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    Clinical Trial Results:
    A Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel-Group Study of the Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder

    Summary
    EudraCT number
    2015-001463-39
    Trial protocol
    DE   FI   PL   ES  
    Global end of trial date
    08 Jan 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2006-G000-303
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02952820
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake,New Jersey, United States, 07677
    Public contact
    Medical Information, Eisai, Inc., +1 888-274-2378, esi_medinfo@eisai.com
    Scientific contact
    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
    08 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in subjects with insomnia disorder
    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, 2008) - 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 Subject Information and Informed Consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Germany: 124
    Country: Number of subjects enrolled
    Japan: 161
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 3
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    New Zealand: 15
    Country: Number of subjects enrolled
    Romania: 52
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    United States: 310
    Country: Number of subjects enrolled
    Finland: 206
    Worldwide total number of subjects
    971
    EEA total number of subjects
    471
    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)
    709
    From 65 to 84 years
    259
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 119 investigative sites in Japan, Korea, Finland, Germany, Italy, New Zealand, Poland, Romania, Spain, Canada, Mexico, and the United States from 15 November 2016 to 08 January 2019.

    Pre-assignment
    Screening details
    A total of 2059 subjects were screened, of which 1088 were screen failures and 971 subjects were randomized to receive study treatment.

    Period 1
    Period 1 title
    Placebo -Controlled Treatment (6 Months)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period. Then they were re-randomized to lemborexant 5 milligram (mg) or lemborexant 10 mg up to Month 12 .
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period.

    Arm title
    Lemborexant 5 mg
    Arm description
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).
    Arm type
    Experimental

    Investigational medicinal product name
    Lemborexant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 6-12 (in Period 2).

    Arm title
    Lemborexant 10 mg
    Arm description
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).
    Arm type
    Experimental

    Investigational medicinal product name
    Lemborexant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 6-12 (in Period 2).

    Number of subjects in period 1
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Started
    325
    323
    323
    Treated
    321
    319
    319
    Safety Analysis Set
    319
    314
    314
    Completed
    261
    254
    235
    Not completed
    64
    69
    88
         Other than specified
    -
    14
    13
         Withdrawal of consent
    13
    11
    21
         Adverse event, non-fatal
    8
    9
    16
         Inadequate therapeutic effect
    17
    12
    11
         Subject choice
    15
    12
    17
         Lost to follow-up
    7
    7
    6
         Not treated
    4
    4
    4
    Period 2
    Period 2 title
    Active Treatment Period (6 Months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lemborexant 5 mg
    Arm description
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).
    Arm type
    Experimental

    Investigational medicinal product name
    Lemborexant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 12.

    Arm title
    Lemborexant 10 mg
    Arm description
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).
    Arm type
    Experimental

    Investigational medicinal product name
    Lemborexant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 12.

    Number of subjects in period 2 [1]
    Lemborexant 5 mg Lemborexant 10 mg
    Started
    384
    352
    Completed
    346
    321
    Not completed
    38
    31
         Other than specified
    6
    2
         Withdrawal of consent
    6
    8
         Adverse event, non-fatal
    6
    5
         Inadequate therapeutic effect
    6
    2
         Not treated
    -
    1
         Subject choice
    10
    7
         Lost to follow-up
    4
    6
    Notes
    [1] - 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: Subjects from Placebo were re-randomized to Lemborexant 5 mg and Lemborexant 10 mg.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period. Then they were re-randomized to lemborexant 5 milligram (mg) or lemborexant 10 mg up to Month 12 .

    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

    Reporting group values
    Placebo Lemborexant 5 mg Lemborexant 10 mg Total
    Number of subjects
    325 323 323 971
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.262 ± 14.017 54.087 ± 13.656 54.715 ± 13.59 -
    Gender categorical
    Units: Subjects
        Female
    220 213 225 658
        Male
    105 110 98 313

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period. Then they were re-randomized to lemborexant 5 milligram (mg) or lemborexant 10 mg up to Month 12 .

    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).
    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

    Subject analysis set title
    Lemborexant 5 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received lemborexant 5 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 5 mg, tablets, orally, once daily through Month 7-12 (in Period 2)

    Subject analysis set title
    Lemborexant 10 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received lemborexant 10 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 10 mg, tablets, orally, once daily through Month 7-12 (in Period 2).

