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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study with Open-Label Extension Phase of the Efficacy and Safety of Lemborexant in Subjects with Irregular Sleep-Wake Rhythm Disorder and Mild to Moderate Alzheimer’s Disease Dementia

    Summary
    EudraCT number
    		 2017-003306-40
    Trial protocol
    		 GB  
    Global end of trial date
    17 Apr 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Apr 2021
    First version publication date
    19 Jan 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Results update at study completion date.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    E2006-G000-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03001557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    European Knowledge Centre, Mosquito Way, Hatfield, United Kingdom, AL10 9SN
    Public contact
    Eisai Medical Information, Eisai Inc., 1-888 274-2378, esi_medinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Inc., 1-888 274-2378, esi_medinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of the study is to determine the dose response of lemborexant 2.5 milligram (mg), 5 mg, 10 mg, and 15 mg compared to placebo on the change from baseline in actigraphy-derived sleep efficiency (aSE) during the last week of treatment in subjects with irregular sleep-wake rhythm disorder (ISWRD) and Alzheimer’s disease dementia , determine the efficacy of lemborexant 2.5 mg, 5 mg, 10 mg, and 15 mg compared to placebo on the change from baseline of aSE during each week of treatment, determine the efficacy of lemborexant 2.5 mg, 5 mg, 10 mg, and 15 mg compared to placebo on the change from baseline on the sleep fragmentation index (SFI) during each week of treatment, and to determine the change from baseline of the mean duration of wake bouts over each week of treatment.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2013) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 51
    Country: Number of subjects enrolled
    Japan: 11
    Worldwide total number of subjects
    63
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    5
    From 65 to 84 years
    55
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 57 investigative sites in the United States, Japan and United Kingdom from 20 Dec 2016 to 17 Apr 2020.

    Pre-assignment
    Screening details
    		 A total of 214 subjects were screened, of which 151 were screen failures and 63 were randomized and enrolled in to the study. Of these 63 subjects, 62 received the study treatment (1 subject was inadvertently randomized but did not receive any study drug).

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lemborexant-matched Placebo
    Arm description
    		 Subjects received two lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Lemborexant-matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Arm title
    		 Lemborexant 2.5 mg
    Arm description
    		 Subjects received one lemborexant 2.5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant-matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant-matched placebo, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Investigational medicinal product name
    Lemborexant 2.5 mg
    Investigational medicinal product code
    E2006
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 2.5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Arm title
    		 Lemborexant 5 mg
    Arm description
    		 Subjects received one lemborexant 5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant-matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant-matched placebo, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Investigational medicinal product name
    lemborexant 5 mg
    Investigational medicinal product code
    E2006
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Arm title
    		 Lemborexant 10 mg
    Arm description
    		 Subjects received one lemborexant 10 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    lemborexant-matched placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant-matched placebo, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Investigational medicinal product name
    Lemborexant 10 mg
    Investigational medicinal product code
    E2006
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 10 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Arm title
    		 Lemborexant 15 mg
    Arm description
    		 Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant 5 mg
    Investigational medicinal product code
    E2006
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Investigational medicinal product name
    Lemborexant 10 mg
    Investigational medicinal product code
    E2006
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 10 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Number of subjects in period 1 [1]
    		Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Started
    12
    12
    13
    13
    12
    Completed
    12
    12
    13
    13
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Eligible subjects who completed the Core Phase and agreed to continue in the Extension Phase.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Extension Phase: Lemborexant 5 mg
    Arm description
    		 Subject who completed the core study end of study (EOS) visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is discontinued or up to 30 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    lemborexant, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is discontinued or up to 30 months.

    Arm title
    		 Extension Phase: Lemborexant 10 mg
    Arm description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 10 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lemborexant 10 mg tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Arm title
    		 Extension Phase: Lemborexant 15 mg
    Arm description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lemborexant 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Number of subjects in period 2 [2]
    		Extension Phase: Lemborexant 5 mg Extension Phase: Lemborexant 10 mg Extension Phase: Lemborexant 15 mg
    Started
    5
    14
    6
    Completed
    0
    0
    0
    Not completed
    5
    14
    6
         Consent withdrawn by subject
    1
    5
    2
         Others
    1
    3
    -
         Adverse event, non-fatal
    2
    -
    -
         Loss of caregiver
    -
    1
    -
         Administrative Reason
    1
    3
    3
         Lost to follow-up
    -
    2
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Eligible subjects who completed the Core Phase and agreed to continue in the Extension Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lemborexant-matched Placebo
    Reporting group description
    		 Subjects received two lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 2.5 mg
    Reporting group description
    		 Subjects received one lemborexant 2.5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    		 Subjects received one lemborexant 10 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 15 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg Total
    Number of subjects
    		 12 12 13 13 12 62
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.3 ( 6.15 ) 76.5 ( 6.32 ) 76.9 ( 7.98 ) 71.8 ( 7.05 ) 71.9 ( 6.11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 6 8 6 10 37
        Male
    		 5 6 5 7 2 25
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 2 4 6 8 24
        Not Hispanic or Latino
    		 8 10 9 7 4 38
    Race
    Units: Subjects
        Asian
    		 2 2 2 3 2 11
        Black or African American
    		 2 1 2 1 1 7
        White
    		 8 9 8 9 9 43
        Unknown or Not Reported
    		 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Lemborexant-matched Placebo
    Reporting group description
    		 Subjects received two lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 2.5 mg
    Reporting group description
    		 Subjects received one lemborexant 2.5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    		 Subjects received one lemborexant 10 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Lemborexant 15 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.
    Reporting group title
    Extension Phase: Lemborexant 5 mg
    Reporting group description
    		 Subject who completed the core study end of study (EOS) visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is discontinued or up to 30 months.

