    87.8%
    215
    80.8%
    222
    82.5%
    841
    83.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    153
    73.6%
    173
    65.8%
    199
    74.8%
    202
    75.1%
    727
    72.3%
    Black or African American
    51
    24.5%
    80
    30.4%
    63
    23.7%
    62
    23%
    256
    25.4%
    Japanese
    1
    0.5%
    1
    0.4%
    0
    0%
    0
    0%
    2
    0.2%
    Chinese
    1
    0.5%
    0
    0%
    0
    0%
    1
    0.4%
    2
    0.2%
    Other Asian
    0
    0%
    4
    1.5%
    2
    0.8%
    4
    1.5%
    10
    1%
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific
    0
    0%
    2
    0.8%
    0
    0%
    0
    0%
    2
    0.2%
    Other
    2
    1%
    3
    1.1%
    2
    0.8%
    0
    0%
    7
    0.7%

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Mean Latency to Persistent Sleep (LPS) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30
    Description LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non- wakefulness as measured by PSG. Change from baseline to average LPS on Day 29 and 30 was reported.
    Time Frame Baseline, Days 29/30

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    Baseline
    43.89
    (33.596)
    44.86
    (36.528)
    44.61
    (32.986)
    Change at Days 29/30
    -7.93
    (31.946)
    -19.53
    (33.054)
    -21.46
    (32.436)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0003
    Comments Based on mixed effect model repeated measurement (MMRM) model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter Least Squares Geometric Mean(LSGM) Ratio
    Estimated Value 0.773
    Confidence Interval (2-Sided) 95%
    0.672 to 0.889
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSGM Ratio
    Estimated Value 0.723
    Confidence Interval (2-Sided) 95%
    0.628 to 0.832
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in Mean Sleep Efficiency (SE) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30
    Description SE is defined as percentage of time spent in bed asleep, calculated as total sleep time (TST) divided by interval from lights off until lights on as measured by PSG, multiplied by 100. Change from baseline to average SE on Day 29 and 30 was reported.
    Time Frame Baseline, Days 29/30

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    Baseline
    68.89
    (9.639)
    68.36
    (11.268)
    67.85
    (10.849)
    Change at Days 29/30
    5.35
    (9.897)
    12.93
    (9.741)
    14.09
    (10.514)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean (LSM) Difference
    Estimated Value 7.07
    Confidence Interval (2-Sided) 95%
    5.61 to 8.54
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.746
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 8.03
    Confidence Interval (2-Sided) 95%
    6.57 to 9.49
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.746
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in Mean Wake After Sleep Onset (WASO) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30
    Description WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. Change from baseline to average WASO on Days 29 and 30 was reported.
    Time Frame Baseline, Days 29/30

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    Baseline
    111.75
    (37.179)
    113.44
    (38.953)
    114.83
    (39.997)
    Change at Days 29/30
    -18.58
    (41.931)
    -43.89
    (39.264)
    -46.43
    (39.595)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -23.96
    Confidence Interval (2-Sided) 95%
    -29.98 to -17.95
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.068
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -25.35
    Confidence Interval (2-Sided) 95%
    -31.36 to -19.34
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.067
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline in WASO in the Second Half of the Night (WASO2H) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30
    Description WASO2H is defined as time in minutes of wake during the interval from 240 minutes after lights off until lights on as measured by PSG. Change from baseline to average WASO2H on Days 29 and 30 was reported.
    Time Frame Baseline, Days 29/30

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized Participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 262 266 269
    Baseline
    78.04
    (33.849)
    76.60
    (32.903)
    76.88
    (32.126)
    Change at Days 29/30
    -21.42
    (36.257)
    -27.19
    (33.047)
    -28.84
    (33.138)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments
    Type of Statistical Test Superiority
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.
    Statistical Test of Hypothesis p-Value = 0.0038
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -6.65
    Confidence Interval (2-Sided) 95%
    -11.15 to -2.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.298
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments
    Type of Statistical Test Superiority
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.
    Statistical Test of Hypothesis p-Value = 0.0005
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -8
    Confidence Interval (2-Sided) 95%
    -12.53 to -3.47
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.309
    Estimation Comments
    5. Other Pre-specified Outcome
    Title Change From Baseline in Mean Body Sway Upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3
    Description Body sway is detected through a cable around the participant's waist by the ataxia meter. Body sway is measured in units of one-third degree of the angle of arc. For ease in reporting, these are called arbitrary units, with a higher number indicating more body sway (less postural stability). Change from baseline in mean body sway on Days 2 and 3 was reported.
    Time Frame Baseline, Days 2/3