    Primary: Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6

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    End point title
    Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6
    End point description
    sSOL was defined as estimated minutes from the time that the subject attempted to sleep until sleep onset. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Primary
    End point timeframe
    Baseline and Month 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=316, 314, 312)
    64.03 ± 45.209
    62.19 ± 45.674
    64.97 ± 44.020
        Change at Month 6 (249, 245, 229)
    -16.57 ± 35.313
    -29.39 ± 33.261
    -32.49 ± 35.962
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was based on mixed effect model repeated measurement analysis (MMRM) model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be missing not at random (missing not at random/complete case missing value [MNAR/CCMV]).
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    least squares geometric mean (LSGM)ratio
    Point estimate
    0.732
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.636
         upper limit
    0.843
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.701
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.607
         upper limit
    0.81

    Secondary: Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3

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    End point title
    Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3
    End point description
    sSOL was defined as estimated minutes from time attempted to sleep to sleep onset. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, (mean of 7 nights [approximately Week 1]), Months 1 and 3
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=316, 314, 312)
    64.03 ± 45.209
    62.19 ± 45.674
    64.97 ± 44.020
        Change at 1st 7 nights (n= 314, 310, 310)
    -4.11 ± 27.671
    -16.86 ± 27.784
    -18.89 ± 31.003
        Change at Month 1 (n=299, 298, 297)
    -11.48 ± 32.726
    -19.41 ± 32.221
    -24.06 ± 35.234
        Change at Month 3 (n=279, 268, 264)
    -13.84 ± 35.277
    -25.08 ± 34.081
    -27.94 ± 39.192
    Statistical analysis title
    First 7 nights (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.781
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.725
         upper limit
    0.842
    Statistical analysis title
    First 7 nights (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.752
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.698
         upper limit
    0.811
    Statistical analysis title
    Month 1 (Statistical analysis 3)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.735
         upper limit
    0.893
    Statistical analysis title
    Month 1 (Statistical analysis 4)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.698
         upper limit
    0.848
    Statistical analysis title
    Month 3 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.778
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    0.878
    Statistical analysis title
    Month 3 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSGM ratio
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.681
         upper limit
    0.869

    Secondary: Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

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    End point title
    Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6
    End point description
    sSE was defined as percentage of subjective total sleep time (sTST) divided by subjective time spent in bed, calculated as the interval from the time the subject reported attempting to sleep until the time subject stopped trying to sleep for the night (operationalized as the time the subject got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: percentage of sTST
    arithmetic mean (standard deviation)
        Baseline (n=307, 302, 299)
    61.34 ± 17.836
    63.14 ± 18.231
    62.03 ± 17.248
        Change at 1st 7 nights (n=303, 295, 296)
    2.68 ± 10.765
    6.61 ± 10.386
    8.27 ± 10.566
        Change at Month 1 (n= 291, 284, 282)
    6.11 ± 12.876
    7.87 ± 12.263
    9.92 ± 12.922
        Change at Month 3 (n= 269, 256, 251)
    9.16 ± 13.644
    13.03 ± 13.522
    13.61 ± 14.035
        Change at Month 6 (n= 242, 235, 220)
    10.36 ± 13.799
    15.34 ± 14.613
    15.55 ± 15.617
    Statistical analysis title
    First 7 nights (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    4.299
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.638
         upper limit
    5.961
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.848
    Statistical analysis title
    First 7 nights (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    5.793
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.133
         upper limit
    7.452
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.846
    Statistical analysis title
    Month 1 (Statistical Analysis 3)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.023
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    2.227
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.307
         upper limit
    4.146
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.979
    Statistical analysis title
    Month 1 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    3.615
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.635
         upper limit
    5.595
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.01
    Statistical analysis title
    Month 3 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.068
         upper limit
    6.377
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.099
    Statistical analysis title
    Month 3 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    4.361
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.22
         upper limit
    6.501
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.092
    Statistical analysis title
    Month 6 (Statistical Analysis 7)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    4.549
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.236
         upper limit
    6.861
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.179
    Statistical analysis title
    Month 6 (Statistical Analysis 8)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    4.667
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.373
         upper limit
    6.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.17

