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    Clinical Trial Results:
    A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression

    Summary
    EudraCT number
    2013-004005-11
    Trial protocol
    BE  
    Global end of trial date
    25 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESKETINTRD2003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01998958
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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
    25 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to assess the efficacy and dose response of intranasal esketamine (Panel A: 28 mg, 56 mg, 84 mg; Panel B: 14 mg and 56 mg) compared with placebo in improving depressive symptoms in participants with treatment-resistant depression (TRD), as assessed by a change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score for the combined periods in the double-blind treatment phase.
    Protection of trial subjects
    Safety evaluations included monitoring of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital sign measurements, physical examination, height and body weight and electrocardiograms (ECG).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Japan: 41
    Country: Number of subjects enrolled
    United States: 56
    Worldwide total number of subjects
    108
    EEA total number of subjects
    11
    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)
    108
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Recruitment period: 28 January 2014 - 25 September 2015

    Pre-assignment
    Screening details
    A total of 126 participants were screened for entry in Panel A, of these 67 participants were randomized and received treatment. A total of 54 participants were screened for entry in Panel B, of these 41 participants were randomized and treated with treatment.

    Period 1
    Period 1 title
    Double-Blind Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants in Panel A and B were self-administered intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants received intranasal placebo on Days 8 and 11 or were re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants self-administered with placebo as an intranasal formulation 1 spray into each nostril at t=0, 5, and 10 minutes on each dosing day.

    Arm title
    Esketamine 56 milligrams (mg)/Esketamine 56 mg
    Arm description
    Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 56 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants self-administered 1 to 6 sprays of esketamine 56 mg as an intranasal formulation into each nostril on Days 1, 4, 8, and 11.

    Arm title
    Esketamine 84 mg/Esketamine 84 mg
    Arm description
    Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 84 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of esketamine 84 mg as an intranasal formulation for up to 2 weeks (Days 1, 4, 8, 11).

    Arm title
    Placebo/Placebo
    Arm description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and responders [Quick Inventory of Depressive Symptomatology – 16-item Self Report {QIDS-SR16} total score less than 11]) were self-administered with Placebo on Day 8 and 11; non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to [>=] 11) on Day 8 were re-randomized to intranasal placebo or esketamine on Days 8 and 11 during the double-blind phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of placebo as an intranasal formulation for up to 2 weeks (Days 1, 4, 8, and 11).

    Arm title
    Placebo/Esketamine 14 mg
    Arm description
    Participants in Panel B (who received placebo on Day 1 and 4 and non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to (>=) 11) on Day 8) were self-administered intranasal esketamine 14 mg on Days 8, and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 14 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants self-administered with esketamine 14 mg as an intranasal formulation into each nostril on Days 8 and 11.

    Arm title
    Placebo/Esketamine 28 mg
    Arm description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 28 mg on Days 8 and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 28 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of esketamine 28 mg as an intranasal formulation on Day 8, 11.

    Arm title
    Placebo/Esketamine 56 mg
    Arm description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 56 mg on Day 8 and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 56 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of esketamine 56 mg as an intranasal formulation on Days 8, and 11.

    Arm title
    Placebo/Esketamine 84 mg
    Arm description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 84 mg on Days 8 and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 84 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of intranasal esketamine 84 mg on Days 8 and 11.

    Arm title
    Esketamine 14 mg/Esketamine 14 mg
    Arm description
    Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 14 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11.

    Arm title
    Esketamine 28 mg
    Arm description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 28 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered 1 to 6 sprays of esketamine 28 mg as an intranasal formulation into each nostril.

    Arm title
    Esketamine 28 mg/ Esketamine 28 mg
    Arm description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine 28 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were self-administered with esketamine 28 mg as an intranasal formulation on Days 1, 4, 8, and 11.

