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    Clinical Trial Results:
    Multi-center, double-blind, randomized, placebo-controlled, parallel-group, polysomnography study to assess the efficacy and safety of ACT-541468 in adult and elderly subjects with insomnia disorder

    Summary
    EudraCT number
    		 2017-004643-20
    Trial protocol
    		 BG   FI   DE   SE   FR   CZ   BE   HU  
    Global end of trial date
    14 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2021
    First version publication date
    22 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ID-078A302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03575104
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Idorsia Pharmaceuticals Ltd
    Sponsor organisation address
    Hegenheimermattweg 91, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
    Scientific contact
    Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.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
    18 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 10 mg and 25 mg daridorexant (ACT-541468) on objective and subjective sleep parameters in subjects with insomnia disorder.
    Protection of trial subjects
    Prior to the start of the study, each study site consulted an IEC or IRB, i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The protocol and any material provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC or IRB before the study was started. Sponsor personnel and the investigators were required to conduct the study in full compliance with ICHGCP Guidelines, the principles of the Declaration of Helsinki, and with the laws and regulations of the countries in which the study is conducted. Both the sponsor and the investigators had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. The investigators were responsible for maintaining the subjects’ identities in strictest confidence. Written informed consent was required to be obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    United States: 325
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Bulgaria: 63
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 436
    Country: Number of subjects enrolled
    Hungary: 34
    Worldwide total number of subjects
    924
    EEA total number of subjects
    559
    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)
    561
    From 65 to 84 years
    362
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 81 sites in 11 countries (Canada, Republic of Korea, United States, Belgium, Sweden, Bulgaria, Czech Republic, Finland, France, Germany, Hungary), of which 61 sites randomized subjects.

    Pre-assignment
    Screening details
    		 Screening details: The screening phase lasted for 20 to 31 days, from signing informed consent at Visit 1 until randomization (Visit 4).

    Period 1
    Period 1 title
    DB treatment period (up to EOS) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daridorexant 10 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daridorexant 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daridorexant was supplied as film-coated tablets at the strength of 10 mg for oral use.

    Arm title
    		 Daridorexant 25 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daridorexant 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daridorexant was supplied as film-coated tablets at the strength of 25 mg for oral use.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was supplied as film-coated tablets for oral use.

    Number of subjects in period 1
    		Daridorexant 10 mg Daridorexant 25 mg Placebo
    Started
    307
    309
    308
    Completed
    283
    280
    286
    Not completed
    24
    29
    22
         Consent withdrawn by subject
    13
    16
    11
         Adverse event, non-fatal
    4
    3
    4
         Other reasons
    6
    8
    6
         Lost to follow-up
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daridorexant 10 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 25 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo Total
    Number of subjects
    		 307 309 308 924
    Age categorical
    Units: Subjects
        From 18-64 years
    		 186 188 187 561
        >=65 years
    		 121 121 121 363
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ( 14.0 ) 56.3 ( 14.4 ) 56.7 ( 14.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 215 218 205 638
        Male
    		 92 91 103 286

    End points

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    End points reporting groups
    Reporting group title
    Daridorexant 10 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 25 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Change in WASO from baseline to Month 1 (sleep maintenance)

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    End point title
    		 Change in WASO from baseline to Month 1 (sleep maintenance)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: mean of the 2 PSG nights at Visit 3 Month 1: mean of the 2 PSG nights at Visit 6
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    -15.31 (-19.531 to -11.087)
    -24.19 (-28.466 to -19.911)
    -12.57 (-16.817 to -8.323)
    Statistical analysis title
    		 Betw.-treatm. for change in WASO to Month 1
    Statistical analysis description
    Between-treatment analysis for change in WASO (min) from baseline to Month 1 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3669 [1]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.693
         upper limit
    		 3.215
    Notes
    [1] - [1] - Mixed effects model for repeated measures: change in WASO from baseline = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in WASO to Month 1
    Statistical analysis description
    Between-treatment analysis for change in WASO (min) from baseline to Month 1 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001 [2]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -11.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.604
         upper limit
    		 -5.633
    Notes
    [2] - [2] - Mixed effects model for repeated measures: change in WASO from baseline = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Primary: Change in WASO from baseline to Month 3

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    End point title
    		 Change in WASO from baseline to Month 3
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: mean of the 2 PSG nights at Visit 3. Month 3: mean of the 2 PSG nights at Visit 8.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    -15.95 (-20.734 to -11.165)
    -24.25 (-29.021 to -19.474)
    -14.00 (-18.756 to -9.241)
    Statistical analysis title
    		 Betw.-treatm. for change in WASO to Month 3
    Statistical analysis description
    Between-treatment analysis for change in WASO (min) from baseline to Month 3 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5686 [3]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS Mean difference to placebo
    Point estimate
    -1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.666
         upper limit
    		 4.764
    Notes
    [3] - [3] - Mixed effects model for repeated measures: change in WASO from baseline = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in WASO to Month 3
    Statistical analysis description
    Between-treatment analysis for change in WASO (min) from baseline to Month 3 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0028 [4]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS Mean difference to placebo
    Point estimate
    -10.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.95
         upper limit
    		 -3.548
    Notes
    [4] - [4] - Mixed effects model for repeated measures: change in WASO from baseline = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Primary: Change in LPS from baseline to Month 1 (sleep onset)