    Secondary: Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

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    End point title
    Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6
    End point description
    sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the subject stopped trying to sleep for the night, operationalized as the time the subject got out of bed for the day. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=314, 313, 311)
    132.49 ± 80.198
    132.77 ± 82.518
    136.83 ± 87.391
        Change at first 7 nights (n= 312, 308, 309)
    -6.12 ± 45.893
    -20.21 ± 46.015
    -23.30 ± 47.700
        Change at Month 1 (n=297, 297, 293)
    -19.01 ± 50.279
    -23.42 ± 56.251
    -26.82 ± 56.989
        Change at Month 3 (n=278, 267, 262)
    -27.08 ± 54.408
    -42.98 ± 60.064
    -39.42 ± 62.783
        Change at Month 6 (n=248, 244, 227)
    -32.14 ± 55.279
    -51.45 ± 67.295
    -48.12 ± 68.550
    Statistical analysis title
    First 7 nights (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -14.328
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.411
         upper limit
    -7.245
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.614
    Statistical analysis title
    First 7 nights (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -16.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.813
         upper limit
    -9.626
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.619
    Statistical analysis title
    Month 1 (Statistical Analysis 3)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1796
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -5.514
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.568
         upper limit
    2.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.109
    Statistical analysis title
    Month 1 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0898
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -7.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.098
         upper limit
    1.088
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.129
    Statistical analysis title
    Month 3 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0028
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -13.424
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.218
         upper limit
    -4.631
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.486
    Statistical analysis title
    Month 3 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0277
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -10.079
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.053
         upper limit
    -1.104
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.578
    Statistical analysis title
    Month 6 (Statistical Analysis 7)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -17.474
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.306
         upper limit
    -7.643
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.014
    Statistical analysis title
    Month 6 (Statistical Analysis 8)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0105
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -12.671
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.378
         upper limit
    -2.964
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.951

    Secondary: Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

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    End point title
    Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6
    End point description
    sTST was defined as minutes of sleep from sleep onset to time stopped trying to sleep for the night. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline (n=307, 302, 299)
    304.25 ± 91.459
    315.52 ± 93.498
    306.89 ± 88.031
        Change at first 7 nights (n=303, 295, 296)
    14.78 ± 54.995
    34.29 ± 54.142
    46.01 ± 55.110
        Change at Month 1 (n=291, 284, 282)
    30.74 ± 70.687
    39.32 ± 63.548
    53.22 ± 67.910
        Change at Month 3 (n= 269, 256, 251)
    48.16 ± 75.859
    65.82 ± 71.331
    70.95 ± 70.913
        Change at Month 6 (n=242, 235, 220)
    53.53 ± 74.539
    76.21 ± 77.714
    78.32 ± 80.741
    Statistical analysis title
    First 7 Nights (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be missing at random (MAR).
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    22.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.488
         upper limit
    30.579
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.354
    Statistical analysis title
    First 7 nights (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    31.796
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.258
         upper limit
    40.334
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.35
    Statistical analysis title
    Month 1 (Statistical analysis 3)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0259
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    11.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.418
         upper limit
    22.102
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.269
    Statistical analysis title
    Month 1 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    22.131
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.757
         upper limit
    32.505
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.286
    Statistical analysis title
    Month 3 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0034
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    17.374
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.781
         upper limit
    28.968
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.906
    Statistical analysis title
    Month 3 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    21.686
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.014
         upper limit
    33.359
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.946
    Statistical analysis title
    Month 6 (Statistical Analysis 7)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0034
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    18.555
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.14
         upper limit
    30.969
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.324
    Statistical analysis title
    Month 6 (Statistical Analysis 8)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    22.686
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.137
         upper limit
    35.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.392

    Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6

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    End point title
    Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6
    End point description
    Sleep onset responder was defined as follows: sSOL at study Baseline was greater than or equal to (>=) 30 minutes and mean sSOL at 6 months was less than or equal to (<=) 20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of greater than (>)10 minutes compared to Study Baseline. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to number of subjects evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: percentage of responders
    number (not applicable)
        Sleep Onset Responders (n= 254, 250, 249)
    17.7
    31.2
    30.1
        Sleep Maintenance Responders (n=250, 263, 257)
    20.4
    35.0
    30.0
    Statistical analysis title
    Sleep Onset Responders: Statistical Analysis 1
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference of percentage
    Point estimate
    13.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.24
         upper limit
    21.1
    Statistical analysis title
    Sleep Onset Responders: Statistical Analysis 2
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference of percentage
    Point estimate
    12.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.2
         upper limit
    19.86
    Statistical analysis title
    Sleep Maintenance Responders
    Statistical analysis description
    Statistical Analysis 3
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference of percentage
    Point estimate
    14.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.97
         upper limit
    22.33
    Statistical analysis title
    Sleep Maintenance Responders
    Statistical analysis description
    Statistical Analysis 4
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference of percentage
    Point estimate
    9.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.29
         upper limit
    17.35

    Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12

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    End point title
    Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12
    End point description
    Sleep onset responder was defined as follows: sSOL at study Baseline was >=30 minutes and mean sSOL at 6 months was <=20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of > 10 minutes compared to study Baseline. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of subjects
    number (not applicable)
        Sleep Onset Responders (n= 310, 285)
    34.2
    37.2
        Sleep Maintainance Responders (n= 317, 280)
    35.0
    39.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6

