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

    Summary
    EudraCT number
    2016-000826-21
    Trial protocol
    DE   SE   HU   ES  
    Global end of trial date
    20 Jun 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Nov 2019
    First version publication date
    06 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-078A201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02839200
    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
    13 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the dose-response of ACT-541468 on the change of WASO [Wake After Sleep Onset] assessed by Polysomnography [PSG] after treatment on Days 1 and 2.
    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
    29 Sep 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
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Germany: 199
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    United States: 101
    Worldwide total number of subjects
    360
    EEA total number of subjects
    256
    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)
    360
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Conducted at 38 sites in 6 countries (Germany, Hungary, Israel, Spain, Sweden, and the USA)

    Pre-assignment
    Screening details
    Screening phase: screening period (screening visit followed by at least 7 days at home) and a run-in period (2 PSG nights on single-blind placebo, followed by 5–12 days with no treatment), and lasting a max. of 28 days. N = 360 subjects were randomized; N = 359 subjects were treated; N = 1 subject discontinued due to "randomization error."

    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
    Yes

    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.

    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.

    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.

    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.

    Arm title
    Zolpidem 10 mg
    Arm description
    -
    Arm type
    Active reference

    Investigational medicinal product name
    Zolpidem 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated tablets of commercially available Stilnox® for oral administration once daily.

    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
    Placebo (2 types of placebo: one matching ACT-541468, one matching zolpidem) administered orally once daily during the treatment period. Placebo was also administered during the run-in period and during the run-out period.

    Number of subjects in period 1 [1]
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo
    Started
    60
    58
    60
    61
    60
    60
    Completed
    56
    58
    59
    61
    58
    59
    Not completed
    4
    0
    1
    0
    2
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    2
    -
    1
    -
    -
    1
         Lost to follow-up
    2
    -
    -
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: See version 1.

    Baseline characteristics

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    Baseline characteristics 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
    Zolpidem 10 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo Total
    Number of subjects
    60 58 60 61 60 60 359
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    60 58 60 61 60 60 359
    Age continuous
    Units: years
        median (full range (min-max))
    41 (22 to 64) 48 (21 to 63) 48 (18 to 64) 46 (18 to 63) 43 (23 to 61) 48 (23 to 64) -
    Gender categorical
    Units: Subjects
        Female
    38 38 39 39 38 38 230
        Male
    22 20 21 22 22 22 129

    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
    Zolpidem 10 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Change in WASO from baseline to Days 1&2

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    End point title
    Change in WASO from baseline to Days 1&2
    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 with the MCP-Mod method (see attachment for dose-response relationship). Modified full analysis set.
    End point type
    Primary
    End point timeframe
    From baseline to Days 1&2
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo
    Number of subjects analysed
    60
    58
    60
    61
    60
    60
    Units: minutes
        least squares mean (standard error)
    -28.4 ± 4.24
    -32.3 ± 4.32
    -37.7 ± 4.25
    -47.1 ± 4.21
    -29.9 ± 4.30
    -21.4 ± 4.24
    Attachments
    Predicted mean (95% CL) dose-response profile
    Statistical analysis title
    Between treatment - change in WASO - 5 mg
    Comparison groups
    Placebo v ACT-541468 5 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.241
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    -7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.7
         upper limit
    4.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.95
    Statistical analysis title
    Between treatment - change in WASO - 10 mg
    Comparison groups
    ACT-541468 10 mg v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.072
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    -10.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.6
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    6
    Statistical analysis title
    Between treatment - change in WASO - 25 mg
    Comparison groups
    ACT-541468 25 mg v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.007
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    -16.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.9
         upper limit
    -4.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.95
    Statistical analysis title
    Between treatment - change in WASO - 50 mg
    Comparison groups
    ACT-541468 50 mg v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    -25.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.3
         upper limit
    -13.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.92
    Statistical analysis title
    Between treatment - change in WASO - Zolpidem 10mg
    Comparison groups
    Placebo v Zolpidem 10 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.155
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    -8.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.4
         upper limit
    3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.97
    Notes
    [1] - Separate ANCOVA model.