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 239 245 243
    Baseline
    26.96
    (26.502)
    26.40
    (20.781)
    36.29
    (197.282)
    Change at Days 2/3
    8.47
    (69.894)
    -0.82
    (20.383)
    -8.97
    (146.679)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0171
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline posture stability of body sway as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -9.63
    Confidence Interval (2-Sided) 95%
    -17.53 to -1.72
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.029
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.008
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline posture stability of body sway as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -10.74
    Confidence Interval (2-Sided) 95%
    -18.67 to -2.81
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.04
    Estimation Comments
    6. Other Pre-specified Outcome
    Title Change From Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30
    Description LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness as measured by the PSG. WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. TST is defined as the amount of sleep in minutes from LPS until terminal awakening as measured by PSG. Change from baseline to average LPS, WASO, and TST on Days 1 and 2, and Days 29 and 30 were reported.
    Time Frame Baseline, Days 1/2, and Days 29/30

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 262 266 269
    LPS: Baseline
    44.52
    (38.349)
    44.86
    (36.528)
    44.61
    (32.986)
    LPS: Change at Days 1/2
    -12.56
    (32.506)
    -16.59
    (28.742)
    -19.48
    (31.809)
    LPS: Change at Days 29/30
    -7.51
    (35.065)
    -19.53
    (33.054)
    -21.46
    (32.436)
    WASO: Baseline
    114.31
    (39.992)
    113.44
    (38.953)
    114.83
    (39.997)
    WASO: Change at Days 1/2
    -44.36
    (38.074)
    -49.96
    (39.578)
    -59.59
    (37.749)
    WASO: Change at Days 29/30
    -36.50
    (43.406)
    -43.89
    (39.264)
    -46.43
    (39.595)
    TST: Baseline
    326.99
    (54.852)
    328.00
    (54.224)
    325.07
    (52.819)
    TST: Change at Days 1/2
    55.31
    (48.138)
    65.22
    (46.695)
    79.58
    (47.350)
    TST: Change at Days 29/30
    43.34
    (54.012)
    61.99
    (46.817)
    67.86
    (52.117)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments LPS, Days 1/2: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0218
    Comments Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.874
    Confidence Interval (2-Sided) 95%
    0.78 to 0.981
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 1/2: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value = 0.0006
    Comments Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.818
    Confidence Interval (2-Sided) 95%
    0.729 to 0.917
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments LPS, Days 29/30: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.634
    Confidence Interval (2-Sided) 95%
    0.556 to 0.724
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 29/30: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.594
    Confidence Interval (2-Sided) 95%
    0.521 to 0.677
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments WASO, Days 1/2: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0154
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -6.16
    Confidence Interval (2-Sided) 95%
    -11.15 to -1.17
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.544
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 1/2: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -15.03
    Confidence Interval (2-Sided) 95%
    -20.01 to -10.05
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.542
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments WASO, Days 29/30: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0073
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -7.72
    Confidence Interval (2-Sided) 95%
    -13.36 to -2.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.876
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 29/30: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0016
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -9.1
    Confidence Interval (2-Sided) 95%
    -14.75 to -3.45
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.883
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments TST, Days 1/2: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.001
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 10.25
    Confidence Interval (2-Sided) 95%
    4.18 to 16.32
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.094
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments TST, Days 1/2: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 23.1
    Confidence Interval (2-Sided) 95%
    17.04 to 29.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.085
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments TST, Days 29/30: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 19.41
    Confidence Interval (2-Sided) 95%
    12.63 to 26.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.457
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments TST, Days 29/30: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 24.1
    Confidence Interval (2-Sided) 95%
    17.32 to 30.88
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.456
    Estimation Comments
    7. Other Pre-specified Outcome
    Title Change From Baseline in Subjective Sleep Onset Latency (sSOL), Subjective Wake After Sleep Onset (sWASO) and Subjective Total Sleep Time (sTST) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER
    Description sSOL: estimated minutes from time attempted to sleep to sleep onset. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. sSOL, sWASO, sTST were analyzed with diary handling rules (DHR) on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.
    Time Frame First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 259 264 269
    sSOL: Baseline: With DHR
    60.54
    (36.350)
    65.79
    (43.530)
    60.88
    (42.514)
    sSOL: 1st 7 nights: With DHR
    -16.23
    (29.531)
    -22.54
    (32.812)
    -21.88
    (29.269)
    sSOL: last 7 nights: With DHR
    -17.04
    (30.683)
    -25.20
    (34.854)
    -24.79
    (34.068)
    sWASO: Baseline: With DHR
    173.06
    (77.212)
    166.76
    (82.047)
    175.35
    (83.453)
    sWASO: Change at 1st 7 nights: With DHR
    -48.91
    (51.761)