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    End point title
    		 Change in LPS from baseline to Month 1 (sleep onset)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: mean of the 2 PSG nights at Visit 3. Month 1: mean of the 2 PSG nights at Visit 6.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    -22.62 (-26.733 to -18.503)
    -26.46 (-30.626 to -22.292)
    -20.01 (-24.148 to -15.875)
    Statistical analysis title
    		 Betw.-treatm. for change in LPS to Month 1
    Statistical analysis description
    Between-treatment analysis for change in LPS (min) from baseline to Month 1 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3782 [5]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.41
         upper limit
    		 3.197
    Notes
    [5] - [5] - Mixed effects model for repeated measures: change in LPS from baseline = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in LPS to Month 1
    Statistical analysis description
    Between-treatment analysis for change in LPS (min) from baseline to Month 1 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0303 [6]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -6.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.282
         upper limit
    		 -0.614
    Notes
    [6] - [6] - Mixed effects model for repeated measures: change in LPS from baseline = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Primary: Change in LPS from baseline to Month 3

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    End point title
    		 Change in LPS from baseline to Month 3
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: mean of the 2 PSG nights at Visit 3. Month 3: mean of the 2 PSG nights at Visit 8.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    -23.09 (-27.600 to -18.571)
    -28.91 (-33.413 to -24.399)
    -19.89 (-24.384 to -15.405)
    Statistical analysis title
    		 Betw.-treatm. for change in LPS to Month 3
    Statistical analysis description
    Between-treatment analysis for change in LPS (min) from baseline to Month 3 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3233 [7]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.528
         upper limit
    		 3.146
    Notes
    [7] - [7] - Mixed effects model for repeated measures: change in LPS from baseline = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in LPS to Month 3
    Statistical analysis description
    Between-treatment analysis for change in LPS (min) from baseline to Month 3 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0053 [8]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -9.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.339
         upper limit
    		 -2.684
    Notes
    [8] - [7] - Mixed effects model for repeated measures: change in LPS from baseline = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Secondary: Change in the subjective Total Sleep Time (sTST) from baseline to Month 1

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    End point title
    		 Change in the subjective Total Sleep Time (sTST) from baseline to Month 1
    End point description
    End point type
    Secondary
    End point timeframe
    "Baseline" is the mean value based on the screening sleep diary in the 7 days preceding the first PSG at Visit 3. "Month 1" is the mean value based on the sleep diary in the 7 days preceding the first PSG at Visit 6.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    41.01 (35.439 to 46.584)
    43.77 (38.136 to 49.412)
    27.64 (22.015 to 33.274)
    Statistical analysis title
    		 Betw.-treatm. for change in sTST to Month 1
    Statistical analysis description
    Between-treatment analysis for change from baseline in sTST (min) to Month 1 (daridorexant 10 mg vs placebo) Statistical
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0009 [9]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    13.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.507
         upper limit
    		 21.226
    Notes
    [9] - Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in sTST to Month 1
    Statistical analysis description
    Between-treatment analysis for change from baseline in sTST (min) to Month 1 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    16.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.224
         upper limit
    		 24.035
    Notes
    [10] - Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Secondary: Change in sTST from baseline to Month 3

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    End point title
    		 Change in sTST from baseline to Month 3
    End point description
    End point type
    Secondary
    End point timeframe
    "Baseline" is the mean value based on the screening sleep diary in the 7 days preceding the first PSG at Visit 3. "Month 3" is the mean value based on the sleep diary in the 7 days preceding the first PSG at Visit 8.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: minutes
        least squares mean (confidence interval 95%)
    50.70 (44.398 to 57.008)
    56.18 (49.812 to 62.547)
    37.12 (30.776 to 43.464)
    Statistical analysis title
    		 Betw.-treatm. for change in sTST to Month 3
    Statistical analysis description
    Between-treatment analysis for change from baseline in sTST (min) to Month 3 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0028 [11]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    13.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.691
         upper limit
    		 22.475
    Notes
    [11] - Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in sTST to Month 3
    Statistical analysis description
    Between-treatment analysis for change from baseline in sTST (min) to Month 3 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    19.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.125
         upper limit
    		 27.994
    Notes
    [12] - Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Secondary: Change in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 1