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    End point title
    Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6
    End point description
    The ISI is a 4-7 item, self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: 1. severity of sleep onset; 2. sleep maintenance; 3. early morning awakening problems; 4. sleep dissatisfaction; 5. interference of sleep difficulties with daytime functioning; 6. noticeability of the sleep problems by others; and 7. distress caused by the sleep difficulties. A 5-point Likert scale was used to rate each item (from 0=no problem to 4=very severe problem). Daytime functioning score (sum of items 4 to 7) were analyzed. Higher score indicated severe insomnia problem. The total score range for sum of items is 0-16. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, and 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=318, 316, 315)
    11.0 ± 2.10
    11.4 ± 2.02
    11.0 ± 2.15
        Change at Month 1 (n= 296, 300, 286)
    -3.1 ± 3.41
    -4.1 ± 3.66
    -4.2 ± 4.01
        Change at Month 3 (n=283, 274, 259)
    -3.7 ± 3.55
    -5.2 ± 3.88
    -5.2 ± 4.05
        Change at Month 6 (n= 257, 258, 234)
    -4.3 ± 3.66
    -6.0 ± 3.76
    -5.7 ± 4.00
    Statistical analysis title
    Month 1 (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0137
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.27
         upper limit
    -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.287
    Statistical analysis title
    Month 1 (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.51
         upper limit
    -0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.289
    Statistical analysis title
    Month 3 (Statistical Analysis 3)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.75
         upper limit
    -0.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.302
    Statistical analysis title
    Month 3 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.96
         upper limit
    -0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.305
    Statistical analysis title
    Month 6 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    -0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.302
    Statistical analysis title
    Month 6 (Statistical Analysis 8)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.92
         upper limit
    -0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.307

    Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and

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    End point title
    Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and
    End point description
    The FSS is a self-reported scale on which subjects were instructed to choose a number from 1 to 7 that indicated their degree of agreement with 9 statements about their fatigue where “1” indicates strongly disagree and “7”, strongly agree. The FSS total score was the sum of all responses to the 9 questions. Higher total scores and average item scores indicated greater fatigue. Total score range is 9 to 63. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3 and 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=318, 316, 315)
    35.2 ± 13.55
    37.4 ± 12.74
    36.0 ± 13.01
        Change at Month 1 (n= 296, 300, 286)
    -3.9 ± 11.62
    -6.6 ± 11.83
    -6.4 ± 13.68
        Change at Month 3 (n= 283, 274, 259)
    -4.3 ± 11.37
    -7.7 ± 12.97
    -7.9 ± 13.56
        Change at Month 6 (n= 257, 258, 234)
    -6.3 ± 12.07
    -10.1 ± 13.56
    -8.9 ± 14.91
    Statistical analysis title
    Month 1 (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.067
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.44
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.905
    Statistical analysis title
    Month 1 (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0257
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -2.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.83
         upper limit
    -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.913
    Statistical analysis title
    Month 3 (Statistical Analysis 3)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0206
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -2.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.02
         upper limit
    -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.939
    Statistical analysis title
    Month 3 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -3.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.91
         upper limit
    -1.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95
    Statistical analysis title
    Month 6 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0134
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.48
         upper limit
    -0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.112
    Statistical analysis title
    Month 6 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0128
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -2.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.57
         upper limit
    -0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.026

    Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6

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    End point title
    Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6
    End point description
    The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, (mean of 7 nights [approximately Week 1]) in placebo-controlled period, Month 1, 3, 6
    End point values
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    318
    316
    315
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=316, 314, 312)
    3.94 ± 1.558
    3.93 ± 1.349
    3.93 ± 1.324
        Change at First 7 nights (n= 314, 310, 310)
    0.15 ± 0.991
    0.36 ± 0.964
    0.33 ± 1.018
        Change at Month 1 (n= 300, 298, 297)
    0.44 ± 1.233
    0.53 ± 1.172
    0.55 ± 1.298
        Change at Month 3 (n= 280, 268, 264)
    0.62 ± 1.366
    0.74 ± 1.325
    0.90 ± 1.452
        Change at Month 6 (n=249, 245, 229)
    0.79 ± 1.392
    0.98 ± 1.463
    1.05 ± 1.524
    Statistical analysis title
    First 7 nights (Statistical Analysis 1)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0067
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.205
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.057
         upper limit
    0.353
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    First 7 nights (Statistical Analysis 2)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0237
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.171
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    Month 1 (Statistical analysis 3)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.412
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.077
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.107
         upper limit
    0.261
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Statistical analysis title
    Month 1 (Statistical Analysis 4)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4347
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.073
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.111
         upper limit
    0.258
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Statistical analysis title
    Month 3 (Statistical Analysis 5)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4992
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.074
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.141
         upper limit
    0.289
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.109
    Statistical analysis title
    Month 3 (Statistical Analysis 6)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0208
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.255
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.471
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Statistical analysis title
    Month 6 (Statistical Analysis 7)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 5 mg
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2248
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.144
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.089
         upper limit
    0.378
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.119
    Statistical analysis title
    Month 6 (Statistical Analysis 8)
    Statistical analysis description
    Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.
    Comparison groups
    Placebo v Lemborexant 10 mg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0298
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.261
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.026
         upper limit
    0.497
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12

    Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)

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    End point title
    Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)
    End point description
    Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, First 7 nights (approximately Week 1) in active treatment period
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: score on scale
    arithmetic mean (standard deviation)
        Baseline (n=442, 434)
    4.15 ± 1.526
    4.16 ± 1.428
        Change at First 7 nights (n=310, 310)
    0.36 ± 0.964
    0.33 ± 1.018
    No statistical analyses for this end point

    Secondary: Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period

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    End point title
    Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period
    End point description
    The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” Subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed here is based on the number in the "On-Treatment FAS". Hence these numbers include the lemborexant data from the subjects re-randomized from placebo in Period 1.
    End point type
    Secondary
    End point timeframe
    Screening, First and second 7 mornings in follow-up period (Week 52 to 54)
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: score on a scale
    arithmetic mean (standard deviation)
        Screening (n=440, 436)
    3.63 ± 1.393
    3.54 ± 1.197
        Change at First 7 mornings (n=335, 328)
    1.03 ± 1.615
    1.32 ± 1.611
        Change at Second 7 mornings (n=327, 313)
    0.98 ± 1.699
    1.22 ± 1.635
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12

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    End point title
    Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12
    End point description
    The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” Subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9 and 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=442, 434)
    4.15 ± 1.516
    4.16 ± 1.428
        Change at Month 1 of exposure (n=415, 412)
    0.46 ± 1.082
    0.42 ± 1.223
        Change at Month 3 of exposure (n=386, 375)
    0.60 ± 1.264
    0.70 ± 1.356
        Change at Month 6 of exposure (n=352, 331)
    0.78 ± 1.424
    0.86 ± 1.461
        Change at Month 9 of exposure (n=233, 213)
    1.00 ± 1.512
    1.08 ± 1.489
        Change at Month 12 of exposure (216, 204)
    1.11 ± 1.499
    1.31 ± 1.604
    No statistical analyses for this end point

    Secondary: Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

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    End point title
    Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period
    End point description
    Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sSOL was defined as estimated minutes from the time that the subject attempted to sleep until sleep onset. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: minutes
    arithmetic mean (standard deviation)
        Mean of first 3 nights (n=287, 284)
    40.35 ± 48.661
    41.73 ± 55.694
        Mean sSOL of the first 7 nights (n=337, 328)
    41.35 ± 38.967
    41.90 ± 47.826
        Mean sSOL of the second 7 nights (329, 312)
    44.10 ± 38.030
    41.30 ± 47.471
    No statistical analyses for this end point

    Secondary: Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

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    End point title
    Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period
    End point description
    Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the subject stopped trying to sleep for the night, operationalized as the time the subject got out of bed for the day. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: minutes
    arithmetic mean (standard deviation)
        Mean of first 3 nights (n=282, 282)
    86.66 ± 80.038
    97.88 ± 83.302
        Mean of the first 7 nights (337, 326)
    91.56 ± 81.738
    95.79 ± 79.784
        Mean of the Last 7 nights (329, 312)
    92.62 ± 82.672
    98.19 ± 80.668
    No statistical analyses for this end point

    Secondary: Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period

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    End point title
    Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period
    End point description
    Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sSOL was defined as estimated minutes from the time that the subject attempted to sleep until sleep onset. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of subjects
    number (not applicable)
        Average of first 3 nights (285, 284)
    9.46
    9.38
        Average of first 7 nights (n=335, 328)
    11.94
    10.53
        Average of second 7 nights (327, 312)
    11.71
    9.38
    No statistical analyses for this end point