    Number of subjects in period 1
    Placebo Esketamine 56 milligrams (mg)/Esketamine 56 mg Esketamine 84 mg/Esketamine 84 mg Placebo/Placebo Placebo/Esketamine 14 mg Placebo/Esketamine 28 mg Placebo/Esketamine 56 mg Placebo/Esketamine 84 mg Esketamine 14 mg/Esketamine 14 mg Esketamine 28 mg Esketamine 28 mg/ Esketamine 28 mg
    Started
    1
    20
    12
    23
    5
    8
    12
    5
    11
    3
    8
    Completed
    0
    20
    10
    23
    5
    8
    10
    5
    11
    0
    8
    Not completed
    1
    0
    2
    0
    0
    0
    2
    0
    0
    3
    0
         Other
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Lack of efficacy
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    1
    -
    -
    -
    1
    -
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
    1
    -
    -
    1
    -
    Period 2
    Period 2 title
    Open-label Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Esketamine
    Arm description
    Participants were received intranasal esketamine with a starting dose of 56-mg on Day 15 and subsequent doses on Days 18, 22, 25, 32, 39, and 46 and on Days 18, 22, and 25 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability) in Panel A and Panel B respectively.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Participants were received intranasal esketamine with a starting dose of 56-mg on Day 15 and subsequent doses on Days 18, 22, 25, 32, 39, and 46 and on Days 18, 22, and 25 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability) in Panel A and Panel B respectively.

    Number of subjects in period 2 [1]
    Esketamine
    Started
    96
    Completed
    80
    Not completed
    16
         Other
    6
         Lack of efficacy
    3
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    5
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 100 subjects were completed the double blind phase, However only 96 subjects were entered into open label treatment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants in Panel A and B were self-administered intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants received intranasal placebo on Days 8 and 11 or were re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.

    Reporting group title
    Esketamine 56 milligrams (mg)/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Esketamine 84 mg/Esketamine 84 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Placebo/Placebo
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and responders [Quick Inventory of Depressive Symptomatology – 16-item Self Report {QIDS-SR16} total score less than 11]) were self-administered with Placebo on Day 8 and 11; non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to [>=] 11) on Day 8 were re-randomized to intranasal placebo or esketamine on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 14 mg
    Reporting group description
    Participants in Panel B (who received placebo on Day 1 and 4 and non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to (>=) 11) on Day 8) were self-administered intranasal esketamine 14 mg on Days 8, and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 28 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 28 mg on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 56 mg on Day 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 84 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 84 mg on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Esketamine 14 mg/Esketamine 14 mg
    Reporting group description
    Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

    Reporting group title
    Esketamine 28 mg/ Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group values
    Placebo Esketamine 56 milligrams (mg)/Esketamine 56 mg Esketamine 84 mg/Esketamine 84 mg Placebo/Placebo Placebo/Esketamine 14 mg Placebo/Esketamine 28 mg Placebo/Esketamine 56 mg Placebo/Esketamine 84 mg Esketamine 14 mg/Esketamine 14 mg Esketamine 28 mg Esketamine 28 mg/ Esketamine 28 mg Total
    Number of subjects
    1 20 12 23 5 8 12 5 11 3 8 108
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    1 20 12 23 5 8 12 5 11 3 8 108
        From 65 to 84 years
    0 0 0 0 0 0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    52 ± 0 44 ± 9.55 49.8 ± 9.29 45.1 ± 6.84 50.6 ± 9.37 42.1 ± 12.17 42.4 ± 9.25 45.4 ± 10.31 42.2 ± 9.43 48.7 ± 5.77 39.6 ± 10.81 -
    Title for Gender
    Units: subjects
        Female
    0 13 6 10 2 5 8 2 4 1 4 55
        Male
    1 7 6 13 3 3 4 3 7 2 4 53

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants in Panel A and B were self-administered intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants received intranasal placebo on Days 8 and 11 or were re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.

    Reporting group title
    Esketamine 56 milligrams (mg)/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Esketamine 84 mg/Esketamine 84 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Placebo/Placebo
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and responders [Quick Inventory of Depressive Symptomatology – 16-item Self Report {QIDS-SR16} total score less than 11]) were self-administered with Placebo on Day 8 and 11; non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to [>=] 11) on Day 8 were re-randomized to intranasal placebo or esketamine on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 14 mg
    Reporting group description
    Participants in Panel B (who received placebo on Day 1 and 4 and non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to (>=) 11) on Day 8) were self-administered intranasal esketamine 14 mg on Days 8, and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 28 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 28 mg on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 56 mg on Day 8 and 11 during the double-blind phase.