    -39.33
    (55.022)
    -55.06
    (66.696)
    sWASO: Change at last 7 nights: With DHR
    -63.52
    (64.161)
    -44.51
    (58.090)
    -57.96
    (72.791)
    sTST: Baseline: With DHR
    273.07
    (81.207)
    275.74
    (83.650)
    266.10
    (92.164)
    sTST: Change at 1st 7 nights: With DHR
    56.99
    (62.880)
    50.30
    (60.065)
    67.80
    (71.134)
    sTST: Change at last 7 nights: With DHR
    71.01
    (76.574)
    62.41
    (68.555)
    79.95
    (81.211)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSOL, First 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0122
    Comments Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.898
    Confidence Interval (2-Sided) 95%
    0.825 to 0.977
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.83
    Confidence Interval (2-Sided) 95%
    0.763 to 0.902
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSOL, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0176
    Comments Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.882
    Confidence Interval (2-Sided) 95%
    0.796 to 0.978
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, Last 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model model with log transformation of sSOL and with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.811
    Confidence Interval (2-Sided) 95%
    0.732 to 0.899
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sWASO, First 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0706
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 8.12
    Confidence Interval (2-Sided) 95%
    -0.68 to 16.91
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.484
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, First 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.1949
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -5.81
    Confidence Interval (2-Sided) 95%
    -14.61 to 2.98
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.481
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sWASO, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0059
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 14.45
    Confidence Interval (2-Sided) 95%
    4.16 to 24.73
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.241
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.3064
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 5.36
    Confidence Interval (2-Sided) 95%
    -4.92 to 15.65
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.241
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sTST, First 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2174
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -6.57
    Confidence Interval (2-Sided) 95%
    -17.02 to 3.88
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.325
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sTST, First 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0949
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 8.88
    Confidence Interval (2-Sided) 95%
    -1.55 to 19.31
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.313
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sTST, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2718
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -6.82
    Confidence Interval (2-Sided) 95%
    -19.01 to 5.36
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.207
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sTST, Last 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2317
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.43
    Confidence Interval (2-Sided) 95%
    -4.75 to 19.61
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.206
    Estimation Comments
    8. Other Pre-specified Outcome
    Title Change From Baseline in Subjective Sleep Efficiency (sSE) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER
    Description sSE: percentage of sTST per subjective time spent in bed asleep, calculated as the interval from the time attempted to sleep to time stopped trying to sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sSE was analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.
    Time Frame First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received ZOL ER 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 247 253 258
    sSE: Baseline: With DHR
    55.49
    (15.802)
    56.05
    (17.094)
    54.31
    (18.318)
    sSE: Change at 1st 7 nights: With DHR
    11.96
    (12.526)
    10.56
    (12.296)
    13.97
    (14.188)
    sSE: Change at last 7 nights: With DHR
    14.83
    (15.011)
    12.92
    (13.884)
    16.12
    (16.300)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSE, First 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.1963
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.37
    Confidence Interval (2-Sided) 95%
    -3.46 to 0.71
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.063
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSE, First 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate
    Statistical Test of Hypothesis p-Value = 0.1093
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 1.7
    Confidence Interval (2-Sided) 95%
    -0.38 to 3.78
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.06
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSE, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2196
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.53
    Confidence Interval (2-Sided) 95%
    -3.98 to 0.92
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.247
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSE, Last 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.4013
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 1.05
    Confidence Interval (2-Sided) 95%
    -1.4 to 3.49
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.246
    Estimation Comments
    9. Other Pre-specified Outcome
    Title Change From Baseline in Mean LPS, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2
    Description LPS: amount of time in minutes from lights off to first epoch of 20 consecutive epochs of non-wakefulness. WASO: amount of time in minutes of wake from the onset of persistent sleep until lights. WASO2H: amount of time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST: amount of time in minutes of sleep from sleep onset until terminal awakening. LPS, WASO, WASO2H, and TST were measured by PSG. Change from baseline to average LPS, WASO, WASO2H, and TST on Day 1 and 2 were reported.
    Time Frame Baseline, Days 1/2