    Reporting group title
    Extension Phase: Lemborexant 10 mg
    Reporting group description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 10 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Reporting group title
    Extension Phase: Lemborexant 15 mg
    Reporting group description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Primary: Core Phase: Change From Baseline in Mean Actigraphy Sleep Efficiency (aSE) With Lemborexant Compared to Placebo During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Actigraphy Sleep Efficiency (aSE) With Lemborexant Compared to Placebo During Week 1 of Treatment [1]
    End point description
    aSE was defined as the percentage of time spent in bed nocturnal sleeping, as measured by actigraphy. Sleep efficiency was calculated as the total duration of sleep epochs during the predefined 8-hour nocturnal sleep period divided by 8 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The full analysis set (FAS) included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of sleep time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    76.34 ( 6.559 )
    77.64 ( 7.883 )
    78.45 ( 6.844 )
    76.38 ( 8.037 )
    77.35 ( 8.624 )
        Change at Week 1 (n=12, 11, 13, 13, 12)
    0.14 ( 5.766 )
    2.43 ( 3.910 )
    3.87 ( 4.646 )
    -0.17 ( 5.861 )
    0.05 ( 4.475 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 2 of Treatment [2]
    End point description
    aSE was defined as the percentage of time spent in bed nocturnal sleeping, as measured by actigraphy. Sleep efficiency was calculated as the total duration of sleep epochs during the predefined 8-hour nocturnal sleep period divided by 8 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of sleep time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    76.34 ( 6.559 )
    77.64 ( 7.883 )
    78.45 ( 6.844 )
    76.38 ( 8.037 )
    77.35 ( 8.624 )
        Change at Week 2 (n=12, 10, 13, 13, 12)
    -1.31 ( 7.004 )
    2.17 ( 2.833 )
    1.65 ( 4.644 )
    -1.41 ( 5.896 )
    -0.07 ( 5.449 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 3 of Treatment [3]
    End point description
    aSE was defined as the percentage of time spent in bed nocturnal sleeping, as measured by actigraphy. Sleep efficiency was calculated as the total duration of sleep epochs during the predefined 8-hour nocturnal sleep period divided by 8 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of sleep time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    76.34 ( 6.559 )
    77.64 ( 7.883 )
    78.45 ( 6.844 )
    76.38 ( 8.037 )
    77.35 ( 8.624 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -0.30 ( 10.552 )
    1.68 ( 3.229 )
    0.91 ( 7.571 )
    -1.49 ( 4.442 )
    1.10 ( 7.112 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean aSE With Lemborexant Compared to Placebo During Week 4 of Treatment
    End point description
    aSE was defined as the percentage of time spent in bed nocturnal sleeping, as measured by actigraphy. Sleep efficiency was calculated as the total duration of sleep epochs during the predefined 8-hour nocturnal sleep period divided by 8 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of sleep time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    76.34 ( 6.559 )
    77.64 ( 7.883 )
    78.45 ( 6.844 )
    76.38 ( 8.037 )
    77.35 ( 8.624 )
        Change at Week 4 (n=11, 11, 12, 11, 12)
    -0.78 ( 9.555 )
    1.68 ( 4.696 )
    0.00 ( 5.547 )
    -1.04 ( 5.920 )
    -0.81 ( 7.735 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant 2.5 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1099 [4]
    Method
    		 MMRM
    Parameter type
    		 Least square mean (LSM) difference
    Point estimate
    3.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.741
         upper limit
    		 7.096
    Notes
    [4] - Based on a mixed model for repeated measure (MMRM) analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1576 [5]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    2.802
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.119
         upper limit
    		 6.723
    Notes
    [5] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.616 [6]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.777
         upper limit
    		 2.857
    Notes
    [6] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7135 [7]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.713
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.16
         upper limit
    		 4.585
    Notes
    [7] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Mean SFI During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean SFI During Week 1 of Treatment [8]
    End point description
    The SFI was defined as sum of a movement index (MI) and a fragmentation index (FI) during logged sleep period. The MI was equal to epochs of wake per time in bed (TBI) multiplied by 100. The FI was equal to the number of less than or equal to (<=) 1-minute periods of immobility/total number of periods of immobility of all durations during the defined nocturnal sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). SFI was determined by Actigraphy. Actigraphy was performed with accelerometer that was worn on wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included randomized subjects received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    58.51 ( 12.923 )
    53.87 ( 17.594 )
    50.07 ( 12.493 )
    54.75 ( 16.380 )
    54.78 ( 15.338 )
        Change at Week 1 (n=12, 11, 13, 12, 12)
    -1.43 ( 9.294 )
    -5.80 ( 11.388 )
    -8.16 ( 8.802 )
    -2.55 ( 11.756 )
    -3.52 ( 8.882 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean SFI During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean SFI During Week 2 of Treatment [9]
    End point description
    The SFI was defined as sum of a MI and a FI during logged sleep period. The MI was equal to epochs of wake per TBI multiplied by 100. The FI was equal to the number of <=1-minute periods of immobility/total number of periods of immobility of all durations during the defined nocturnal sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). SFI was determined by Actigraphy. Actigraphy was performed with accelerometer that was worn on wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included randomized subjects received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    58.51 ( 12.923 )
    53.87 ( 17.594 )
    50.07 ( 12.493 )
    54.75 ( 16.380 )
    54.78 ( 15.338 )
        Change at Week 2 (n=12, 10, 13, 13, 12)
    2.52 ( 11.845 )
    -6.91 ( 5.994 )
    -4.95 ( 8.399 )
    0.34 ( 14.194 )
    -3.18 ( 8.971 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean SFI During Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean SFI During Week 3 of Treatment [10]
    End point description
    The SFI was defined as sum of a MI and a FI during logged sleep period. The MI was equal to epochs of wake per TBI multiplied by 100. The FI was equal to the number of <=1-minute periods of immobility/total number of periods of immobility of all durations during the defined nocturnal sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). SFI was determined by Actigraphy. Actigraphy was performed with accelerometer that was worn on wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included randomized subjects received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    58.51 ( 12.923 )
    53.87 ( 17.594 )
    50.07 ( 12.493 )
    54.75 ( 16.380 )
    54.78 ( 15.338 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -3.30 ( 18.512 )
    -2.79 ( 7.541 )
    -5.22 ( 11.974 )
    0.36 ( 9.018 )
    -4.92 ( 9.572 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean SFI During Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean SFI During Week 4 of Treatment
    End point description
    The SFI was defined as sum of a MI and a FI during logged sleep period. The MI was equal to epochs of wake per TBI multiplied by 100. The FI was equal to the number of <=1-minute periods of immobility/total number of periods of immobility of all durations during the defined nocturnal sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). SFI was determined by Actigraphy. Actigraphy was performed with accelerometer that was worn on wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included randomized subjects received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    58.51 ( 12.923 )
    53.87 ( 17.594 )
    50.07 ( 12.493 )
    54.75 ( 16.380 )
    54.78 ( 15.338 )
        Change at Week 4 (n=11, 11, 12, 11, 12)
    -1.39 ( 19.383 )
    -1.35 ( 8.821 )
    -1.96 ( 8.459 )
    -0.45 ( 13.389 )
    -1.68 ( 12.683 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant 2.5 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1582 [11]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -5.098
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.24
         upper limit
    		 2.045
    Notes
    [11] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0961 [12]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -6.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.332
         upper limit
    		 1.122
    Notes
    [12] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8449 [13]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.262
         upper limit
    		 7.623
    Notes
    [13] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3747 [14]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -3.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.178
         upper limit
    		 3.897
    Notes
    [14] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in the Mean Duration of Wake Bouts (aMeanDurWB) During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the Mean Duration of Wake Bouts (aMeanDurWB) During Week 1 of Treatment [15]
    End point description
    aMeanDurWB was defined as an average duration of all wake bouts that occurred during the defined nocturnal predefined sleep period. The wake bout was defined as continuous wake of 10 minutes or longer. Lower values were better. aMeanDurWB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    20.32 ( 6.625 )
    20.40 ( 5.140 )
    20.62 ( 5.898 )
    21.89 ( 4.885 )
    21.94 ( 7.790 )
        Change at Week 1 (n=12, 11, 13, 12, 12)
    -1.65 ( 5.078 )
    -1.99 ( 2.825 )
    -0.51 ( 6.522 )
    -0.82 ( 5.722 )
    1.54 ( 5.378 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurWB During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the aMeanDurWB During Week 2 of Treatment [16]
    End point description
    aMeanDurWB was defined as an average duration of all wake bouts that occurred during the defined nocturnal predefined sleep period. The wake bout was defined as continuous wake of 10 minutes or longer. Lower values were better. aMeanDurWB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    20.32 ( 6.625 )
    20.40 ( 5.140 )
    20.62 ( 5.898 )
    21.89 ( 4.885 )
    21.94 ( 7.790 )
        Change at Week 2 (n=12, 10, 13, 12, 12)
    -0.32 ( 7.904 )
    1.79 ( 12.957 )
    4.71 ( 13.845 )
    1.54 ( 6.333 )
    2.57 ( 6.708 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurWB During Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the aMeanDurWB During Week 3 of Treatment [17]
    End point description
    aMeanDurWB was defined as an average duration of all wake bouts that occurred during the defined nocturnal predefined sleep period. The wake bout was defined as continuous wake of 10 minutes or longer. Lower values were better. aMeanDurWB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    20.32 ( 6.625 )
    20.40 ( 5.140 )
    20.62 ( 5.898 )
    21.89 ( 4.885 )
    21.94 ( 7.790 )
        Change at Week 3 (n=11, 11, 11, 12, 12)
    -2.88 ( 7.928 )
    3.67 ( 7.833 )
    -0.52 ( 4.595 )
    -0.64 ( 5.482 )
    2.76 ( 7.489 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurWB During Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the aMeanDurWB During Week 4 of Treatment
    End point description
    aMeanDurWB was defined as an average duration of all wake bouts that occurred during the defined nocturnal predefined sleep period. The wake bout was defined as continuous wake of 10 minutes or longer. Lower values were better. aMeanDurWB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    20.32 ( 6.625 )
    20.40 ( 5.140 )
    20.62 ( 5.898 )
    21.89 ( 4.885 )
    21.94 ( 7.790 )
        Change at Week 4 (n=11, 11, 11, 11, 12)
    1.26 ( 8.621 )
    -0.43 ( 8.053 )
    3.16 ( 8.140 )
    -2.03 ( 4.947 )
    3.38 ( 12.354 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3966 [18]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    1.932
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.601
         upper limit
    		 6.465
    Notes
    [18] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1381 [19]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    3.386
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.125
         upper limit
    		 7.897
    Notes
    [19] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5487 [20]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    1.337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.104
         upper limit
    		 5.778
    Notes