    Reporting group title
    Placebo/Esketamine 84 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 84 mg on Days 8 and 11 during the double-blind phase.

    Reporting group title
    Esketamine 14 mg/Esketamine 14 mg
    Reporting group description
    Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.

    Reporting group title
    Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

    Reporting group title
    Esketamine 28 mg/ Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.
    Reporting group title
    Esketamine
    Reporting group description
    Participants were received intranasal esketamine with a starting dose of 56-mg on Day 15 and subsequent doses on Days 18, 22, 25, 32, 39, and 46 and on Days 18, 22, and 25 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability) in Panel A and Panel B respectively.

    Subject analysis set title
    Panel A: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who received Placebo in Panel A.

    Subject analysis set title
    Panel A: Esketamine 28 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    subjects who received at least one dose of Intranasal Esketamine 28 mg in Panel A.

    Subject analysis set title
    Panel A: Esketamine 56mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subject who received at least one dose of Intranasal Esketamine 56 mg in Panel A.

    Subject analysis set title
    Panel A: Esketamine 84mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who received at least one dose of Intranasal Esketamine 84mg in Panel A.

    Subject analysis set title
    Panel B: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who received Placebo in Panel B were included.

    Subject analysis set title
    Panel B: Esketamine 14mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    subjects who received Intranasal Esketamine 14mg in Panel B were included.

    Subject analysis set title
    Panel B: Esketamine 56 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who received Intranasal Esketamine 56 mg in Panel B were included.

    Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

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    End point title
    Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score
    End point description
    The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score less than 11) to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: Units on a scale
    least squares mean (standard error)
        Double-blind(DB): Period 1 (n=33,11,11,12,21,11,9)
    -4.9 ± 1.74
    -9.8 ± 2.72
    -12.4 ± 2.66
    -15.3 ± 2.56
    -6.6 ± 1.53
    -4.8 ± 2.13
    -10.3 ± 2.36
        DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)
    -4.5 ± 2.92
    -7.6 ± 2.49
    -8.9 ± 2.51
    -11.4 ± 2.68
    -0.7 ± 3.32
    -6.6 ± 4.02
    -1.2 ± 6.04
    Statistical analysis title
    Statistical analyses: Panel A: 1
    Comparison groups
    Panel A: Esketamine 28 mg v Panel A: Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.021
    Method
    ANCOVA
    Parameter type
    Mean Difference
    Point estimate
    -4.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -7.67
         upper limit
    -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.09
    Statistical analysis title
    Statistical analyses: Panel A: 2
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 56mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    Mean Difference
    Point estimate
    -6.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -9.71
         upper limit
    -2.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.07
    Statistical analysis title
    Statistical analyses: Panel A: 3
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 84mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean Difference
    Point estimate
    -9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -12.53
         upper limit
    -5.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13
    Statistical analysis title
    Statistical analyses: Panel B: 1
    Comparison groups
    Panel B: Placebo v Panel B: Esketamine 14mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Consistency
    Point estimate
    -10.5
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -29.27
         upper limit
    8.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.72
    Statistical analysis title
    Statistical analyses: Panel B: 2
    Comparison groups
    Panel B: Esketamine 56 mg v Panel B: Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Consistency
    Point estimate
    1.8
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -21.42
         upper limit
    24.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.49

    Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

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    End point title
    Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)
    End point description
    Sustained response was defined as at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.
    End point type
    Secondary
    End point timeframe
    Day 2 to Day 15
    End point values
    Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    8
    11
    12
    11
    9
    Units: participants
    1
    1
    3
    2
    2
    No statistical analyses for this end point

    Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

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    End point title
    Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit
    End point description
    A subject was defined as a responder at a given timepoint if the percentage improvement from baseline (ie, reduction from baseline) in the subject’s MADRS total score was greater than or equal to (> =) 50 %. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: Participants
    number (not applicable)
        Period 1 Day 1 DB: 2 h (n=33,11,11,12,21,11,9)
    6
    6
    4
    7
    7
    4
    4
        Period 1 Day 2 DB (n=33,11,11,12,21,11,9)
    1
    4
    3
    5
    6
    4
    4
        Period 1 Day 8 DB (n=33,11,11,12,21,11,9)
    2
    1
    2
    5
    5
    2
    2
        Period 2 Day 1 DB: 2 h (n=6,8,9,5,5,5,3)
    1
    1
    2
    2
    0
    3
    0
        Period 2 Day 2 DB (n=6,8,9,5,5,5,3)
    0
    0
    1
    2
    0
    4
    0
        Period 2 Day 8 DB (n=6,8,9,5,5,5,3)
    0
    1
    0
    1
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

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    End point title
    Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit
    End point description
    A subject was defined as a remitter at a given timepoint if the subject’s MADRS total score was less than or equal to 10. Here 'n' signifies the number of participants evaluated at this time point. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: participants
    number (not applicable)
        Period 1 Day 1 DB: 2 h (n=33,11,11,12,21,11,9)
    1
    3
    2
    2
    4
    4
    3
        Period 1 Day 2 DB (n=33,11,11,12,21,11,9)
    0
    4
    2
    3
    4
    3
    3
        Period 1 Day 8 DB (n=33,11,11,12,21,11,9)
    1
    1
    1
    3
    3
    2
    2
        Period 2 Day 1 DB: 2 h (n=6,8,9,5,5,5,3)
    1
    1
    0
    2
    0
    3
    0
        Period 2 Day 2 DB (n=6,8,9,5,5,5,3)
    0
    0
    0
    1
    0
    4
    0
        Period 2 Day 8 DB (n=6,8,9,5,5,5,3)
    0
    1
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

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    End point title
    Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )
    End point description
    The QIDS-SR16 is a patient reported measure designed to assess the severity of depressive symptoms. The QIDS-SR16 assesses all the criterion symptom domains designated by the DSM-IV to diagnose a major depressive episode. This assessment can be used to screen for depression, although it has been used predominantly as a measure of symptom severity. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: participants
    least squares mean (standard error)
        DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)
    -1.8 ± 0.93
    -4 ± 1.43
    -4.4 ± 1.43
    -4.2 ± 1.39
    -1.1 ± 0.78
    -0.6 ± 1.1
    -3 ± 1.2
        DB: Period 2 (n=6, 8, 9, 5, 5, 5, 3)
    -2 ± 1.5
    -3.1 ± 1.35
    -2 ± 1.41
    -3.3 ± 1.48
    -2.1 ± 1.78
    -5.7 ± 1.78
    -1.5 ± 2.31
    Statistical analysis title
    Statistical analyses_Panel A_1
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 28 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.069 [1]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - One sided P-value
    Statistical analysis title
    Statistical analyses_Panel A_3
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 84mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046 [2]
    Method
    ANCOVA
    Confidence interval
    Notes
    [2] - One sided P-value
    Statistical analysis title
    Statistical analyses_Panel A_2
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 56mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.096 [3]
    Method
    ANCOVA
    Confidence interval
    Notes
    [3] - One sided P-value

    Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

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    End point title
    Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale
    End point description
    The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill participants". Higher scores indicate worsening. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: participants
    median (full range (min-max))
        DB: Period 1 (n=33,11,11,12,21,11,9)
    5 (1 to 6)
    4 (3 to 5)
    4 (1 to 5)
    4 (1 to 6)
    4 (1 to 6)
    4 (2 to 6)
    3 (3 to 6)
        DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)
    5 (4 to 5)
    4 (3 to 5)
    5 (4 to 6)
    4 (3 to 5)
    4 (3 to 6)
    3 (3 to 4)
    4 (4 to 5)
    Statistical analysis title
    Statistical analyses_Panel A_1
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 28 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical analyses_Panel A_2
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 56mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical analyses_Panel A_3
    Comparison groups
    Panel A: Placebo v Panel A: Esketamine 84mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    ANCOVA
    Confidence interval

    Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

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    End point title
    Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale
    End point description
    The PGI-S is a 4-point scale that requires the participant to rate the severity of their illness at the time of assessment, relative to the participant's past experience. Considering their total experience, the patient assesses the severity of their depression illness at the time of rating as none, mild, moderate, or severe. Paper and pen format will be used for this study. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: participants
    median (full range (min-max))
        DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)
    3 (2 to 4)
    3 (1 to 4)
    3 (1 to 3)
    3 (1 to 4)
    3 (2 to 4)
    3 (1 to 3)
    3 (2 to 3)
        DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)
    3 (2 to 4)
    3 (2 to 4)
    4 (2 to 4)
    3 (2 to 4)
    3 (2 to 3)
    3 (2 to 3)
    3 (2 to 4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

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    End point title
    Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale
    End point description
    The GAD-7 is a 7-item self-report assessment of severity of anxiety. Each item is scored on a 4-point scale (0-3), with a total score range of 0-30. The standard recall period used is 2 weeks, but in the current study we plan to use a 7-day recall. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    Panel A: Placebo Panel A: Esketamine 28 mg Panel A: Esketamine 56mg Panel A: Esketamine 84mg Panel B: Placebo Panel B: Esketamine 14mg Panel B: Esketamine 56 mg
    Number of subjects analysed
    33
    11
    11
    12
    21
    11
    9
    Units: participants
    least squares mean (standard error)
        DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)
    -1.7 ± 0.88
    -1.5 ± 1.34
    -3.1 ± 1.34
    -5.1 ± 1.3
    -1.7 ± 0.68
    -1.9 ± 0.94
    -3.2 ± 1.03
        DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)
    0.4 ± 1.02
    -1.6 ± 0.87
    1 ± 0.98
    -0.9 ± 1.02
    -2.7 ± 1.68
    -6.6 ± 1.68
    -0.7 ± 2.27
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to follow-up phase (8 weeks after last dose of drug administration)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo/Placebo
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and responders [Quick Inventory of Depressive Symptomatology – 16-item Self Report {QIDS-SR16} total score less than 11]) were self-administered with Placebo on Day 8 and 11; non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to [>=] 11) on Day 8 were re-randomized to intranasal placebo or esketamine on Days 8 and 11 during the doubleblind phase.

    Reporting group title
    Placebo
    Reporting group description
    Participants in Panel A and B were self-administered intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants received intranasal placebo on Days 8 and 11 or were re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.

    Reporting group title
    Placebo/Esketamine 14 mg
    Reporting group description
    Participants in Panel B (who received placebo on Day 1 and 4 and non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to (>=) 11) on Day 8) were self-administered intranasal esketamine 14 mg on Days 8, and 11 during the double-blind phase and continued in the open label treatment phase for up to 2 weeks (Days 15, 18, 22, and 25). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

    Reporting group title
    Placebo/Esketamine 28 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 28 mg on Days 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks (Days 15, 18, 22, 25, 32, 39, 46, 60, and 74). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

    Reporting group title
    Placebo/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 56 mg on Day 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks in Panel A and up to 2 weeks in Panel B. The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

    Reporting group title
    Placebo/Esketamine 84 mg
    Reporting group description
    Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 84 mg on Days 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks (Days 15, 18, 22, 25, 32, 39, 46, 60, and 74). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

    Reporting group title
    Esketamine 28 mg/Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

    Reporting group title
    Esketamine 28 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

    Reporting group title
    Esketamine 14 mg/Esketamine 14 mg
    Reporting group description
    Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, and 25 during the optional open-label phase. During the optional open-label phase, participants were started with treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

    Reporting group title
    Esketamine 84 mg/Esketamine 84 mg
    Reporting group description
    Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine for up to 9 weeks. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

    Reporting group title
    Esketamine 56 mg/Esketamine 56 mg
    Reporting group description
    Participants in Panel A and B were self-administered intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine for up to 9 weeks in Panel A and for up to 2 weeks in Panel B. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