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    LPS: Baseline
    43.89
    (33.596)
    44.86
    (36.528)
    44.61
    (32.986)
    LPS: Change at Days 1/2
    -6.45
    (32.618)
    -16.59
    (28.742)
    -19.48
    (31.809)
    WASO: Baseline
    111.75
    (37.179)
    113.44
    (38.953)
    114.83
    (39.997)
    WASO: Change at Days 1/2
    -15.07
    (36.938)
    -49.96
    (39.578)
    -59.59
    (37.749)
    WASO2H: Baseline
    74.44
    (30.109)
    76.60
    (32.903)
    76.88
    (32.126)
    WASO2H: Change at Days 1/2
    -7.06
    (31.097)
    -30.28
    (32.056)
    -37.10
    (30.815)
    TST: Baseline
    330.67
    (46.268)
    328.00
    (54.224)
    325.07
    (52.819)
    TST: Change at Days 1/2
    19.44
    (43.348)
    65.22
    (46.695)
    79.58
    (47.350)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments LPS: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0092
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.752 to 0.961
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0002
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.795
    Confidence Interval (2-Sided) 95%
    0.704 to 0.899
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments WASO: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -33.4
    Confidence Interval (2-Sided) 95%
    -38.71 to -28.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.711
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -42.27
    Confidence Interval (2-Sided) 95%
    -47.57 to -36.97
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.705
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments WASO2H: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO2H as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -21.66
    Confidence Interval (2-Sided) 95%
    -26.01 to -17.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.221
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO2H: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO2H as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -28.33
    Confidence Interval (2-Sided) 95%
    -32.68 to -23.98
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.219
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments TST: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 44.05
    Confidence Interval (2-Sided) 95%
    37.59 to 50.51
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.291
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments TST: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 56.9
    Confidence Interval (2-Sided) 95%
    50.46 to 63.34
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.284
    Estimation Comments
    10. Other Pre-specified Outcome
    Title Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2
    Description SE is defined as percentage of time spent in bed asleep, calculated as TST divided by interval from lights off until lights on as measured by PSG, multiplied by 100. Change from baseline to average SE on Day 1 and 2 were reported.
    Time Frame Baseline, Days 1/2