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    End point title
    		 Change in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 1
    End point description
    End point type
    Secondary
    End point timeframe
    "Baseline" is the mean value based on the screening IDSIQ entries in the 7 days preceding the first PSG at Visit 3. "Month 1" is the mean value based on the IDSIQ entries in the 7 days preceding the first PSG at Visit 6.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: Score units
        least squares mean (confidence interval 95%)
    -3.18 (-3.763 to -2.599)
    -3.51 (-4.096 to -2.917)
    -2.75 (-3.340 to -2.163)
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 1
    Statistical analysis description
    Between-treatment analysis for change in in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 1 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3048 [13]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.251
         upper limit
    		 0.392
    Notes
    [13] - Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 1
    Statistical analysis description
    Between-treatment analysis for change in in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 1 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0733 [14]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.581
         upper limit
    		 0.071
    Notes
    [14] - Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Secondary: Change in IDSIQ sleepiness domain score from baseline to Month 3

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    End point title
    		 Change in IDSIQ sleepiness domain score from baseline to Month 3
    End point description
    End point type
    Secondary
    End point timeframe
    "Baseline" is the mean value based on the screening IDSIQ entries in the 7 days preceding the first PSG at Visit 3. "Month 3" is the mean value based on the IDSIQ entries in the 7 days preceding the first PSG at Visit 8.
    End point values
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Number of subjects analysed
    307
    309
    308
    Units: Score units
        least squares mean (confidence interval 95%)
    -4.75 (-5.437 to -4.056)
    -5.27 (-5.964 to -4.569)
    -4.01 (-4.705 to -3.322)
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 3
    Statistical analysis description
    Between-treatment analysis for change in in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 3 (daridorexant 10 mg vs placebo)
    Comparison groups
    Daridorexant 10 mg v Placebo
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1393
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.706
         upper limit
    		 0.239
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 3
    Statistical analysis description
    Between-treatment analysis for change in in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score from baseline to Month 3 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.012 [15]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.23
         upper limit
    		 -0.276
    Notes
    [15] - Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were AEs that started or worsened on or after DB study treatment start date up to 30 days after DB study treatment end date or the date of enrollment in the ID-078A303 extension study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Daridorexant 10 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 25 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 306 (0.98%)
    3 / 308 (0.97%)
    4 / 306 (1.31%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 308 (0.00%)
    1 / 306 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 308 (0.00%)
    1 / 306 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 308 (0.00%)
    1 / 306 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Microvascular coronary artery disease
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
    0 / 306 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
    0 / 306 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
    0 / 306 (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
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
    0 / 306 (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
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
    0 / 306 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 308 (0.00%)
    1 / 306 (0.33%)
         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
    Appendicitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
    0 / 306 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daridorexant 10 mg Daridorexant 25 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 306 (16.01%)
    28 / 308 (9.09%)
    30 / 306 (9.80%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 306 (4.58%)
    16 / 308 (5.19%)
    11 / 306 (3.59%)
         occurrences all number
    19
    16
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    38 / 306 (12.42%)
    13 / 308 (4.22%)
    20 / 306 (6.54%)
         occurrences all number
    41
    15
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2018
    The IDSIQ was updated to add the item ‘energetic’, in line with FDA requirements.
    19 Apr 2018
    • Inclusion/exclusion criteria: – Exclusion criteria #16 and 17 (concerning treatment with CYP3A4 inhibitors/inducers, and consumption of grapefruit / bitter oranges, respectively), previously assessed at Visit 2, were shifted to be assessed at Visit 1. – Exclusion criterion #3 was updated to clarify the indication for acceptable CBT since it was considered that any CBT could impact the efficacy endpoints. • Safety visit at Month 2 (Visit 7): – A safety visit taking place after 2 months of treatment (Visit 7) was added, as treatment with the study drug had been evaluated for a maximum of 1 month in the Phase 2 studies. • Contraception requirement: – The protocol was aligned with the Heads of Medicines Agencies Clinical Trials Facilitation Group recommendations for the use of an acceptable contraception method. • Forbidden concomitant activities: – The following activity was added: Driving or engaging in activities that require operating vehicles or dangerous machinery within 8 hours following study treatment intake for adult and elderly subjects. • A rationale for the run-in period was added. • The categories of AESIs were modified: the three original categories were placed under ‘Narcolepsy-like symptoms’ and sub-categories were created. • Exclusion criterion #5 was amended to mention that the subjects with a history of major depressive disorder currently without any symptoms and not requiring treatment were eligible. • Clarification regarding study treatment discontinuation: upon discontinuation of study treatment for any reason, subjects were encouraged to remain in the study and perform the visits and assessments as planned by the protocol (except the run-out period) until the End-of-Study. This would decrease the amount of missing data which was important from a study integrity perspective.
    30 Jul 2018
    Two assessments (PGI-C and PGI-S, both capturing night-time symptoms) were added as requested by the FDA to anchor and better understand the data collected with the SDQ. In addition, the sponsor clarified the use of a back-up device for alcohol tests.
    08 Nov 2018
    The patient preferences sub-study (PAUSe) was implemented at ID-078A302 study sites in Germany and the USA to support the recruitment of at least 360 subjects in these countries.

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

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