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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
    		 2017-004642-20
    Trial protocol
    		 DK   DE   ES   IT  
    Global end of trial date
    25 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2021
    First version publication date
    11 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ID-078A301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03545191
    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
    31 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 25 mg and 50 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 ICH-GCP 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
    04 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    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
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 91
    Country: Number of subjects enrolled
    Denmark: 63
    Country: Number of subjects enrolled
    Germany: 444
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    United States: 300
    Worldwide total number of subjects
    930
    EEA total number of subjects
    612
    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)
    566
    From 65 to 84 years
    361
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 75 sites in 10 countries (Australia, Canada, Denmark, Germany, Italy, Poland, Serbia, Spain, Switzerland, and the USA), of which 51 sites in 7 countries (Canada, Denmark, Germany, Poland, Spain, Switzerland, and the USA) randomized subjects.

    Pre-assignment
    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 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 25 mg was supplied as film-coated tablets at the strength of 25 mg for oral use.

    Arm title
    		 Daridorexant 50 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daridorexant 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daridorexant 50 mg was supplied as film-coated tablets at the strength of 50 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 25 mg Daridorexant 50 mg Placebo
    Started
    310
    310
    310
    Completed
    288
    285
    280
    Not completed
    22
    25
    30
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    13
    10
    12
         Adverse event, non-fatal
    4
    2
    7
         Other reasons
    3
    11
    8
         Lost to follow-up
    1
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daridorexant 25 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 50 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Daridorexant 25 mg Daridorexant 50 mg Placebo Total
    Number of subjects
    		 310 310 310 930
    Age categorical
    Units: Subjects
        From 18-64 years
    		 189 189 188 566
        >=65 year
    		 121 121 122 364
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.8 ( 15.3 ) 55.5 ( 15.3 ) 55.1 ( 15.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 215 199 210 624
        Male
    		 95 111 100 306

    End points

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    End points reporting groups
    Reporting group title
    Daridorexant 25 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 50 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

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

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    End point title
    		 Change in WASO (sleep maintenance) from baseline to Month 1
    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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minutes
        least squares mean (confidence interval 95%)
    -18.40 (-22.126 to -14.674)
    -28.98 (-32.668 to -25.299)
    -6.20 (-9.928 to -2.475)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.435
         upper limit
    		 -6.961
    Notes
    [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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    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
    -22.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.996
         upper limit
    		 -17.567
    Notes
    [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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minutes
        least squares mean (confidence interval 95%)
    -22.97 (-26.955 to -18.988)
    -29.41 (-33.399 to -25.427)
    -11.11 (-15.131 to -7.088)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS Mean difference to placebo
    Point estimate
    -11.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.494
         upper limit
    		 -6.23
    Notes
    [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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS Mean difference to placebo
    Point estimate
    -18.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.945
         upper limit
    		 -12.661
    Notes
    [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 (sleep onset) from baseline to Month 1

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    End point title
    		 Change in LPS (sleep onset) from baseline to Month 1
    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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minutes
        least squares mean (confidence interval 95%)
    -28.17 (-31.509 to -24.827)
    -31.20 (-34.506 to -27.896)
    -19.85 (-23.177 to -16.515)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0005 [5]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -8.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.014
         upper limit
    		 -3.629
    Notes
    [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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -11.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.022
         upper limit
    		 -6.687
    Notes
    [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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minutes
        least squares mean (confidence interval 95%)
    -30.73 (-34.037 to -27.417)
    -34.80 (-38.118 to -31.490)
    -23.13 (-26.464 to -19.803)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0015 [7]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -7.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.265
         upper limit
    		 -2.923
    Notes
    [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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -11.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.348
         upper limit
    		 -6.994
    Notes
    [8] - 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 entries in the 7 days preceding the first PSG at Visit 6.
    End point values
    		 Daridorexant 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minute
        least squares mean (confidence interval 95%)
    34.18 (28.718 to 39.645)
    43.62 (38.173 to 49.063)
    21.56 (16.101 to 27.022)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0013 [9]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    12.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.953
         upper limit
    		 20.288
    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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    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
    22.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.405
         upper limit
    		 29.708
    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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: minutes
        least squares mean (confidence interval 95%)
    47.83 (41.333 to 54.328)
    57.67 (51.171 to 64.168)
    37.90 (31.393 to 44.404)
    Statistical analysis title
    		 Betw.-treatm. for change in sTST to Month 3
    Statistical analysis description
    Between-treatment analysis for change in sTST (min) from baseline to Month 3 (daridorexant 25 mg vs placebo)
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0334 [11]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    9.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.782
         upper limit
    		 19.082
    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 in sTST (min) from baseline to Month 3 (daridorexant 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    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
    19.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.623
         upper limit
    		 28.918
    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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: score
        least squares mean (confidence interval 95%)
    -2.77 (-3.316 to -2.225)
    -3.77 (-4.309 to -3.224)
    -2.02 (-2.566 to -1.476)
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0547 [13]
    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
    		 -1.515
         upper limit
    		 0.015
    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 50 mg vs placebo)
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.508
         upper limit
    		 -0.983
    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 25 mg Daridorexant 50 mg Placebo
    Number of subjects analysed
    310
    310
    310
    Units: score
        least squares mean (confidence interval 95%)
    -4.78 (-5.491 to -4.067)
    -5.70 (-6.405 to -4.987)
    -3.79 (-4.503 to -3.080)
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 3
    Comparison groups
    Daridorexant 25 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0534 [15]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 0.014
    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.
    Statistical analysis title
    		 Betw.-treatm. for change in IDSIQ to Month 3
    Comparison groups
    Daridorexant 50 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0002 [16]
    Method
    		 Mixed effects model (repeated measures)
    Parameter type
    		 LS mean difference to placebo
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.905
         upper limit
    		 -0.905
    Notes
    [16] - 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 25 mg
    Reporting group description
    		 -

    Reporting group title
    Daridorexant 50 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Daridorexant 25 mg Daridorexant 50 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 310 (0.65%)
    3 / 308 (0.97%)
    7 / 309 (2.27%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 308 (0.32%)
    0 / 309 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 308 (0.32%)
    0 / 309 (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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 308 (0.32%)
    0 / 309 (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
    Ankle fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 308 (0.00%)
    1 / 309 (0.32%)
         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
    Cardiac arrest
         subjects affected / exposed
    1 / 310 (0.32%)
    0 / 308 (0.00%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 308 (0.32%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 310 (0.32%)
    0 / 308 (0.00%)
    0 / 309 (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
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 308 (0.32%)
    0 / 309 (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
    Depression
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 308 (0.00%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 308 (0.00%)
    1 / 309 (0.32%)
         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
    Anal abscess
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 308 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 308 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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 25 mg Daridorexant 50 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 310 (14.19%)
    41 / 308 (13.31%)
    35 / 309 (11.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 310 (5.48%)
    20 / 308 (6.49%)
    12 / 309 (3.88%)
         occurrences all number
    24
    27
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    28 / 310 (9.03%)
    24 / 308 (7.79%)
    24 / 309 (7.77%)
         occurrences all number
    28
    26
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2018
    Changes were made regarding inclusion/exclusion criteria, safety visit at Month 2 (Visit 7), contraception requirement, forbidden concomitant activities, and categories of AESIs.
    30 Jul 2018
    Two assessments (PGI-C and PGI-S, both capturing night-time symptoms) were added to anchor and better understand the data collected with the SDQ.

    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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