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    SE: Baseline
    68.89
    (9.639)
    68.36
    (11.268)
    67.85
    (10.849)
    SE: Change at Days 1/2
    4.22
    (9.033)
    13.60
    (9.725)
    16.48
    (9.623)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments SE: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline SE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 9.01
    Confidence Interval (2-Sided) 95%
    7.7 to 10.31
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.666
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments SE: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 11.6
    Confidence Interval (2-Sided) 95%
    10.3 to 12.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.664
    Estimation Comments
    11. Other Pre-specified Outcome
    Title Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30
    Description WASO2H is defined as the time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST is defined as the amount of sleep in minutes from sleep onset until terminal awakening. WASO and TST were measured by PSG. Change from baseline to average WASO and TST on Day 29 and 30 were reported.
    Time Frame Baseline, Days 29/30

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 266 269
    WASO2H: Baseline
    74.44
    (30.109)
    76.60
    (32.903)
    76.88
    (32.126)
    WASO2H: Days 29 /30
    -8.92
    (31.909)
    -27.19
    (33.047)
    -28.84
    (33.138)
    TST: Baseline
    330.67
    (46.268)
    328.00
    (54.224)
    325.07
    (52.819)
    TST: Days 29/30
    25.65
    (47.587)
    61.99
    (46.817)
    67.86
    (52.117)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments WASO2H: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -16.41
    Confidence Interval (2-Sided) 95%
    -21.23 to -11.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.457
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO2H: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -17.76
    Confidence Interval (2-Sided) 95%
    -22.57 to -12.96
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.451
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments TST: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 34.16
    Confidence Interval (2-Sided) 95%
    26.95 to 41.36
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.673
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments TST: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 38.85
    Confidence Interval (2-Sided) 95%
    31.64 to 46.05
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.672
    Estimation Comments
    12. Other Pre-specified Outcome
    Title Change From Baseline in Mean sSOL, sWASO, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo
    Description sSOL: estimated minutes from time attempted to sleep to sleep onset. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. sSOL, sWASO, sTST were analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.
    Time Frame First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 206 264 269
    sSOL: Baseline: With DHR
    55.90
    (37.389)
    65.79
    (43.530)
    60.88
    (42.514)
    sSOL: Change at 1st 7 nights :With DHR
    -6.83
    (23.040)
    -22.54
    (32.812)
    -21.88
    (29.269)
    sSOL: Change at last 7 nights: With DHR
    -8.10
    (27.447)
    -25.20
    (34.854)
    -24.79
    (34.068)
    sWASO: Baseline: With DHR
    170.89
    (80.676)
    166.76
    (82.047)
    175.35
    (83.453)
    sWASO: Change at 1st 7 nights: With DHR
    -27.92
    (45.201)
    -39.33
    (55.022)
    -55.06
    (66.696)
    sWASO: Change at last 7 nights: With DHR
    -36.01
    (57.584)
    -44.51
    (58.090)
    -57.96
    (72.791)
    sTST: Baseline: With DHR
    276.23
    (87.649)
    275.74
    (83.650)
    266.10
    (92.164)
    sTST: Change at 1st 7 nights: With DHR
    30.86
    (57.437)
    50.30
    (60.065)
    67.80
    (71.134)
    sTST: Change at last 7 nights: With DHR
    38.98
    (66.174)
    62.41
    (68.555)
    79.95
    (81.211)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSOL, First 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.815
    Confidence Interval (2-Sided) 95%
    0.745 to 0.891
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.753
    Confidence Interval (2-Sided) 95%
    0.689 to 0.823
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSOL, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.671 to 0.837
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.689
    Confidence Interval (2-Sided) 95%
    0.618 to 0.769
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sWASO, First 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0093
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -12.41
    Confidence Interval (2-Sided) 95%
    -21.76 to -3.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.764
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -26.34
    Confidence Interval (2-Sided) 95%
    -35.68 to -16.99
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.762
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sWASO, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0396
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -11.49
    Confidence Interval (2-Sided) 95%
    -22.42 to -0.55
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.573
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0002
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -20.57
    Confidence Interval (2-Sided) 95%
    -31.51 to -9.63
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.574
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sTST, First 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0007
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 19.05
    Confidence Interval (2-Sided) 95%
    8.03 to 30.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.619
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sTST, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 34.51
    Confidence Interval (2-Sided) 95%
    23.5 to 45.52
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.609
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sTST, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0003
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 23.57
    Confidence Interval (2-Sided) 95%
    10.68 to 36.45
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.565
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sTST, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 37.82
    Confidence Interval (2-Sided) 95%
    24.94 to 50.71
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.565
    Estimation Comments
    13. Other Pre-specified Outcome
    Title Change From Baseline in Mean sSE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo
    Description sSE: percentage of sTST per subjective time spent in bed asleep, calculated as the interval from the time attempted to sleep to time stopped trying to sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sSE was analyzed with DHR on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals.
    Time Frame First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 201 253 258
    sSE: Baseline: With DHR
    56.08
    (17.343)
    56.05
    (17.094)
    54.31
    (18.318)
    sSE: Change at 1st 7 nights: With DHR
    6.73
    (10.930)
    10.56
    (12.296)
    13.97
    (14.188)
    sSE: Change at last 7 nights: With DHR
    8.35
    (13.273)
    12.92
    (13.884)
    16.12
    (16.300)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSE, First 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0008
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 3.76
    Confidence Interval (2-Sided) 95%
    1.56 to 5.97
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.122
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSE, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 6.84
    Confidence Interval (2-Sided) 95%
    4.64 to 9.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.12
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 5 mg
    Comments sSE, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0005
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 4.61
    Confidence Interval (2-Sided) 95%
    2.02 to 7.19
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.319
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSE, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.18
    Confidence Interval (2-Sided) 95%
    4.6 to 9.77
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.319
    Estimation Comments
    14. Other Pre-specified Outcome
    Title Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response
    Description Objective sleep onset response: LPS less than or equal to (<=) 20 minutes (mins) provided baseline LPS was greater than (>) 30 mins. Subjective sleep onset response: sSOL <=20 mins provided mean baseline sSOL was >30 mins. Objective sleep maintenance response: WASO <=60 minutes provided baseline WASO was >60 mins and was reduced by >10 mins compared to baseline. Subjective sleep maintenance response: sWASO <=60 mins provided mean WASO was >60 mins and was reduced by >10 mins compared to baseline. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals. Average data for Days 1 and 2, Days 29 and 30, and first and last 7 nights of treatment period was reported.
    Time Frame Days 1/2, Days 29/30, first 7 night (approximately Week 1), and Last seven nights (approximately Week 4)