    [20] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0581 [21]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    4.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.153
         upper limit
    		 8.793
    Notes
    [21] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Mean Actigraphy Wake Efficiency (aWE) During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Actigraphy Wake Efficiency (aWE) During Week 1 of Treatment [22]
    End point description
    aWE was defined as the percentage of time spent awake in bed during defined wake period, as measured by actigraphy. Wake efficiency was calculated as the total duration of wake epochs during 16 hours outside of the predefined sleep period divided by 16 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of wake time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    69.74 ( 12.609 )
    70.57 ( 11.669 )
    72.53 ( 11.473 )
    67.19 ( 11.523 )
    70.67 ( 11.221 )
        Change at Week 1 (n=12, 11, 13, 12, 12)
    0.59 ( 4.177 )
    -2.41 ( 6.726 )
    1.09 ( 6.793 )
    -1.55 ( 9.216 )
    -2.37 ( 8.779 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aWE During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean aWE During Week 2 of Treatment [23]
    End point description
    aWE was defined as the percentage of time spent awake in bed during defined wake period, as measured by actigraphy. Wake efficiency was calculated as the total duration of wake epochs during 16 hours outside of the predefined sleep period divided by 16 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of wake time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    69.74 ( 12.609 )
    70.57 ( 11.669 )
    72.53 ( 11.473 )
    67.19 ( 11.523 )
    70.67 ( 11.221 )
        Change at Week 2 (n=12, 10, 13, 12, 12)
    2.14 ( 2.773 )
    -1.54 ( 6.550 )
    1.04 ( 7.511 )
    -3.16 ( 12.816 )
    -0.63 ( 5.617 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aWE During Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean aWE During Week 3 of Treatment [24]
    End point description
    aWE was defined as the percentage of time spent awake in bed during defined wake period, as measured by actigraphy. Wake efficiency was calculated as the total duration of wake epochs during 16 hours outside of the predefined sleep period divided by 16 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of wake time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    69.74 ( 12.609 )
    70.57 ( 11.669 )
    72.53 ( 11.473 )
    67.19 ( 11.523 )
    70.67 ( 11.221 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    1.64 ( 5.451 )
    -2.37 ( 6.239 )
    2.34 ( 8.370 )
    -4.99 ( 11.479 )
    -1.83 ( 5.579 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean aWE During Week 4 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Mean aWE During Week 4 of Treatment
    End point description
    aWE was defined as the percentage of time spent awake in bed during defined wake period, as measured by actigraphy. Wake efficiency was calculated as the total duration of wake epochs during 16 hours outside of the predefined sleep period divided by 16 hours and multiplied by 100. Higher values were better. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of wake time
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    69.74 ( 12.609 )
    70.57 ( 11.669 )
    72.53 ( 11.473 )
    67.19 ( 11.523 )
    70.67 ( 11.221 )
        Change at Week 4 (n=11, 11, 12, 11, 12)
    2.03 ( 6.841 )
    -2.29 ( 7.724 )
    3.62 ( 8.586 )
    -2.65 ( 9.627 )
    -0.43 ( 5.848 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1777 [25]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -3.437
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.481
         upper limit
    		 1.608
    Notes
    [25] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.563 [26]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    1.458
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.564
         upper limit
    		 6.479
    Notes
    [26] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0482 [27]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -4.994
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.946
         upper limit
    		 -0.041
    Notes
    [27] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3036 [28]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -2.593
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.599
         upper limit
    		 2.413
    Notes
    [28] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Mean Wake Fragmentation Index (WFI) During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Wake Fragmentation Index (WFI) During Week 1 of Treatment [29]
    End point description
    The WFI were calculated as sum of an immobility index (II) and FI during the logged wake period. The II was equal to the epochs of immobility per the 16 hours outside of the defined sleep period multiplied by 100. The FI was equal to the number of <=1-minute periods of mobility/total number of periods of mobility the 16 hours outside of defined sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). The WFI was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    92.43 ( 18.547 )
    85.72 ( 16.137 )
    86.53 ( 18.705 )
    94.76 ( 17.262 )
    87.96 ( 15.928 )
        Change at Week 1 (n=12, 11, 13, 12, 12)
    -0.14 ( 6.968 )
    4.22 ( 9.988 )
    -2.18 ( 10.571 )
    2.01 ( 13.017 )
    3.25 ( 13.006 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean WFI During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean WFI During Week 2 of Treatment [30]
    End point description
    The WFI were calculated as the sum of an II and a FI during the logged wake period. The II was equal to the epochs of immobility per the 16 hours outside of the defined sleep period multiplied by 100. The FI was equal to the number of <=1-minute periods of mobility/total number of periods of mobility the 16 hours outside of the defined sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). The WFI was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    92.43 ( 18.547 )
    85.72 ( 16.137 )
    86.53 ( 18.705 )
    94.76 ( 17.262 )
    87.96 ( 15.928 )
        Change at Week 2 (n=12, 10, 13, 12, 12)
    -3.76 ( 3.940 )
    4.12 ( 8.671 )
    -2.36 ( 11.453 )
    5.09 ( 19.006 )
    1.78 ( 9.271 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean WFI During Week 3 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Mean WFI During Week 3 of Treatment [31]
    End point description
    The WFI were calculated as the sum of an II and a FI during the logged wake period. The II was equal to the epochs of immobility per the 16 hours outside of the defined sleep period multiplied by 100. The FI was equal to the number of <=1-minute periods of mobility/total number of periods of mobility the 16 hours outside of the defined sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). The WFI was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    92.43 ( 18.547 )
    85.72 ( 16.137 )
    86.53 ( 94.76 )
    94.76 ( 17.262 )
    87.96 ( 15.928 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -1.65 ( 7.980 )
    4.70 ( 9.674 )
    -3.69 ( 13.236 )
    6.88 ( 16.704 )
    2.10 ( 8.631 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean WFI During Week 4 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Mean WFI During Week 4 of Treatment
    End point description
    The WFI were calculated as the sum of an II and a FI during the logged wake period. The II was equal to the epochs of immobility per the 16 hours outside of the defined sleep period multiplied by 100. The FI was equal to the number of <=1-minute periods of mobility/total number of periods of mobility the 16 hours outside of the defined sleep period multiplied by 100. Value ranges from 0-100 percent (lower values were better). The WFI was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: percentage of immobile bouts
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    92.43 ( 18.547 )
    85.72 ( 16.137 )
    86.53 ( 18.705 )
    94.76 ( 17.262 )
    87.96 ( 15.928 )
        Change at Week 4 (n=11, 11, 12, 11, 12)
    -3.01 ( 10.620 )
    4.55 ( 10.930 )
    -6.93 ( 14.428 )
    2.77 ( 13.407 )
    1.22 ( 8.054 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1991 [32]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    4.845
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.624
         upper limit
    		 12.313
    Notes
    [32] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2982 [33]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -3.872
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.263
         upper limit
    		 3.518
    Notes
    [33] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0664 [34]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    6.776
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.474
         upper limit
    		 14.025
    Notes
    [34] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4148 [35]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    3.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.344
         upper limit
    		 10.379
    Notes
    [35] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in the Mean Duration of Sleep Bouts (aMeanDurSB) During Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the Mean Duration of Sleep Bouts (aMeanDurSB) During Week 1 of Treatment [36]
    End point description
    aMeanDurSB was defined as an average duration of all sleep bouts that occurred during the 16 hours outside of the predefined nocturnal sleep period. The sleep bout was defined as the continuous sleep of 10 minutes or longer. Lower values were better. aMeanDurSB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    18.36 ( 4.620 )
    20.65 ( 3.638 )
    23.13 ( 5.919 )
    19.84 ( 3.364 )
    23.30 ( 10.862 )
        Change at Week 1 (n=12, 11, 13, 12, 12)
    2.15 ( 2.539 )
    0.09 ( 4.056 )
    -1.12 ( 5.202 )
    -0.40 ( 3.394 )
    -3.19 ( 10.405 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurSB During Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the aMeanDurSB During Week 2 of Treatment [37]
    End point description
    aMeanDurSB was defined as an average duration of all sleep bouts that occurred during the 16 hours outside of the predefined nocturnal sleep period. The sleep bout was defined as the continuous sleep of 10 minutes or longer. lower values were better. aMeanDurSB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    18.36 ( 4.620 )
    20.65 ( 3.638 )
    23.13 ( 5.919 )
    19.84 ( 3.364 )
    23.30 ( 10.862 )
        Change at Week 2 (n=12, 10, 13, 12, 12)
    0.25 ( 2.999 )
    -0.88 ( 4.679 )
    -2.52 ( 5.965 )
    -0.80 ( 2.961 )
    -3.95 ( 8.980 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurSB During Week 3 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in the aMeanDurSB During Week 3 of Treatment [38]
    End point description
    aMeanDurSB was defined as an average duration of all sleep bouts that occurred during the 16 hours outside of the predefined nocturnal sleep period. The sleep bout was defined as the continuous sleep of 10 minutes or longer. lower values were better. aMeanDurSB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [38] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    18.36 ( 4.620 )
    20.65 ( 3.638 )
    23.13 ( 5.919 )
    19.84 ( 3.364 )
    23.30 ( 10.862 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -0.14 ( 3.249 )
    -1.17 ( 4.056 )
    -3.80 ( 3.701 )
    -0.68 ( 2.292 )
    -4.15 ( 10.264 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the aMeanDurSB During Week 4 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in the aMeanDurSB During Week 4 of Treatment
    End point description
    aMeanDurSB was defined as an average duration of all sleep bouts that occurred during the 16 hours outside of the predefined nocturnal sleep period. The sleep bout was defined as the continuous sleep of 10 minutes or longer. lower values were better. aMeanDurSB was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    18.36 ( 4.620 )
    20.65 ( 3.638 )
    23.13 ( 5.919 )
    19.84 ( 3.364 )
    23.30 ( 10.862 )
        Change at Week 4 (n=11, 11, 12, 11, 12)
    1.00 ( 4.568 )
    -1.31 ( 3.639 )
    -2.80 ( 5.727 )
    -0.03 ( 2.307 )
    -5.30 ( 9.745 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9599 [39]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.452
         upper limit
    		 2.579
    Notes
    [39] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8541 [40]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.238
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.817
         upper limit
    		 2.342
    Notes
    [40] - Based on a MMRM analysis adjusted for baseline value, country, Visit and treatment by Visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8117 [41]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.293
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.745
         upper limit
    		 2.16
    Notes
    [41] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2274 [42]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -1.557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.113
         upper limit
    		 1
    Notes