    Secondary: Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period

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    End point title
    Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period
    End point description
    Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the subject stopped trying to sleep for the night, operationalized as the time the subject got out of bed for the day. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    First 3 nights, First and Last 7 nights of the follow up period (Week 52 to 54)
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of subjects
    number (not applicable)
        Average of first 3 nights (n=280, 282)
    11.26
    12.59
        Average of first 7 nights (n= 335, 325)
    12.39
    14.19
        Average of second 7 nights (n= 327, 311)
    13.51
    11.90
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1

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    End point title
    Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1
    End point description
    At each month beyond Month 1, the change from Baseline was compared to either the lower bound of the 95% CI (for sTST) or the upper bound of the 95% CI (for sSOL and sWASO) at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sTST and below the upper bound of the 95% CI at Month 1 for sSOL and sWASO. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, 3, 6, 9, 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: minutes
    least squares mean (confidence interval 95%)
        sSOL: Change at Month 1 of exposure (n=415, 412)
    -17.17 (-19.76 to -14.58)
    -18.64 (-21.26 to -16.02)
        sSOL: Change at Month 3 of exposure (n=386, 375)
    -21.47 (-24.46 to -18.48)
    -21.58 (-24.61 to -18.54)
        sSOL: Change at Month 6 of exposure (n=352, 331)
    -24.13 (-27.22 to -21.04)
    -22.99 (-26.14 to -19.83)
        sSOL: Change at Month 9 of exposure (n=233, 213)
    -26.00 (-29.25 to -22.75)
    -27.36 (-30.70 to -24.01)
        sSOL: Change at Month 12 of exposure (n=216, 214)
    -25.83 (-29.44 to -22.22)
    -26.32 (-30.03 to -22.61)
        sWASO: Change at Month 1 of exposure (n=414, 408)
    -17.26 (-22.54 to -11.97)
    -18.69 (-24.05 to -13.33)
        sWASO: Change at Month 3 of exposure (n=385, 373)
    -31.34 (-37.12 to -25.57)
    -28.97 (-34.86 to -23.09)
        sWASO: Change at Month 6 of exposure (n=351, 329)
    -36.10 (-42.57 to -29.63)
    -31.54 (-38.16 to -24.91)
        sWASO: Change at Month 9 of exposure (n=232, 212)
    -39.28 (-46.74 to -31.83)
    -40.39 (-48.08 to -32.71)
        sWASO: Change at Month 12 of exposure (n=215, 203)
    -42.87 (-50.13 to -35.61)
    -43.76 (-51.21 to -36.31)
        sTST: Change at Month 1 of exposure (n=400, 396)
    31.98 (25.54 to 38.42)
    38.04 (31.51 to 44.57)
        sTST: Change at Month 3 of exposure (n=373, 361)
    49.27 (42.33 to 56.22)
    53.51 (46.42 to 60.61)
        sTST: Change at Month 6 of exposure (n=342, 321)
    54.99 (47.18 to 62.80)
    56.36 (48.35 to 64.36)
        sTST: Change at Month 9 of exposure (n=222, 205)
    55.41 (46.49 to 64.33)
    61.13 (51.93 to 70.32)
        sTST: Change at Month 12 of exposure (n=207, 196)
    58.15 (49.29 to 67.01)
    66.50 (57.41 to 75.60)
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1

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    End point title
    Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1
    End point description
    sSE was defined as percentage of sTST per subjective time spent in bed, calculated as the interval from the time the subject reports attempting to sleep until the time the subject stopped trying to sleep for the night (operationalized as the time the participant got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 1, the change from Baseline was compared to the lower bound of the 95% CI at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, and 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of sTST
    least squares mean (confidence interval 95%)
        Change at Month 1 of exposure (n= 400, 396)
    6.35 (5.13 to 7.57)
    7.32 (6.09 to 8.56)
        Change at Month 3 of exposure (n=373, 361)
    10.01 (8.69 to 11.34)
    10.25 (8.90 to 11.60)
        Change at Month 6 of exposure (n=342, 321)
    11.10 (9.61 to 12.58)
    11.08 (9.56 to 12.60)
        Change at Month 9 of exposure (n=222, 205)
    11.85 (10.13 to 13.56)
    12.84 (11.08 to 14.61)
        Change at Month 12 of exposure (n=207, 196)
    12.61 (10.92 to 14.31)
    13.66 (11.92 to 15.40)
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7