    Secondary: Change in latency to persistent sleep (LPS) to Days 1&2

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    End point title
    Change in latency to persistent sleep (LPS) to Days 1&2
    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
    From baseline to Days 1&2.
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo
    Number of subjects analysed
    60
    58
    60
    61
    60
    60
    Units: minutes
        arithmetic mean (standard deviation)
    -26.88 ± 45.42
    -29.31 ± 26.79
    -36.14 ± 34.34
    -36.41 ± 26.71
    -45.12 ± 32.82
    -22.02 ± 46.63
    No statistical analyses for this end point

    Secondary: Change in subjective latency to sleep onset (sLSO) to Week 4

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    End point title
    Change in subjective latency to sleep onset (sLSO) to Week 4
    End point description
    Full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4.
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo
    Number of subjects analysed
    58
    52
    56
    57
    59
    57
    Units: minutes
        arithmetic mean (standard deviation)
    -13.38 ± 27.79
    -21.07 ± 24.26
    -15.5 ± 25.51
    -23.65 ± 24.12
    -19.98 ± 19.28
    -16.32 ± 21.16
    No statistical analyses for this end point

    Secondary: Change in subjective WASO (sWASO) to Week 4

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    End point title
    Change in subjective WASO (sWASO) to Week 4
    End point description
    Full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4.
    End point values
    ACT-541468 5 mg ACT-541468 10 mg ACT-541468 25 mg ACT-541468 50 mg Zolpidem 10 mg Placebo
    Number of subjects analysed
    51
    45
    53
    49
    48
    50
    Units: minutes
        arithmetic mean (standard deviation)
    -31.32 ± 33.32
    -24.35 ± 33.4
    -29.8 ± 39.88
    -35.45 ± 37.53
    -29.08 ± 27.28
    -23.61 ± 32.62
    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 (TEAEs).
    Adverse event reporting additional description
    Safety set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    PLACEBO
    Reporting group description
    PLACEBO

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

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

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

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

    Reporting group title
    ZOLPIDEM 10mg
    Reporting group description
    ZOLPIDEM 10mg

    Serious adverse events
    PLACEBO ACT-541468 5mg ACT-541468 10mg ACT-541468 25mg ACT-541468 50mg ZOLPIDEM 10mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (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
    Injury, poisoning and procedural complications
    Accident at work
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    PLACEBO ACT-541468 5mg ACT-541468 10mg ACT-541468 25mg ACT-541468 50mg ZOLPIDEM 10mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 60 (30.00%)
    21 / 60 (35.00%)
    21 / 58 (36.21%)
    23 / 60 (38.33%)
    21 / 61 (34.43%)
    24 / 60 (40.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    2
    2
    1
    3
    0
    5
    Feeling hot
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Medical device site erythema
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Medical device site inflammation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Medical device site irritation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Medical device site pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nervousness
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nightmare
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Stress
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hand fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    1
    2
    2
    1
    1
    0
    ECG signs of myocardial infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Atrial tachycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    1
    1
    4
    0
    0
    4
    Dizziness postural
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    6 / 60 (10.00%)
    5 / 58 (8.62%)
    5 / 60 (8.33%)
    5 / 61 (8.20%)
    6 / 60 (10.00%)
         occurrences all number
    1
    7
    5
    5
    6
    8
    Hypersomnia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 60 (5.00%)
    3 / 58 (5.17%)
    4 / 60 (6.67%)
    4 / 61 (6.56%)
    3 / 60 (5.00%)
         occurrences all number
    3
    4
    3
    5
    5
    3
    Eye disorders
    Chromatopsia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Paraesthesia ear
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    3
    0
    1
    0
    1
    5
    Constipation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    2
    1
    0
    3
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Faeces pale
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Nausea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    1
    2
    1
    5
    Renal and urinary disorders
    Bladder discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    2 / 61 (3.28%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Muscle tightness
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 60 (3.33%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
    2 / 61 (3.28%)
    5 / 60 (8.33%)
         occurrences all number
    4
    2
    2
    0
    2
    5
    Pharyngitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    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
    03 Aug 2016
    Two global amendments were issued to the original AC-078A201 protocol (dated 3 May 2016). Global Amendment 1 was issued before enrolment of the first subject. Hence, all subjects were enrolled and treated under Global Protocol Versions 2 and 3. Some changes of Amendment 1: • The list of forbidden concomitant medications was expanded (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 sleep diary questionnaire was amended by two additional questions
    16 Dec 2016
    Two global amendments were issued to the original AC-078A201 protocol (dated 3 May 2016). Global Amendment 1 was issued before enrolment of the first subject. Hence, all subjects were enrolled and treated under Global Protocol Versions 2 and 3. Some changes of Amendment 2: • The list of forbidden concomitant medications was expanded (e.g., ethinylestradiol was removed) • The sleep diary questionnaire was improved

    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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