    [42] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 1 of Treatment [43]
    End point description
    Intradaily variability gives an indication of ISWRD by quantifying the number and strength of transitions between rest and activity bouts, derived by the ratio of the mean squares of the difference between all successive hours (first derivative) and the mean squares around the grand mean(overall variance). The variable has a theoretical range of 0 to 2, with higher values indicating higher fragmentation. Intradaily variability was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1.10 ( 0.262 )
    0.90 ( 0.272 )
    0.98 ( 0.295 )
    1.10 ( 0.295 )
    1.03 ( 0.330 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    -0.01 ( 0.200 )
    0.06 ( 0.218 )
    -0.03 ( 0.237 )
    0.10 ( 0.271 )
    -0.01 ( 0.278 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 2 of Treatment [44]
    End point description
    Intradaily variability gives an indication of ISWRD by quantifying the number and strength of transitions between rest and activity bouts, derived by the ratio of the mean squares of the difference between all successive hours (first derivative) and the mean squares around the grand mean (overall variance). The variable has a theoretical range of 0 to 2, with higher values indicating higher fragmentation. Intradaily variability was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [44] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1.10 ( 0.262 )
    0.90 ( 0.272 )
    0.98 ( 0.295 )
    1.10 ( 0.295 )
    1.03 ( 0.330 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    -0.05 ( 0.132 )
    0.14 ( 0.325 )
    0.02 ( 0.235 )
    0.07 ( 0.143 )
    0.05 ( 0.234 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 3 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 3 of Treatment [45]
    End point description
    Intradaily variability gives an indication of ISWRD by quantifying the number and strength of transitions between rest and activity bouts, derived by the ratio of the mean squares of the difference between all successive hours (first derivative) and the mean squares around the grand mean (overall variance). The variable has a theoretical range of 0 to 2, with higher values indicating higher fragmentation. Intradaily variability was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1.10 ( 0.262 )
    0.90 ( 0.272 )
    0.98 ( 0.295 )
    1.10 ( 0.295 )
    1.03 ( 0.330 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -0.06 ( 0.243 )
    0.07 ( 0.246 )
    -0.00 ( 0.241 )
    -0.06 ( 0.311 )
    -0.01 ( 0.219 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 4 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Mean Intradaily Variability Over Week 4 of Treatment
    End point description
    Intradaily variability gives an indication of ISWRD by quantifying the number and strength of transitions between rest and activity bouts, derived by the ratio of the mean squares of the difference between all successive hours (first derivative) and the mean squares around the grand mean (overall variance). The variable has a theoretical range of 0 to 2, with higher values indicating higher fragmentation. Intradaily variability was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1.10 ( 0.262 )
    0.90 ( 0.272 )
    0.98 ( 0.295 )
    1.10 ( 0.295 )
    1.03 ( 0.330 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    -0.10 ( 0.324 )
    0.10 ( 0.196 )
    0.02 ( 0.157 )
    -0.12 ( 0.274 )
    -0.10 ( 0.222 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2421 [46]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.232
    Notes
    [46] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8661 [47]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.155
         upper limit
    		 0.131
    Notes
    [47] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4251 [48]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.085
         upper limit
    		 0.199
    Notes
    [48] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7248 [49]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.116
         upper limit
    		 0.166
    Notes
    [49] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Mean Interdaily Stability (IS) Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean Interdaily Stability (IS) Over Week 1 of Treatment [50]
    End point description
    IS gives an indication of the stability of the sleep-wake rhythm across days, and varies from zero (low stability) to 1 (high stability). IS was derived by the ratio between the variance of the average 24-hour pattern around the mean and the overall variance. Higher values indicated stable rhythm. IS was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [50] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.45 ( 0.173 )
    0.47 ( 0.111 )
    0.49 ( 0.118 )
    0.46 ( 0.160 )
    0.41 ( 0.104 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    0.04 ( 0.083 )
    -0.02 ( 0.089 )
    0.04 ( 0.115 )
    -0.00 ( 0.155 )
    0.06 ( 0.063 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean IS Over Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean IS Over Week 2 of Treatment [51]
    End point description
    IS gives an indication of the stability of the sleep-wake rhythm across days, and varies from zero (low stability) to 1 (high stability). IS was derived by the ratio between the variance of the average 24-hour pattern around the mean and the overall variance. Higher values indicated stable rhythm. IS was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [51] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.45 ( 0.173 )
    0.47 ( 0.111 )
    0.49 ( 0.118 )
    0.46 ( 0.160 )
    0.41 ( 0.104 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    0.06 ( 0.093 )
    -0.01 ( 0.101 )
    0.03 ( 0.133 )
    -0.06 ( 0.091 )
    0.09 ( 0.085 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean IS Over Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean IS Over Week 3 of Treatment [52]
    End point description
    IS gives an indication of the stability of the sleep-wake rhythm across days, and varies from zero (low stability) to 1 (high stability). IS was derived by the ratio between the variance of the average 24-hour pattern around the mean and the overall variance. Higher values indicated stable rhythm. IS was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [52] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.45 ( 0.173 )
    0.47 ( 0.111 )
    0.49 ( 0.118 )
    0.46 ( 0.160 )
    0.41 ( 0.104 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    0.03 ( 0.104 )
    -0.01 ( 0.107 )
    0.03 ( 0.115 )
    -0.04 ( 0.136 )
    0.04 ( 0.075 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Mean IS Over Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Mean IS Over Week 4 of Treatment
    End point description
    IS gives an indication of the stability of the sleep-wake rhythm across days, and varies from zero (low stability) to 1 (high stability). IS was derived by the ratio between the variance of the average 24-hour pattern around the mean and the overall variance. Higher values indicated stable rhythm. IS was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.45 ( 0.173 )
    0.47 ( 0.111 )
    0.49 ( 0.118 )
    0.46 ( 0.160 )
    0.41 ( 0.104 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    0.02 ( 0.098 )
    0.01 ( 0.119 )
    0.08 ( 0.092 )
    0.03 ( 0.127 )
    0.00 ( 0.102 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2991 [53]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.094
         upper limit
    		 0.029
    Notes
    [53] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2861 [54]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.095
    Notes
    [54] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0938 [55]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.113
         upper limit
    		 0.009
    Notes
    [55] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant 15 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8618 [56]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.066
    Notes
    [56] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Average Activity Counts Across Least Active 5-hour Period (L5) Per 24-Hour Period Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Average Activity Counts Across Least Active 5-hour Period (L5) Per 24-Hour Period Over Week 1 of Treatment [57]
    End point description
    L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. This value provides an indication of how restful (inactive) and regular the sleep periods are. L5 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [57] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1163.5 ( 373.3 )
    1266.4 ( 678.1 )
    1163.2 ( 591.8 )
    1257.1 ( 836.6 )
    1490.4 ( 963.1 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    200.9 ( 633.3 )
    -259.8 ( 450.3 )
    -243.2 ( 333.6 )
    -211.6 ( 378.3 )
    -434.2 ( 509.1 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 2 of Treatment [58]
    End point description
    L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. This value provides an indication of how restful (inactive) and regular the sleep periods are. L5 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [58] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1163.5 ( 373.3 )
    1266.4 ( 678.1 )
    1163.2 ( 591.8 )
    1257.1 ( 836.6 )
    1490.4 ( 963.1 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    85.8 ( 525.3 )
    -259.8 ( 244.9 )
    -218.7 ( 321.6 )
    218.5 ( 455.9 )
    -246.1 ( 637.6 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 3 of Treatment [59]
    End point description
    L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. This value provides an indication of how restful (inactive) and regular the sleep periods are. L5 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [59] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1163.5 ( 373.3 )
    1266.4 ( 678.1 )
    1163.2 ( 591.8 )
    1257.1 ( 836.6 )
    1490.4 ( 963.1 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    299.2 ( 1070.2 )
    -265.3 ( 507.0 )
    -233.0 ( 369.3 )
    -114.6 ( 376.6 )
    -396.1 ( 543.9 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 4 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in Average Activity Counts Across L5 Per 24-Hour Period Over Week 4 of Treatment
    End point description
    L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. This value provides an indication of how restful (inactive) and regular the sleep periods are. L5 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    1163.5 ( 373.3 )
    1266.4 ( 678.1 )
    1163.2 ( 591.8 )
    1257.1 ( 836.6 )
    1490.4 ( 963.1 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    293.1 ( 662.6 )
    -334.0 ( 476.4 )
    -344.5 ( 419.1 )
    30.5 ( 772.5 )
    -160.7 ( 471.3 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant 2.5 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0294 [60]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -389.873
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -739.177
         upper limit
    		 -40.569
    Notes
    [60] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0243 [61]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -402.994
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -751.67
         upper limit
    		 -54.319
    Notes
    [61] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4209 [62]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -141.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -489.805
         upper limit
    		 207.752
    Notes
    [62] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0398 [63]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -367.845
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -717.87
         upper limit
    		 -17.82
    Notes
    [63] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in the Average Activity Count During the Most Active 10-hour Period (M10) Per 24-Hour Period Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the Average Activity Count During the Most Active 10-hour Period (M10) Per 24-Hour Period Over Week 1 of Treatment [64]
    End point description
    M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. M10 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [64] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    8560.4 ( 2631.2 )
    11567.0 ( 4266.3 )
    12158.1 ( 3639.9 )
    10662.1 ( 5023.6 )
    11460.5 ( 4954.3 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    59.7 ( 1832.6 )
    -731.4 ( 3373.5 )
    42.5 ( 1789.3 )
    -334.6 ( 2659.2 )
    -111.2 ( 2558.0 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 2 of Treatment [65]
    End point description
    M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. M10 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [65] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    8560.4 ( 2631.2 )
    11567.0 ( 4266.3 )
    12158.1 ( 3639.9 )
    10662.1 ( 5023.6 )
    11460.5 ( 4954.3 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    232.7 ( 1829.1 )
    -968.8 ( 2885.6 )
    -121.1 ( 2137.3 )
    -564.2 ( 1975.7 )
    -325.4 ( 1585.4 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 3 of Treatment