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    End point title
    Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7
    End point description
    At each month beyond Month 7, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sTST and below the upper bound of the 95% CI at Month 7 for sSOL and sWASO. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 7, 9, 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: minutes
    least squares mean (confidence interval 95%)
        sSOL: Change at Month 7 of exposure (n=355, 334)
    -28.55 (-32.39 to -24.70)
    -29.46 (-33.42 to -25.50)
        sSOL: Change at Month 9 of exposure (n=349, 324)
    -32.10 (-35.39 to -28.80)
    -30.91 (-34.31 to -27.52)
        sSOL: Change at Month 12 of exposure (n=323, 306)
    -31.40 (-34.85 to -27.96)
    -31.33 (-34.88 to -27.78)
        sWASO: Change at Month 7 of exposure (n=355, 304)
    -45.62 (-52.53 to -38.70)
    -43.09 (-50.20 to -35.99)
        sWASO: Change at Month 9 of exposure (n=349, 324)
    -47.70 (-54.54 to -40.86)
    -48.87 (-55.92 to -41.82)
        sWASO: Change at Month 12 of exposure (n=323, 306)
    -48.46 (-55.35 to -41.57)
    -49.28 (-56.36 to -42.19)
        sTST: Change at Month 7 of exposure (n=355, 334)
    75.00 (65.30 to 84.71)
    76.95 (66.97 to 86.92)
        sTST: Change at Month 9 of exposure (n=349, 324)
    78.69 (68.99 to 88.39)
    81.24 (71.26 to 91.23)
        sTST: Change at Month 12 of exposure (n=323, 306)
    78.61 (68.61 to 88.61)
    83.61 (73.33 to 93.90)
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7

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    End point title
    Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7
    End point description
    sSE: percentage of sTST per subjective time spent in bed, calculated as the interval from the time the subject reports attempting to sleep until the time the subject stopped trying to sleep for the night (operationalized as the time the subject got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 7, the change from Baseline was compared to the lower bound of the 95% CI for sSE at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 7, 9, 12
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of sTST
    least squares mean (confidence interval 95%)
        Change at Month 7 of exposure (n=354, 334)
    12.88 (9.01 to 16.75)
    15.12 (11.13 to 19.10)
        Change at Month 9 of exposure (n=349, 324)
    16.54 (14.88 to 18.20)
    16.49 (14.78 to 18.20)
        Change at Month 12 of exposure (n=323, 306)
    16.34 (14.70 to 17.98)
    16.82 (15.13 to 18.50)
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1

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    End point title
    Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1
    End point description
    At 3 and 6 months of exposure, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sTST and below the upper bound of the 95% CI at 1 month of exposure for sSOL and sWASO. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, 3, 6
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: minutes
    least squares mean (confidence interval 95%)
        sSOL: Change at Month 1 of exposure (n=415, 412)
    -17.17 (-19.76 to -14.58)
    -18.64 (-21.26 to -16.02)
        sSOL: Change at Month 3 of exposure (n=386, 375)
    -21.47 (-24.46 to -18.48)
    -21.58 (-24.61 to -18.54)
        sSOL: Change at Month 6 of exposure (n=352, 331)
    -24.13 (-27.22 to -21.04)
    -22.99 (-26.14 to -19.83)
        sWASO: Change at Month 1 of exposure (n=414, 408)
    -17.26 (-22.54 to -11.97)
    -18.69 (-24.05 to -13.33)
        sWASO: Change at Month 3 of exposure (n=385, 373)
    -31.34 (-37.12 to 25.57)
    -28.97 (-34.86 to -23.09)
        sWASO: Change at Month 6 of exposure (n=351, 329)
    -36.10 (-42.57 to -29.63)
    -31.54 (-38.16 to -24.91)
        sTST: Change at Month 1 of exposure (n=400, 396)
    31.98 (25.54 to 38.42)
    38.04 (31.51 to 44.57)
        sTST: Change at Month 3 of exposure (n=373, 361)
    49.27 (42.33 to 56.22)
    53.51 (46.42 to 60.61)
        sTST: Change at Month 6 of exposure (n=342, 321)
    54.99 (47.18 to 62.80)
    56.36 (48.35 to 64.36)
    No statistical analyses for this end point

    Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1

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    End point title
    Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1
    End point description
    At 3 and 6 months of exposure, the change from Baseline was compared to the lower bound of the 95% CI for sSE at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, 3, 6
    End point values
    Lemborexant 5 mg Lemborexant 10 mg
    Number of subjects analysed
    444
    437
    Units: percentage of sTST
    least squares mean (confidence interval 95%)
        Change at Month 1 of exposure (n=400, 396)
    6.35 (5.13 to 7.57)
    7.32 (6.09 to 8.56)
        Change at Month 3 of exposure (n=373, 361)
    10.01 (8.69 to 11.34)
    10.25 (8.90 to 11.60)
        Change at Month 6 of exposure (n=342, 321)
    11.10 (9.61 to 12.58)
    11.08 (9.56 to 12.60)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to Week 54
    Adverse event reporting additional description
    Placebo arm included AE data for subjects who received placebo in Period 1. Lemborexant 5 mg and 10 mg arms included AE data of subjects who received either lemborexant 5 mg or 10 mg throughout the study (Period 1 and 2 both) and subjects re-randomized from placebo (in Period 1) to either lemborexant 5 mg or lemborexant 10 mg in Period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period. Then they were re-randomized to lemborexant 5 mg or lemborexant 10 mg up to Month 12 .