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 263 266 269
    LPS: Days 1/2
    15.4
    7.4%
    10.3
    3.9%
    15.8
    5.9%
    17.8
    6.6%
    LPS: Days 29/30
    15.9
    7.6%
    11.4
    4.3%
    20.3
    7.6%
    22.3
    8.3%
    sSOL: First 7 nights (with DHR)
    2.9
    1.4%
    7.6
    2.9%
    9.8
    3.7%
    10.4
    3.9%
    sSOL: Last 7 nights (with DHR)
    7.2
    3.5%
    8.7
    3.3%
    16.9
    6.4%
    14.5
    5.4%
    WASO: Days 1/2
    16.8
    8.1%
    46.0
    17.5%
    51.1
    19.2%
    64.3
    23.9%
    WASO: Days 29/30
    22.1
    10.6%
    34.6
    13.2%
    44.4
    16.7%
    46.1
    17.1%
    sWASO: First 7 nights (with DHR)
    9.6
    4.6%
    16.7
    6.3%
    16.9
    6.4%
    20.4
    7.6%
    sWASO: Last 7 nights (with DHR)
    15.4
    7.4%
    23.2
    8.8%
    23.3
    8.8%
    23.0
    8.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 1/2: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.9028
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.41
    Confidence Interval (2-Sided) 95%
    -6.22 to 7.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 1/2: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.4699
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 2.49
    Confidence Interval (2-Sided) 95%
    -4.2 to 9.18
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments LPS, Days 1/2: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0566
    Comments
    Method Cochran-Mantel-Haenszel
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 5.58
    Confidence Interval (2-Sided) 95%
    -0.14 to 11.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments LPS, Days 1/2: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0122
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.57
    Confidence Interval (2-Sided) 95%
    1.71 to 13.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 29/30: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2176
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 4.42
    Confidence Interval (2-Sided) 95%
    -2.5 to 11.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments LPS, Days 29/30: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0773
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 6.47
    Confidence Interval (2-Sided) 95%
    -0.55 to 13.49
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments LPS, Days 29/30: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0054
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 8.85
    Confidence Interval (2-Sided) 95%
    2.68 to 15.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments LPS, Days 29/30: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0008
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 10.89
    Confidence Interval (2-Sided) 95%
    4.61 to 17.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.003
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 6.9
    Confidence Interval (2-Sided) 95%
    2.66 to 11.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0016
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.5
    Confidence Interval (2-Sided) 95%
    3.19 to 11.81
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Zolpidem, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.3643
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 2.22
    Confidence Interval (2-Sided) 95%
    -2.56 to 7.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sSOL, First 7 nights: Zolpidem, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2553
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 2.82
    Confidence Interval (2-Sided) 95%
    -2.02 to 7.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0016
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 9.69
    Confidence Interval (2-Sided) 95%
    3.98 to 15.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sSOL, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0128
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.29
    Confidence Interval (2-Sided) 95%
    1.8 to 12.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sSOL, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0051
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 8.16
    Confidence Interval (2-Sided) 95%
    2.51 to 13.81
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sSOL, Last 7nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0389
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 5.76
    Confidence Interval (2-Sided) 95%
    0.34 to 11.18
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 1/2: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 34.26
    Confidence Interval (2-Sided) 95%
    26.46 to 42.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 1/2: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 47.57
    Confidence Interval (2-Sided) 95%
    40.02 to 55.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments WASO, Days 1/2: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2534
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 4.89
    Confidence Interval (2-Sided) 95%
    -3.49 to 13.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments WASO: Days 1/2: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 18.25
    Confidence Interval (2-Sided) 95%
    10.1 to 26.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 29/30: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 22.2
    Confidence Interval (2-Sided) 95%
    14.06 to 30.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments WASO, Days 29/30: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 24.13
    Confidence Interval (2-Sided) 95%
    16.16 to 32.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments WASO, Days 29/30: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.023
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 9.59
    Confidence Interval (2-Sided) 95%
    1.36 to 17.81
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments WASO, Days 29/30: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0058
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 11.43
    Confidence Interval (2-Sided) 95%
    3.38 to 19.48
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, First 7 nights: Placebo, Lemborexant 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0222
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.3
    Confidence Interval (2-Sided) 95%
    1.27 to 13.33
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, First 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0013
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 10.84
    Confidence Interval (2-Sided) 95%
    4.57 to 17.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sWASO, First 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.9495
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.21
    Confidence Interval (2-Sided) 95%
    -6.17 to 6.58
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sWASO: First 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2708
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 3.72
    Confidence Interval (2-Sided) 95%
    -2.88 to 10.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0322
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.91
    Confidence Interval (2-Sided) 95%
    0.86 to 14.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0363
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 7.69
    Confidence Interval (2-Sided) 95%
    0.68 to 14.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 31
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.9885
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -7.14 to 7.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 32
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments sWASO, Last 7 nights: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.9651
    Comments Based on Cochran-Mantel-Haenszel test stratified by age group.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -0.16
    Confidence Interval (2-Sided) 95%
    -7.31 to 6.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Other Pre-specified Outcome
    Title Change From Baseline in Score From Items 4 to 7 on the Insomnia Severity Index (ISI) of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31
    Description The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: severity of sleep onset; sleep maintenance; early morning awakening problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning; noticeability of the sleep problems by others; and 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) yielding a total score from 0 to 28.
    Time Frame Baseline and Day 31

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 263 266 269
    Baseline
    11.21
    (2.436)
    11.06
    (2.508)
    10.91
    (2.419)
    10.84
    (2.334)
    Change at Day 31
    -3.88
    (3.559)
    -5.24
    (3.764)
    -4.83
    (3.593)
    -4.77
    (3.735)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0006
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.1
    Confidence Interval (2-Sided) 95%
    -1.73 to -0.47
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.319
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0007
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.08
    Confidence Interval (2-Sided) 95%
    -1.71 to -0.46
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.32
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2951
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.32
    Confidence Interval (2-Sided) 95%
    -0.28 to 0.91
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.301
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2744
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.33
    Confidence Interval (2-Sided) 95%
    -0.26 to 0.92
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.303
    Estimation Comments
    16. Other Pre-specified Outcome
    Title Change From Baseline in Fatigue Severity Scale (FSS) Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31
    Description The FSS is a self-report scale on which participants are instructed to choose a number from 1 to 7 that indicates their degree of agreement with each of 9 statements about their fatigue where "1" indicates strongly disagree, and "7" indicates strongly agree. The FSS total score was the sum of all responses to the 9 questions. The FSS average item score was the average of the score for each item. Higher total scores and higher average item scores indicated greater fatigue.
    Time Frame Baseline and Day 31