    		 Close Top of page
    End point title
    		 Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 3 of Treatment [66]
    End point description
    M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. M10 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [66] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    8560.4 ( 2631.2 )
    11567.0 ( 4266.3 )
    12158.1 ( 3639.9 )
    10662.1 ( 5023.6 )
    11460.5 ( 4954.3 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    300.3 ( 2094.9 )
    -986.2 ( 3502.0 )
    572.6 ( 2216.0 )
    -828.3 ( 1970.2 )
    -635.8 ( 2413.6 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in the Average Activity Count During the M10 Per 24-Hour Period Over Week 4 of Treatment
    End point description
    M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. M10 was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    8560.4 ( 2631.2 )
    11567.0 ( 4266.3 )
    12158.1 ( 3639.9 )
    10662.1 ( 5023.6 )
    11460.5 ( 4954.3 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    1650.4 ( 1815.3 )
    -1392.1 ( 2249.3 )
    -477.4 ( 963.2 )
    279.8 ( 2204.0 )
    -457.8 ( 1788.7 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant 2.5 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1162 [67]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -1276.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2878.587
         upper limit
    		 326.226
    Notes
    [67] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7781 [68]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    227.464
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1382.85
         upper limit
    		 1837.777
    Notes
    [68] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4255 [69]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -620.581
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2170.342
         upper limit
    		 929.179
    Notes
    [69] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4672 [70]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -577.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2160.337
         upper limit
    		 1004.697
    Notes
    [70] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Amplitude of the Rest-activity Rhythm (AMP) Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Amplitude of the Rest-activity Rhythm (AMP) Over Week 1 of Treatment [71]
    End point description
    AMP was amplitude of rest-activity rhythm calculated as the difference between M10 and L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. AMP was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [71] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    7396.9 ( 2728.3 )
    10300.6 ( 4235.8 )
    10994.8 ( 3601.8 )
    9405.0 ( 5133.9 )
    9970.0 ( 4905.8 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    -141.1 ( 1583.8 )
    -471.6 ( 3414.4 )
    285.8 ( 1788.6 )
    -123.0 ( 2784.1 )
    323.0 ( 2436.0 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in AMP Over Week 2 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in AMP Over Week 2 of Treatment [72]
    End point description
    AMP was amplitude of rest-activity rhythm calculated as the difference between M10 and L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. AMP was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [72] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    7396.9 ( 2728.3 )
    10300.6 ( 4235.8 )
    10994.8 ( 3601.8 )
    9405.0 ( 5133.9 )
    9970.0 ( 4905.8 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    146.8 ( 1603.7 )
    -708.9 ( 2934.6 )
    97.6 ( 2105.2 )
    -782.7 ( 2141.4 )
    -79.3 ( 1672.5 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in AMP Over Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in AMP Over Week 3 of Treatment [73]
    End point description
    AMP was amplitude of rest-activity rhythm calculated as the difference between M10 and L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. AMP was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [73] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    7396.9 ( 2728.3 )
    10300.6 ( 4235.8 )
    10994.8 ( 3601.8 )
    9405.0 ( 5133.9 )
    9970.0 ( 4905.8 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    1.1 ( 1862.7 )
    -721.0 ( 3502.2 )
    805.6 ( 2195.6 )
    -713.7 ( 2178.3 )
    -239.7 ( 2592.5 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in AMP Over Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in AMP Over Week 4 of Treatment
    End point description
    AMP was amplitude of rest-activity rhythm calculated as the difference between M10 and L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. AMP was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: activity count
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    7396.9 ( 2728.3 )
    10300.6 ( 4235.8 )
    10994.8 ( 3601.8 )
    9405.0 ( 5133.9 )
    9970.0 ( 4905.8 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    1357.3 ( 1801.9 )
    -1058.0 ( 2170.9 )
    -132.9 ( 840.7 )
    249.4 ( 2694.7 )
    -297.1 ( 1608.2 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant 2.5 mg v Lemborexant-matched Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2984 [74]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -839.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2440.854
         upper limit
    		 762.678
    Notes
    [74] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4218 [75]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    651.922
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -962.835
         upper limit
    		 2266.678
    Notes
    [75] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5655 [76]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -447.245
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1998.44
         upper limit
    		 1103.95
    Notes
    [76] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8686 [77]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    -130.603
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1706.478
         upper limit
    		 1445.272
    Notes
    [77] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Primary: Core Phase: Change From Baseline in Relative Amplitude in the Rest-activity Rhythm (RA) Over Week 1 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in Relative Amplitude in the Rest-activity Rhythm (RA) Over Week 1 of Treatment [78]
    End point description
    RA was relative amplitude of the rest-activity rhythm calculated as the difference between M10 and L5 divided by M10 plus L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. RA was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average first 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 1
    Notes
    [78] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.73 ( 0.136 )
    0.79 ( 0.141 )
    0.82 ( 0.089 )
    0.77 ( 0.165 )
    0.76 ( 0.148 )
        Change at Week 1 (n=12, 11, 13, 11, 12)
    -0.02 ( 0.101 )
    0.01 ( 0.080 )
    0.03 ( 0.067 )
    0.02 ( 0.096 )
    0.07 ( 0.073 )
    No statistical analyses for this end point