    Reporting group title
    Lemborexant 5 mg
    Reporting group description
    Subjects received lemborexant 5 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 5 mg, tablets, orally, once daily through Month 7-12 (in Period 2)

    Reporting group title
    Lemborexant 10 mg
    Reporting group description
    Subjects received lemborexant 10 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 10 mg, tablets, orally, once daily through Month 7-12 (in Period 2).

    Serious adverse events
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 319 (1.57%)
    18 / 447 (4.03%)
    16 / 437 (3.66%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Hydrosalpinx
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal Inflammation
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic Neuropathy
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 447 (0.45%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disturbance In Attention
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diabetic Retinopathy
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Floppy Eyelid Syndrome
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Alcoholic Pancreatitis
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus Hernia
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal Cyst
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    3 / 437 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw Fistula
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw Cyst
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 447 (0.00%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 447 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 447 (0.22%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Lemborexant 5 mg Lemborexant 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 319 (23.51%)
    129 / 447 (28.86%)
    140 / 437 (32.04%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    5 / 319 (1.57%)
    38 / 447 (8.50%)
    60 / 437 (13.73%)
         occurrences all number
    5
    44
    64
    Headache
         subjects affected / exposed
    21 / 319 (6.58%)
    43 / 447 (9.62%)
    32 / 437 (7.32%)
         occurrences all number
    33
    76
    41
    Infections and infestations
    Influenza
         subjects affected / exposed
    15 / 319 (4.70%)
    22 / 447 (4.92%)
    26 / 437 (5.95%)
         occurrences all number
    15
    22
    29
    Nasopharyngitis
         subjects affected / exposed
    40 / 319 (12.54%)
    51 / 447 (11.41%)
    48 / 437 (10.98%)
         occurrences all number
    43
    67
    56

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2016
    The purpose of this amendment is 1. Stated that enrollment of subjects <65 years would be limited if the percentage of enrolled subjects >65 years was below expectations toward the end of the study. 2. Clarified that subjects who discontinued study medication but did not agree to return for study visits underwent an EOS visit. 3. Clarified the term abstinence. 4. Clarified excessive caffeine use. 5. Clarified that subjects who lacked capacity and/or whose cognitive decline indicated disorientation to person/place/time and/or situation are excluded. 6. Specified that the statistical model included region if necessary, that countries with small numbers of subjects would be pooled by region, and that regions were grouped in consideration of the number and homogeneity of subjects from each region. 7. Specified that informed consent was taken by personnel in accordance with national legislation. 8. Clarified the reason why subjects should not eat a meal within 3 hours before taking the study drug. 9. Specified that the neurological examination was conducted by a clinician whose clinical experience ensured that an adequate assessment of domains underlying the exclusion criteria could be performed. 10. Specified that the investigator agreed to allow direct access to source documents and study facilities to sponsor representative(s), monitor(s) and auditor(s), and agree to inspection by regulatory authorities or IRB/IEC representative.
    28 Jun 2018
    Amendment 4: 1. Added analysis of Treatment Period 1. Because based on the results of pivotal Study 304 and special safety studies, the sponsor decided to include a database lock with interim analysis to assess efficacy in the double-blind placebo-controlled treatment period. All available safety data were assessed. 2. In the event of an interim analysis, Sponsor staff will be unblinded; however, site personnel, investigator, and subjects will remain blinded 3. To align with Regulatory Authority provision ICH-E9 addendum, analysis sets and analysis plan were updated
    03 Aug 2018
    Amendment 5: Updated interim analysis description (to clarify that no interim analysis was being performed and that when all subjects had completed Period 1, all data were unblinded to the sponsor and that study sites and subjects would remain blinded until the study had been completed.)
    13 Aug 2018
    Amendment 6: 1. Added results from Study E2006-A001-012 2. Updated list of prohibited concomitant medications to prohibit moderate cytochrome P450 3A (CYP3A) inhibitors 3. Revised other secondary endpoint analyses for FSS.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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