    Serious adverse events
    Placebo/Placebo Placebo Placebo/Esketamine 14 mg Placebo/Esketamine 28 mg Placebo/Esketamine 56 mg Placebo/Esketamine 84 mg Esketamine 28 mg/Esketamine 28 mg Esketamine 28 mg Esketamine 14 mg/Esketamine 14 mg Esketamine 84 mg/Esketamine 84 mg Esketamine 56 mg/Esketamine 56 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo/Placebo Placebo Placebo/Esketamine 14 mg Placebo/Esketamine 28 mg Placebo/Esketamine 56 mg Placebo/Esketamine 84 mg Esketamine 28 mg/Esketamine 28 mg Esketamine 28 mg Esketamine 14 mg/Esketamine 14 mg Esketamine 84 mg/Esketamine 84 mg Esketamine 56 mg/Esketamine 56 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 23 (65.22%)
    1 / 1 (100.00%)
    5 / 5 (100.00%)
    4 / 8 (50.00%)
    11 / 12 (91.67%)
    5 / 5 (100.00%)
    6 / 8 (75.00%)
    2 / 3 (66.67%)
    8 / 11 (72.73%)
    10 / 12 (83.33%)
    18 / 20 (90.00%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    7
    0
    0
    0
    1
    4
    4
    Peripheral Coldness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Energy Increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Feeling Abnormal
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
    4 / 20 (20.00%)
         occurrences all number
    2
    0
    6
    0
    0
    0
    2
    0
    8
    10
    12
    Feeling Drunk
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Feeling Hot
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Feeling Jittery
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Gait Disturbance
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hangover
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Injection Site Haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Product Taste Abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Sluggishness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Thirst
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Confusional State
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Daydreaming
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dissociation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 1 (100.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    4 / 12 (33.33%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    3 / 12 (25.00%)
    6 / 20 (30.00%)
         occurrences all number
    0
    1
    1
    0
    5
    2
    0
    0
    0
    7
    18
    Dissociative Disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    3 / 12 (25.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    1
    0
    8
    3
    Dysphoria
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Fear
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hallucination, Visual
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    0
    0
    2
    Illusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Merycism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Somatic Hallucination
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Suspiciousness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Thinking Abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Scratch
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Skin Abrasion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Investigations
    Blood Pressure Diastolic Increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Blood Pressure Increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    4
    0
    0
    1
    0
    0
    0
    0
    5
    Blood Pressure Systolic Increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Oxygen Saturation Decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dry Throat
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperventilation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nasal Congestion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    2
    0
    Nasal Discomfort
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    3
    0
    0
    0
    0
    1
    1
    Nasal Dryness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    3
    0
    Nasal Mucosal Disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Nasal Obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nasal Oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nasal Pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    1
    1
    0
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    0
    2
    1
    2
    Pharyngeal Disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Pharyngeal Hypoaesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Throat Irritation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    1
    0
    0
    10
    0
    Upper-Airway Cough Syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    1
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Altered State of Consciousness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Coordination Abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Disturbance in Attention
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 8 (0.00%)
    4 / 12 (33.33%)
    3 / 5 (60.00%)
    4 / 8 (50.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    5 / 12 (41.67%)
    7 / 20 (35.00%)
         occurrences all number
    0
    0
    3
    0
    6
    6
    16
    0
    2
    11
    25
    Dizziness Postural
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    6 / 23 (26.09%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    3 / 5 (60.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 12 (25.00%)
    4 / 20 (20.00%)
         occurrences all number
    13
    0
    2
    2
    4
    6
    4
    0
    4
    8
    13
    Dysgraphia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    Dyskinesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    3 / 12 (25.00%)
    1 / 5 (20.00%)
    3 / 8 (37.50%)
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    2 / 12 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    8
    0
    0
    2
    4
    1
    4
    1
    5
    2
    5
    Hypersomnia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
    4 / 20 (20.00%)
         occurrences all number
    2
    0
    1
    0
    1
    0
    1
    0
    4
    1
    15
    Loss of Consciousness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Mental Impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Sedation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    6