    Primary: Core Phase: Core Phase: Change From Baseline in RA Over Week 2 of Treatment

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    End point title
    		 Core Phase: Core Phase: Change From Baseline in RA Over Week 2 of Treatment [79]
    End point description
    RA was relative amplitude of the rest-activity rhythm calculated as the difference between M10 and L5 divided by M10 plus L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. RA was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average second 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [79] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.73 ( 0.136 )
    0.79 ( 0.141 )
    0.82 ( 0.089 )
    0.77 ( 0.165 )
    0.76 ( 0.148 )
        Change at Week 2 (n=12, 9, 12, 12, 11)
    -0.00 ( 0.073 )
    0.01 ( 0.063 )
    0.03 ( 0.052 )
    -0.05 ( 0.112 )
    0.05 ( 0.091 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in RA Over Week 3 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in RA Over Week 3 of Treatment [80]
    End point description
    RA was relative amplitude of the rest-activity rhythm calculated as the difference between M10 and L5 divided by M10 plus L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. RA was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average third 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    Notes
    [80] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.73 ( 0.136 )
    0.79 ( 0.141 )
    0.82 ( 0.089 )
    0.01 ( 0.090 )
    0.06 ( 0.080 )
        Change at Week 3 (n=11, 11, 12, 12, 12)
    -0.01 ( 0.143 )
    0.01 ( 0.088 )
    0.04 ( 0.063 )
    0.01 ( 0.090 )
    0.06 ( 0.080 )
    No statistical analyses for this end point

