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    Clinical Trial Results:
    Multi-center, double-blind, randomized, placebo-controlled, 5-period, 5-treatment crossover, polysomnography dose-response study to assess the efficacy and safety of ACT-541468 in elderly subjects with insomnia disorder

    Summary
    EudraCT number
    2016-000827-16
    Trial protocol
    DE  
    Global end of trial date
    29 Jun 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Nov 2019
    First version publication date
    08 Jul 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Change of Sponsor

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-078A202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02841709
    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
    17 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the dose-response of ACT-541468 on the change of Wake After Sleep Onset (WASO) assessed by polysomnography (PSG) on the first two days of each treatment period.
    Protection of trial subjects
    The study was conducted 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 was conducted. Prior to the start of the study, each study site consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety and well-being of human subjects involved. 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. Prior to any study procedure, written informed consent was obtained from each participating subject. It was made clear to each subject that he or she was completely free to withdraw from it at any time for any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    58
    EEA total number of subjects
    34
    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)
    0
    From 65 to 84 years
    57
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Conducted at 10 centers in 2 countries (USA and Germany)

    Pre-assignment
    Screening details
    Screening phase: From signing informed consent to randomization, lasting a maximum of 28 days and comprising a screening period (screening visit + at least 7 days at home) and a run-in period (2 consecutive PSG nights on single-blind placebo treatment, + 5–12 days at home with no treatment; assessments collected were used for baseline).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    ACT-541468 5 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-541468 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    ACT-541468 5 mg orally once daily on the first two evenings of the assigned treatment period.

    Arm title
    ACT-541468 10 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-541468 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    ACT-541468 10 mg orally once daily on the first two evenings of the assigned treatment period.

    Arm title
    ACT-541468 25 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-541468 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    ACT-541468 25 mg orally once daily on the first two evenings of the assigned treatment period.

    Arm title
    ACT-541468 50 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-541468 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    2 x ACT-541468 25 mg orally once daily on the first two evenings of the assigned treatment period.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo orally once daily on the first two evenings of the assigned treatment period.

    Number of subjects in period 1
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Placebo
    Started
    58
    58
    58
    58
    58
    Completed
    58
    58
    58
    58
    58

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    -

    Reporting group values
    Overall study Total
    Number of subjects
    58 58
    Age categorical
    Units: Subjects
        From 65-84 years
    57 57
        85 years and over
    1 1
    Age continuous
    Units: years
        median (full range (min-max))
    69 (65 to 85) -
    Gender categorical
    Units: Subjects
        Female
    39 39
        Male
    19 19
    Insomnia Severity Index
    Range 0 - 28
    Units: Index
        median (full range (min-max))
    20 (15 to 28) -

    End points

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    End points reporting groups
    Reporting group title
    ACT-541468 5 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 10 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 25 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 50 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Change in wake after sleep onset (WASO)