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 263 266 269
    Baseline
    37.48
    (13.602)
    37.15
    (13.788)
    37.47
    (13.518)
    37.42
    (13.111)
    Change at Day 31
    -6.75
    (11.916)
    -7.80
    (12.879)
    -8.14
    (13.411)
    -8.00
    (14.058)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2348
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline FSS as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.26
    Confidence Interval (2-Sided) 95%
    -3.35 to 0.82
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.063
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2745
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline FSS as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.17
    Confidence Interval (2-Sided) 95%
    -3.26 to 0.93
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.067
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.711
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -0.37
    Confidence Interval (2-Sided) 95%
    -2.35 to 1.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.005
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.7854
    Comments Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -0.27
    Confidence Interval (2-Sided) 95%
    -2.26 to 1.71
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.009
    Estimation Comments
    17. Other Pre-specified Outcome
    Title Change From Baseline in Mean Power of Attention (POA) and Speed of Memory Retrieval (SOMT) on Days 2/3
    Description POA reflects the ability to focus attention and process information. POA is calculated from the sum of simple reaction time, choice reaction time and digit vigilance. SOMT reflects time taken to retrieve information from working and episodic memory. SOMT is a composite score created by combining numerical working memory and spatial working memory and word recognition and picture recognition. Cognitive performance assessment was done by a computerized performance assessment battery (PAB) which was administered on a laptop computer. A positive change from baseline reflects impairment and a lower value of decrease from baseline indicates better performance. Change from baseline to average POA and SOMT on Days 2 and 3 was reported.
    Time Frame Baseline, Days 2/3

    Outcome Measure Data

    Analysis Population Description
    FAS was the group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 208 263 266 269
    POA: Baseine
    1421.0
    (210.27)
    1418.7
    (195.95)
    1452.9
    (263.04)
    1399.2
    (192.47)
    POA : Days 2/3
    -14.2
    (149.31)
    37.1
    (107.15)
    8.9
    (154.33)
    31.1
    (142.38)
    SOMT: Baseline
    4507.7
    (1098.73)
    4513.8
    (1097.65)
    4674.3
    (1174.74)
    4619.8
    (1065.00)
    SOMT: Days 2/3
    -177.9
    (668.77)
    60.7
    (749.12)
    -185.1
    (645.18)
    -152.8
    (722.49)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments POA: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0141
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline POA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 30.77
    Confidence Interval (2-Sided) 95%
    6.23 to 55.31
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 12.505
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments POA: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0016
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline POA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 39.67
    Confidence Interval (2-Sided) 95%
    15.05 to 64.29
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 12.542
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments POA: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.1031
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline POA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -19.22
    Confidence Interval (2-Sided) 95%
    -42.34 to 3.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 11.779
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments POA: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.3825
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline POA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -10.32
    Confidence Interval (2-Sided) 95%
    -33.5 to 12.86
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 11.813
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments SOMT: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.6348
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline SOMT as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 28.81
    Confidence Interval (2-Sided) 95%
    -90.18 to 147.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 60.626
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments SOMT: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.4026
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline SOMT as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 50.83
    Confidence Interval (2-Sided) 95%
    -68.3 to 169.97
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 60.702
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments SOMT: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0004
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline SOMT as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -203.36
    Confidence Interval (2-Sided) 95%
    -315.56 to -91.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 57.171
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments SOMT: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0016
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline SOMT as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -181.33
    Confidence Interval (2-Sided) 95%
    -293.71 to -68.96
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 57.255
    Estimation Comments
    18. Other Pre-specified Outcome
    Title Change From Baseline in Mean Quality of Memory (QOM) and Continuity of Attention (COA) on Days 2/3
    Description QOM represents the ability to store information in memory and subsequently retrieve it. It is a composite score created by combining accuracy measures from 2 sets of working memory and 4 sets of episodic memory. Two sets of working memory were included: numerical and spatial working memory, and ranges from -2 to 2. Four sets of episodic memory were included: immediate and delayed word recall, and word and picture recognition, and ranges from -200 to 400. COA is the ability to sustain attention. Number of correct responses (out of 50) for choice reaction time was added to total number of targets correctly identified (out of 45) digit vigilance minus number of false alarms (total score of -45 to 95). Higher values were better. Change from baseline to average QOM and COA on Days 2 and 3 was reported.
    Time Frame Baseline, Days 2/3