    Primary: Core Phase: Change From Baseline in RA Over Week 4 of Treatment

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    End point title
    		 Core Phase: Change From Baseline in RA Over Week 4 of Treatment
    End point description
    RA was relative amplitude of the rest-activity rhythm calculated as the difference between M10 and L5 divided by M10 plus L5. L5 was defined as the average activity across the least active 5-hour period per 24-hour period, with high values indicating restlessness. M10 was defined as the average activity during the most active 10-hour period per 24-hour period with low levels indicating inactivity. RA was determined by Actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to monitor degree and intensity of movements while the device was being worn. Change from baseline to average last 7 nights of treatment was reported. The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 13, 13, 12)
    0.73 ( 0.136 )
    0.79 ( 0.141 )
    0.82 ( 0.089 )
    0.77 ( 0.165 )
    0.76 ( 0.148 )
        Change at Week 4 (n=7, 10, 8, 8, 9)
    -0.00 ( 0.117 )
    0.01 ( 0.060 )
    0.05 ( 0.049 )
    0.01 ( 0.136 )
    0.02 ( 0.069 )
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 2.5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 2.5 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4638 [81]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.074
    Notes
    [81] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 5 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0322 [82]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.005
         upper limit
    		 0.115
    Notes
    [82] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 10 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9144 [83]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.051
         upper limit
    		 0.056
    Notes
    [83] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.
    Statistical analysis title
    		 Lemborexant-matched Placebo, Lemborexant 15 mg
    Comparison groups
    Lemborexant-matched Placebo v Lemborexant 15 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0364 [84]
    Method
    		 MMRM
    Parameter type
    		 LSM Difference
    Point estimate
    0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.11
    Notes
    [84] - Based on a MMRM analysis adjusted for baseline value, country, visit and treatment by visit interaction.

    Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    The safety analysis set included the group of randomized subject who received at least 1 dose of randomized study drug and had at least 1 postdose safety assessment.
    End point type
    Other pre-specified
    End point timeframe
    First dose of study drug (Day 1) to 14 days after last dose of study drug (approximately up to 2 years 7 months)
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg Extension Phase: Lemborexant 5 mg Extension Phase: Lemborexant 10 mg Extension Phase: Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    5
    14
    6
    Units: subjects
        TEAEs
    4
    3
    3
    4
    6
    4
    10
    5
        SAEs
    0
    0
    0
    0
    0
    1
    2
    1
    No statistical analyses for this end point

    Other pre-specified: Core Phase: Number of Subjects in Each Category With Clinician’s Global Impression of Change-Irregular Sleep-Wake Rhythm Disorder (CGIC-ISWRD) Global Score at Day 29

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    End point title
    		 Core Phase: Number of Subjects in Each Category With Clinician’s Global Impression of Change-Irregular Sleep-Wake Rhythm Disorder (CGIC-ISWRD) Global Score at Day 29
    End point description
    The CGIC-ISWRD scale is validated categorical measure of change in subject's clinical condition between baseline and follow-up visits. It relies on direct examination of subject and interview of informant. The instrument consisted of 3 parts:a guided baseline interview administered to subject and informant, a follow-up interview administered to subject and informant, clinician’s rating review. The baseline interview was reference for future ratings. During baseline interview, the rater evaluated subject regarding domains of(1)sleep and wake symptoms;(2)mood and behavioral symptoms;(3)attention/arousal;and(4)social functioning. In follow-up interview, a 7-pointscale used, from 1=marked improvement,4=no change ,to 7=marked worsening, to score each of the 4 domains and to provide a global score(1[marked improvement] to 7[marked worsening]). The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement.
    End point type
    Other pre-specified
    End point timeframe
    Day 29
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: subjects
        Global score: Marked improvement
    1
    0
    0
    0
    0
        Global score: Moderate improvement
    1
    0
    2
    1
    0
        Global score: Minimal improvement
    4
    4
    4
    5
    3
        Global score: No change
    6
    5
    4
    3
    7
        Global score: Minimal worsening
    0
    3
    2
    3
    1
        Global score : Moderate worsening
    0
    0
    0
    0
    0
        Global score : Marked worsening
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Core Phase: Change From Baseline in the Neuropsychiatric Inventory (NPI-10) Total Score at Day 29

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    End point title
    		 Core Phase: Change From Baseline in the Neuropsychiatric Inventory (NPI-10) Total Score at Day 29
    End point description
    The NPI-10 assessed wide range of behaviors seen in dementia for frequency and severity. It’s 10 item questionnaire with domains: delusions,hallucinations,agitation/aggression, depression/dysphoria, anxiety,elation/euphoria,apathy/indifference, disinhibition, irritability/liability and aberrant motor behavior. Total score summarized and analyzed. This scale was administered with caregiver as proxy for subject. The total score was sum of 10 domains, score of each domain calculated as frequency(scale:1=occasionally to 4=very frequently)*Severity(scale:1=Mild to 3=Severe). Each domain has maximum score of 12 and all domains equally weighted for total score,thus range for total score 0 to 120(0=completely healthy and 120=worse score). The FAS included group of randomized subjects received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are subjects who were evaluable for this measure at given time point and were included for assessment.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 29
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 12, 13, 11)
    3.8 ( 4.13 )
    13.1 ( 17.77 )
    7.7 ( 12.32 )
    6.4 ( 10.27 )
    5.5 ( 5.73 )
        Change at Day 29 (n=12, 12, 12, 13, 10)
    -2.8 ( 3.64 )
    -3.4 ( 9.23 )
    -0.3 ( 5.85 )
    -3.4 ( 8.95 )
    3.8 ( 13.02 )
    No statistical analyses for this end point

    Other pre-specified: Core Phase: Change From Baseline in the Sleep Disorders Inventory (SDI) Score at Day 29

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    End point title
    		 Core Phase: Change From Baseline in the Sleep Disorders Inventory (SDI) Score at Day 29
    End point description
    The SDI is an expanded version of one item of the NPI. It described the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period prior to its administration. The SDI consists of the 7 sub questions relating to sleep from the NPI sleep disturbance item. Each of the sub questions is a separate question with frequency, severity, and caregiver distress rated by the caregiver with respect to the patient-subject for the 2 weeks prior to the visit. The SDI score is derived as the product of the average of the frequency ratings and the average of the severity ratings (range: 0–12 [worst]). The FAS included group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. Here ‘n” are the subjects who were evaluable for this measure at given time point and were included for the assessment.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 29
    End point values
    		 Lemborexant-matched Placebo Lemborexant 2.5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 15 mg
    Number of subjects analysed
    12
    12
    13
    13
    12
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 12, 13, 11)
    0.79 ( 0.692 )
    1.24 ( 1.576 )
    0.74 ( 0.653 )
    0.66 ( 0.748 )
    1.44 ( 1.708 )
        Change at Day 29 (n=12, 12, 12, 13, 11)
    -0.48 ( 1.078 )
    -0.10 ( 0.616 )
    -0.33 ( 0.503 )
    -0.09 ( 0.574 )
    -0.49 ( 1.220 )
    No statistical analyses for this end point