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    End point title
    Change in wake after sleep onset (WASO)
    End point description
    WASO is the time (min) spent awake after onset of persistent sleep until lights on, as determined by PSG. The change from baseline to Days 1&2 in WASO (min) was analyzed using the generalized MCP-Mod approach, which combines a Multiple Comparison Procedure (MCP) to assess the efficacy of ACT-541468 versus placebo followed by a modeling (Mod) step to characterize the dose-response relationship (see attachment). Modified full analysis set.
    End point type
    Primary
    End point timeframe
    Baseline to Days 1&2
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Placebo
    Number of subjects analysed
    56
    54
    55
    56
    54
    Units: minute
        least squares mean (standard error)
    -18.9 ± 4.44
    -32.0 ± 4.50
    -45.1 ± 4.47
    -61.4 ± 4.44
    -13.6 ± 4.50
    Attachments
    Predicted mean (95% CL) dose-response profile
    Statistical analysis title
    Between treatment - 5 mg vs. placebo
    Comparison groups
    ACT-541468 5 mg v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.258 [2]
    Method
    Linear mixed effects model
    Parameter type
    LS mean difference
    Point estimate
    -5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.7
         upper limit
    4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.73
    Notes
    [1] - Number of subjects included in the analysis = 56.
    [2] - two-sided
    Statistical analysis title
    Between treatment - 10 mg vs. placebo
    Comparison groups
    ACT-541468 10 mg v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.001 [4]
    Method
    Linear mixed effects model
    Parameter type
    LS mean difference
    Point estimate
    -18.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.8
         upper limit
    -9
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.76
    Notes
    [3] - Number of subjects included in the analysis = 54.
    [4] - two-sided
    Statistical analysis title
    Between treatment - 25 mg vs placebo
    Comparison groups
    Placebo v ACT-541468 25 mg
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    < 0.001 [6]
    Method
    Linear mixed effects model
    Parameter type
    LS mean difference
    Point estimate
    -31.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.9
         upper limit
    -22.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.74
    Notes
    [5] - Number of subjects included in the analysis = 55.
    [6] - two-sided
    Statistical analysis title
    Between treatment - 50 mg vs placebo
    Comparison groups
    Placebo v ACT-541468 50 mg
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    < 0.001 [8]
    Method
    Linear mixed effects model
    Parameter type
    LS mean difference
    Point estimate
    -47.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -57.2
         upper limit
    -38.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.74
    Notes
    [7] - Number of subjects included in the analysis = 56.
    [8] - two-sided

    Secondary: Change in latency to persistent sleep (LPS)

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    End point title
    Change in latency to persistent sleep (LPS)
    End point description
    LPS (min) is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 min) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography (PSG). Full analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline to Days 1&2
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Placebo
    Number of subjects analysed
    56
    54
    55
    56
    54
    Units: minute
        arithmetic mean (standard deviation)
    -37.92 ± 48.76
    -44.61 ± 41.28
    -44.81 ± 41.56
    -44.88 ± 44.22
    -33.88 ± 41.74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Data on adverse events were collected from Screening to Safety Follow-up period. Below, data are reported for treatment-emergent adverse events. Safety set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Run-in period
    Reporting group description
    Run-in period = 2 consecutive PSG nights on single-blind placebo treatment, followed by 5-12 days at home with no treatment.

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    ACT-541468 5 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 10 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 25 mg
    Reporting group description
    -

    Reporting group title
    ACT-541468 50 mg
    Reporting group description
    -

    Serious adverse events
    Run-in period Placebo ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Run-in period Placebo ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 58 (12.07%)
    11 / 54 (20.37%)
    14 / 56 (25.00%)
    12 / 54 (22.22%)
    10 / 55 (18.18%)
    16 / 56 (28.57%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 54 (3.70%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    4 / 56 (7.14%)
         occurrences all number
    0
    2
    0
    1
    0
    4
    Feeling abnormal
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 54 (0.00%)
    2 / 56 (3.57%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
    1 / 56 (1.79%)
         occurrences all number
    1
    0
    3
    1
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Delusional disorder, unspecified type
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hallucination, visual
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Bundle branch block left
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Nasal oedema
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Cerebellar ataxia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    2 / 56 (3.57%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 54 (1.85%)
    2 / 56 (3.57%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    1 / 56 (1.79%)
         occurrences all number
    2
    1
    2
    0
    1
    1
    Hyporeflexia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye disorders
    Photophobia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Defaecation urgency
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 54 (3.70%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hypochloraemia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 54 (1.85%)
    1 / 56 (1.79%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
    2 / 56 (3.57%)
         occurrences all number
    0
    1
    1
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2016
    One global amendment was issued to the original AC-078A202 protocol (dated 15 June 2016 ); this amendment (Global Amendment 1) was issued before enrolment of the first subject. Hence, all subjects were enrolled and treated under Global Protocol Version 2. Some changes: • The list of forbidden concomitant medications was modified (e.g. CYP3A4 substrates, inhibitors and inducers were added) • The list of inclusion/exclusion criteria was modified (e.g. subjects with severe renal impairment were not to be included) • The study-specific criteria for premature discontinuation of double-blind study treatment were defined • The sleep diary questionnaire was amended by two additional questions

    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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