    Outcome Measure Data

    Analysis Population Description
    FAS was group of randomized participants who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement at given time points.
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 milligram (mg) and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.
    Measure Participants 195 239 249 246
    QOM: Baseline
    342.2
    (66.03)
    350.0
    (65.30)
    345.7
    (67.60)
    340.7
    (72.75)
    QOM: Change at Days 2/3
    3.5
    (45.20)
    -12.1
    (46.94)
    1.4
    (44.21)
    -2.8
    (44.11)
    COA: Baseline
    90.7
    (4.77)
    90.6
    (6.0)
    91.0
    (5.15)
    91.3
    (4.15)
    COA: Change at Days2/3
    0.0
    (4.16)
    -1.0
    (4.48)
    0.2
    (4.95)
    -0.7
    (3.92)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments QOM: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.9936
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline QOM as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -0.03
    Confidence Interval (2-Sided) 95%
    -8.16 to 8.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.141
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments QOM: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.1595
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline QOM as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -5.85
    Confidence Interval (2-Sided) 95%
    -14 to 2.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.154
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments QOM: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0011
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline QOM as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 12.73
    Confidence Interval (2-Sided) 95%
    5.09 to 20.38
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.894
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments QOM: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0774
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline QOM as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 6.92
    Confidence Interval (2-Sided) 95%
    -0.76 to 14.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.913
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments COA: Placebo, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.3726
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline COA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.35
    Confidence Interval (2-Sided) 95%
    -0.42 to 1.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.393
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Lemborexant 10 mg
    Comments COA: Placebo, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.2579
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline COA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -0.45
    Confidence Interval (2-Sided) 95%
    -1.22 to 0.33
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.394
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments COA: Zolpidem ER, Lemborexant 5 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0002
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline COA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 1.39
    Confidence Interval (2-Sided) 95%
    0.66 to 2.11
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.37
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Lemborexant 5 mg, Lemborexant 10 mg
    Comments COA: Zolpidem ER, Lemborexant 10 mg
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.112
    Comments Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effects, and the baseline COA as a covariate.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value 0.59
    Confidence Interval (2-Sided) 95%
    -0.14 to 1.32
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.372
    Estimation Comments

    Adverse Events

    Time Frame Run-in Phase (Day -7) up to End of treatment (Day 44)
    Adverse Event Reporting Description
    Arm/Group Title Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg Run -in Period Placebo
    Arm/Group Description Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period. Participants received lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period. Participants received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once on each night for 7 consecutive nights up to Baseline (Day 1), immediately before the time the participant intended to try to sleep of run-in period.
    All Cause Mortality
    Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg Run -in Period Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/209 (0%) 0/263 (0%) 0/266 (0%) 0/268 (0%) 0/1006 (0%)
    Serious Adverse Events
    Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg Run -in Period Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/209 (0%) 4/263 (1.5%) 2/266 (0.8%) 0/268 (0%) 0/1006 (0%)
    Cardiac disorders
    Coronary artery disease 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    Gastrointestinal disorders
    Abdominal hernia 0/209 (0%) 0 0/263 (0%) 0 1/266 (0.4%) 1 0/268 (0%) 0 0/1006 (0%) 0
    Small intestinal obstruction 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    General disorders
    Chest pain 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    Infections and infestations
    Pneumonia 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    Gastroenteritis viral 0/209 (0%) 0 0/263 (0%) 0 1/266 (0.4%) 1 0/268 (0%) 0 0/1006 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    Vascular disorders
    Peripheral vascular disorder 0/209 (0%) 0 1/263 (0.4%) 1 0/266 (0%) 0 0/268 (0%) 0 0/1006 (0%) 0
    Other (Not Including Serious) Adverse Events
    Placebo Zolpidem Tartrate Extended Release 6.25 mg Lemborexant 5 mg Lemborexant 10 mg Run -in Period Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 16/209 (7.7%) 18/263 (6.8%) 27/266 (10.2%) 28/268 (10.4%) 34/1006 (3.4%)
    Nervous system disorders
    Headache 13/209 (6.2%) 13 14/263 (5.3%) 21 17/266 (6.4%) 21 13/268 (4.9%) 15 34/1006 (3.4%) 34
    Somnolence 4/209 (1.9%) 4 4/263 (1.5%) 5 11/266 (4.1%) 11 19/268 (7.1%) 20 0/1006 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Eisai Medical Services
    Organization Eisai, Inc.
    Phone 1-888-422-4743
    Email esi_medinfo@eisai.com
    Responsible Party:
    Eisai Inc.
    ClinicalTrials.gov Identifier:
    NCT02783729
    Other Study ID Numbers:
    • E2006-G000-304
    • 2015-004347-39
    First Posted:
    May 26, 2016
    Last Update Posted:
    Feb 11, 2020
    Last Verified:
    Mar 1, 2018