    Slow Speech
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    7 / 23 (30.43%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    12
    0
    2
    0
    3
    0
    2
    0
    3
    0
    9
    Syncope
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Tunnel Vision
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    7
    0
    Visual Field Defect
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    Eye disorders
    Accommodation Disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Conjunctival Hyperaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vision Blurred
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    1
    2
    0
    Visual Impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Ear and labyrinth disorders
    Ear Congestion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    1
    1
    0
    4
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hypoaesthesia Oral
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    1 / 5 (20.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    1
    0
    0
    3
    8
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    2 / 5 (40.00%)
    2 / 8 (25.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    3 / 12 (25.00%)
    6 / 20 (30.00%)
         occurrences all number
    8
    0
    1
    0
    2
    2
    3
    0
    2
    3
    9
    Oral Discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Paraesthesia Oral
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    4
    Salivary Hypersecretion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Renal and urinary disorders
    Bladder Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Micturition Urgency
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Scab
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Limb Discomfort
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Muscle Tightness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Myalgia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pain in Extremity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2013
    The purpose of this Amendment was: A new panel (Panel B) was added to evaluate the efficacy of intranasal esketamine in Japanese subjects with treatment-resistant depression (TRD); Text was added to indicate that review of the number of re-randomized and drop-out subjects at the end of Period 1 was a blinded Interactive Web Response System (IWRS) review; Clinical Global Assessment of Alertness was added to the safety evaluations to further assess the subject’s level of alertness after dosing; Nasal tolerability questionnaire and Clinical Global Assessment of Alertness were added into the recommended order of assessments; Text revised to indicate that clinical assessment of major depressive disorder (MDD) used diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders (4th edition), text revised (DSM-IV-TR) instead of Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5); Risk language used to describe enrollment criteria and prohibitions and restrictions was revised; Lower end of the age range was revised from 18 to 20 years of age to align Panels A and B; Rhinoplasty was added to the list of excluded anatomical or medical conditions in the exclusion criteria; Additional clarification and guidance for study procedures provided (eg, information regarding staff and equipment requirements for dosing, frequency of pulse oximetry monitoring, duration and recording of prestudy and concomitant therapies, study diary procedures, reasons for withdrawal, requirements for early termination visit, dose adjustment in open-label treatment phase, statistical analysis methods for safety data, prohibited therapies, tympanic temperature, completion of the MGH-ATRQ).
    04 Mar 2014
    The purpose of this Amendment was: Duration of the optional open-label treatment phase for Panel A was extended to allow exploration of the efficacy and safety of intranasal esketamine when the frequency of administration was tapered from twice per week to once per week to once every other week; Safety evaluation (ie, BPIC-SS assessment) was added to monitor subjects for symptoms of cystitis; Timing of the clinical laboratory tests was modified to ensure tests were performed over the extended duration of the open-label treatment phase; Text revised to specify that pharmacogenomic evaluations were only to be used for research releated to esketamine; Potential interim PK/PD analysis was added for Panel A; The PHQ-9 was added to the efficacy measures to provide data on this assessment in the event it is used as the self-report depression rating scale in further studies of intranasal esketamine in subjects with TRD; Text added to specify how the sleep and appetite items of the modified MADRS were to be handled; Respiratory rate was added to the list of vital sign assessments on all dosing days; Exclusion criteria were revised: to exclude subjects with a current or prior diagnosis of post-traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD), to permit enrollment of subjects with signs and symptoms of rhinitis, to add a criterion that defined clinically significant ECG abnormalities that were exclusionary, to exclude subjects with a history or current symptoms of fibromyalgia, and to clarify timing of procedures related to exclusion criteria; Time and Events Schedule was revised: to add evaluation of potential withdrawal symptoms following last dose of study medication in the open-label treatment phase, to add a PK sample on Days 1 and 11, to include a definition of postdose, and to specify collection of past psychiatric and family psychiatric history.
    28 Apr 2014
    The purpose of this Amendment was to included the following changes; Objective cognitive assessments (Cogstate® computerized test battery and HVLT-R) were added to formally assess cognition in Panel A subjects receiving esketamine during the open-label treatment phase; Additional BPIC-SS assessment and urinalysis were added on Day 46 for Panel A; Prohibitions and restrictions of prestudy and concomitant therapies were revised to avoid potential impact of certain therapies on cognitive and/or efficacy assessments.

    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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