    Other pre-specified: Extension Phase: Change From Baseline in SDI Total Score

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    End point title
    		 Extension Phase: Change From Baseline in SDI Total Score
    End point description
    The SDI is an expanded version of one item of the NPI. It described the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period prior to its administration. The SDI consists of the 7 sub questions relating to sleep from the NPI sleep disturbance item. Each of the sub questions is a separate question with frequency, severity, and caregiver distress rated by the caregiver with respect to the patient-subject for the 2 weeks prior to the visit. The SDI score is derived as the product of the average of the frequency ratings and the average of the severity ratings (range:0–12[worst]). The safety analysis set included the group of extension phase subjects who received at least 1 dose of study drug and had at least 1 postdose safety assessment. Number analyzed were the subjects who were evaluable for the measure and “n” were the subjects who were evaluable for the measure for given categories. Here 99999 signifies data not available or no subjects analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 133, 223, 313, 343, 373, 403, 493, 583, 673, and 763
    End point values
    		 Extension Phase: Lemborexant 5 mg Extension Phase: Lemborexant 10 mg Extension Phase: Lemborexant 15 mg
    Number of subjects analysed
    5
    12
    6
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.36 ( 1.948 )
    0.74 ( 0.728 )
    1.45 ( 2.331 )
        Change at Day 133(Visit 9) (n=1,8,3)
    1.40 ( 99999 )
    -0.45 ( 0.600 )
    -0.63 ( 0.473 )
        Change at Day 223(Visit 12) (n=0,6,3)
    99999 ( 99999 )
    -0.60 ( 0.693 )
    0.17 ( 0.306 )
        Change at Day 313(Visit 15) (n=0,4,3)
    99999 ( 99999 )
    -0.65 ( 0.574 )
    -0.17 ( 1.266 )
        Change at Day 343(Visit 16) (n=1,2,2)
    0.60 ( 99999 )
    0.55 ( 1.061 )
    0.45 ( 0.919 )
        Change at Day 373(Visit 17) (n=0,1,0)
    99999 ( 99999 )
    -0.20 ( 99999 )
    99999 ( 99999 )
        Change at Day 403(Visit 18) (n=0,5,4)
    99999 ( 99999 )
    -0.50 ( 0.539 )
    -0.55 ( 0.656 )
        Change at Day 493(Visit 19) (n=0, 3,1)
    99999 ( 99999 )
    -0.13 ( 0.115 )
    -0.10 ( 99999 )
        Change at Day 583(Visit 20) (n=0,2,2)
    99999 ( 99999 )
    -0.15 ( 0.071 )
    -0.35 ( 0.354 )
        Change at Day 673(Visit 21) (n=0,1,2)
    99999 ( 99999 )
    -0.30 ( 99999 )
    -0.15 ( 0.071 )
        Change at Day 763(Visit 22) (n=0,2,0)
    99999 ( 99999 )
    -0.05 ( 0.354 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug (Day 1) to 14 days after last dose of study drug (approximately up to 2 years 7 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Core Phase: Lemborexant-matched Placebo
    Reporting group description
    		 Subjects received two lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Core Phase: Lemborexant 2.5 mg
    Reporting group description
    		 Subjects received one lemborexant 2.5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Core Phase: Lemborexant 5 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Core Phase: Lemborexant 10 mg
    Reporting group description
    		 Subjects received one lemborexant 10 mg and one lemborexant-matched placebo, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Core Phase: Lemborexant 15 mg
    Reporting group description
    		 Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night for 28 consecutive nights in 4-week treatment period.

    Reporting group title
    Extension Phase: Lemborexant 5 mg
    Reporting group description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for Irregular Sleep-Wake Rhythm Disorder (ISWRD) is discontinued or up to 30 months.

    Reporting group title
    Extension Phase: Lemborexant 10 mg
    Reporting group description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 10 mg, tablet, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Reporting group title
    Extension Phase: Lemborexant 15 mg
    Reporting group description
    		 Subject who completed the core study EOS visit within 30 days prior to enrollment in extension phase were eligible to participate in extension phase. Subjects received one lemborexant 5 mg and one lemborexant 10 mg, tablets, orally, once daily, immediately (within 5 minutes) before the bedtime at night until lemborexant is commercially available, or until the lemborexant clinical development program for ISWRD is discontinued or up to 30 months.

    Serious adverse events
    		 Core Phase: Lemborexant-matched Placebo Core Phase: Lemborexant 2.5 mg Core Phase: Lemborexant 5 mg Core Phase: Lemborexant 10 mg Core Phase: Lemborexant 15 mg Extension Phase: Lemborexant 5 mg Extension Phase: Lemborexant 10 mg Extension Phase: Lemborexant 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ilium fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypercapnia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Core Phase: Lemborexant-matched Placebo Core Phase: Lemborexant 2.5 mg Core Phase: Lemborexant 5 mg Core Phase: Lemborexant 10 mg Core Phase: Lemborexant 15 mg Extension Phase: Lemborexant 5 mg Extension Phase: Lemborexant 10 mg Extension Phase: Lemborexant 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 12 (25.00%)
    3 / 13 (23.08%)
    4 / 13 (30.77%)
    6 / 12 (50.00%)
    4 / 5 (80.00%)
    10 / 14 (71.43%)
    5 / 6 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Genital Discharge
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Libido increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Irritability
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Fall
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    1
    Genital Injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Joint Injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Limb Injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    Sedation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    3 / 5 (60.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    4
    0
    0
    Syncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Nephrogenic Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Intestinal obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Diverticulum
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Acute Kidney Injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Chronic Kidney Disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Eye infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    4 / 14 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    4
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Otitis Media
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Tooth Abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2017
    Amendment 01: The protocol was amended to add allowance for caregiver informants and actigraphy data informants for flexibility in caregiving situations without compromising data collection, add allowance for subjects to attend day care for flexibility regarding daytime activities, add allowance for split baseline visits if necessary for flexibility regarding scheduling, revise minimum age from 65 years to 60 years, revise minimal MMSE score from 18 to 15, revise the requirement to remain in bed for at least 7 hours per night, add allowance for subjects with suicidal behavior in the past, but not within 10 years, add allowance for subjects with bundle branch block, add allowance for participate of subjects who are enrolled in observational studies without treatment components and replace the ADCS-CGIC with the CGIC-ISWRD Scale to focus the clinical rating of improvement on the symptoms related to ISWRD.
    01 Mar 2017
    Amendment 02: The protocol was amended to revised minimum criterion for aSE from less than (<) 75% to <85% to be consistent with insomnia program, add potential seizures as AE to be adjudicated as requested by Food and Drug administration (FDA), to include information onpotential seizures for adjudication as potential symptoms of cataplexy and requirement for monitoring of falls per request of FDA and to explicitly evaluate this safety parameter in at-risk population.
    05 Apr 2017
    Amendment 03: The protocol was amended to revise inclusion No. 4 MMSE lower end of range from 15 to 10 to allow for subjects with lower MMSE scores within the moderate range, revise the screening and baseline window for flexibility in scheduling, and revise prohibited medications to allow for subjects taking stable doses of medications used to treat ISWRD-related symptoms but who continue to manifest ISWRD symptoms.
    10 Aug 2017
    Amendment 04: The protocol was amended to include the conduct of the study in the European Union (EU) to facilitate enrollment and total number of sites from approximately 40 to approximately 60 to facilitate enrollment.
    17 Nov 2017
    Amendment 05: The protocol was amended to assess long-term safety and tolerability of lemborexant, added an extension phase of up to 30 months specifying that eligible subjects who elect to receive open- label treatment of lemborexant at 5, 10, or 15 mg per day after completing the end of the study (EOS) Visit and revise inclusion criterion No. 8; updated actigraphy requirement to facilitate enrollment.
    20 Jun 2018
    Amendment 06: The protocol was amended to reduce sample size from approximately 125 subjects to approximately 60 subjects and moderate cytochrome P450 (CYP3A) inhibitors were also prohibited.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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