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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Subjects Assessed to be at Imminent Risk for Suicide

    Summary
    EudraCT number
    2016-003990-17
    Trial protocol
    SK   DE   HU   ES   BG  
    Global end of trial date
    18 Dec 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54135419SUI3001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03039192
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 US Route 202, Raritan,, United States, NJ 08869-0602
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, 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
    18 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of major depressive disorder (MDD), including suicidal ideation, in subjects who are assessed to be at imminent risk for suicide, as measured by the change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) total score at 24 hours post first dose.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety was evaluated based on the following variables: Adverse events, Clinical laboratory tests (hematology, serum chemistry, and urinalysis), Vital sign measurements, Physical examinations, electrocardiogram (ECG), Nasal examinations, Suicide Ideation and Behavior Assessment Tool (SIBAT), Dosing day assessments (pulse oximetry, MOAA/S, CADSS).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Malaysia: 16
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    South Africa: 15
    Worldwide total number of subjects
    226
    EEA total number of subjects
    101
    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)
    226
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 226 subjects were enrolled and treated. Of the 226 subjects, 114 enrolled in the esketamine nasal spray 84 mg + standard of care (SOC) antidepressant treatment group and 112 enrolled in the placebo nasal spray + SOC antidepressant treatment group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Plus SOC Antidepressant treatment
    Arm description
    Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects self-administered placebo intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25).

    Arm title
    Esketamine 84 mg Plus SOC Antidepressant Treatment
    Arm description
    Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    JNJ-54135419
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25)

    Number of subjects in period 1
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Started
    112
    114
    Treated
    112
    113
    Completed
    80
    84
    Not completed
    32
    30
         Subject discontinued from treatment phase
    19
    11
         Randomized, not treated
    -
    1
         Other
    3
    2
         Withdrawal by subject
    6
    9
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    -
    2
         Lost to follow-up
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Plus SOC Antidepressant treatment
    Reporting group description
    Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.

    Reporting group title
    Esketamine 84 mg Plus SOC Antidepressant Treatment
    Reporting group description
    Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1.

    Reporting group values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment Total
    Number of subjects
    112 114 226
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    112 114 226
        From 65 to 84 years
    0 0 0
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    37.9 ± 12.54 40.8 ± 13.11 -
    Title for Gender
    Units: subjects
        Female
    73 66 139
        Male
    39 48 87

    End points

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    End points reporting groups
    Reporting group title
    Placebo Plus SOC Antidepressant treatment
    Reporting group description
    Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.

    Reporting group title
    Esketamine 84 mg Plus SOC Antidepressant Treatment
    Reporting group description
    Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1.

    Primary: Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at 24 hours after the first dose (Day 2) During Double-blind Phase

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    End point title
    Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at 24 hours after the first dose (Day 2) During Double-blind Phase
    End point description
    MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a postbaseline evaluation for the MADRS total score or Clinical Global Impression –Severity of Suicidality - Revised (CGI-SS-R). Here, N (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1, predose) and 24 hours first post dose (Day 2)
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    111
    Units: Unit on a scale
        arithmetic mean (standard deviation)
    -12.8 ± 10.73
    -16.4 ± 11.95
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo Plus SOC Antidepressant treatment v Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.006
    Method
    ANCOVA
    Parameter type
    Difference of Least Square Means
    Point estimate
    -3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.56
         upper limit
    -1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39

    Secondary: Change From Baseline in Clinical Global Impression of Severity of Suicidality- Revised (CGI-SS-R) Score at 24 hours after the first dose (Day 2) During Double-blind Phase

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    End point title
    Change From Baseline in Clinical Global Impression of Severity of Suicidality- Revised (CGI-SS-R) Score at 24 hours after the first dose (Day 2) During Double-blind Phase
    End point description
    CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects) a higher score indicates a more severe condition and a reduction in score indicates improvement (that is, lower severity of suicidality). Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a postbaseline evaluation for the MADRS total score or CGI-SS-R. Here, N (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, predose) and 24 hours first post dose (Day 2)
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    111
    Units: Unit on a scale
        median (full range (min-max))
    -1.0 (-5 to 1)
    -1.0 (-6 to 2)
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase

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    End point title
    Number of Subjects Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase
    End point description
    Subjects who had a MADRS total score of <=12 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R.
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 4, 8, 11, 15, 18, 22 and Day 25 (predose and 4 hours postdose)
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Subjects
        Day 1:(4 Hours)
    9
    12
        Day 2:
    10
    21
        Day 4
    13
    28
        Day 8
    23
    30
        Day 11
    26
    33
        Day 15
    29
    38
        Day 18
    30
    42
        Day 22
    25
    41
        Day 25 (Predose)
    38
    46
        Day 25 (4 hours postdose)
    42
    60
    No statistical analyses for this end point

    Secondary: Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score During Double-blind Phase

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    End point title
    Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score During Double-blind Phase
    End point description
    MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4 hours postdose)
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Unit on a Scale
    arithmetic mean (standard deviation)
        Day 1 (n=112,110)
    -10.9 ± 9.69
    -13.5 ± 10.89
        Day 2 (n=111, 111)
    -12.9 ± 10.72
    -16.4 ± 11.95
        Day 4 (n=110, 109)
    -14.5 ± 11.39
    -19.1 ± 12.29
        Day 8 (n=108, 104)
    -17.4 ± 12.59
    -19.7 ± 12.91
        Day 11(n=103, 100)
    -19.0 ± 12.08
    -21.8 ± 12.20
        Day 15 (n=99, 104)
    -20.4 ± 12.19
    -22.3 ± 11.70
        Day 18 (n=94, 102)
    -21.4 ± 12.00
    -23.9 ± 11.77
        Day 22 (n=92, 103)
    -21.6 ± 12.32
    -24.0 ± 12.38
        Day 25: predose (n=92, 94)
    -23.0 ± 12.41
    -24.8 ± 13.63
        Day 25: 4 hours postdose (n=88, 94)
    -25.8 ± 10.94
    -29.5 ± 10.89
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) Through the Double-blind Phase

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    End point title
    Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) Through the Double-blind Phase
    End point description
    CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects). A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Unit on a scale
    median (full range (min-max))
        Day 1 (n=112,110)
    0.0 (-5 to 1)
    -1.0 (-6 to 1)
        Day 2 (n=112, 112)
    -1.0 (-5 to 1)
    -1.0 (-6 to 2)
        Day 4 (n=110, 110)
    -1.0 (-5 to 1)
    -2.0 (-6 to 2)
        Day 8 (n=108, 105)
    -2.0 (-5 to 0)
    -2.0 (-6 to 1)
        Day 11 (n=102,101)
    -2.0 (-5 to 1)
    -3.0 (-6 to 1)
        Day 15 (n=99, 105)
    -2.0 (-5 to 0)
    -3.0 (-5 to 0)
        Day 18 (n=94, 103)
    -2.5 (-5 to 0)
    -3.0 (-6 to 1)
        Day 22 (n=91, 105)
    -3.0 (-5 to 1)
    -3.0 (-6 to 1)
        Day 25 (n=93, 96)
    -3.0 (-5 to 1)
    -3.0 (-6 to 1)
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Total score Through Double-blind Phase

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    End point title
    Number of Subjects Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Total score Through Double-blind Phase
    End point description
    CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects). A higher score indicates a more severe condition. Negative change in score indicates improvement. A subject was considered to achieve resolution of suicidality at a given time point if the CGI-SS-R score was 0 (normal, not at all suicidal) or 1 (questionably suicidal). Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R.
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Subjects
        Day 1
    25
    37
        Day 2
    39
    42
        Day 4
    45
    49
        Day 8
    48
    53
        Day 11
    46
    60
        Day 15
    52
    68
        Day 18
    55
    68
        Day 22
    62
    70
        Day 25
    57
    71
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score Through Double-blind Phase

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    End point title
    Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score Through Double-blind Phase
    End point description
    The CGI-SR-I is a scale summarizing the clinician’s best assessment of the likelihood that the subject will attempt suicide in the next 7 days. The CGI-SR-I rating is scored on a 7-point scale from 0 (no imminent suicide risk) to 6 (extreme imminent suicide risk). Score ranges from 0-6. A higher score indicates a more severe condition. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    median (full range (min-max))
        Day 1 (n=112,110)
    0.0 (-4 to 2)
    -1.0 (-5 to 3)
        Day 2 (n= 112, 112)
    -1.0 (-5 to 2)
    -1.0 (-5 to 2)
        Day 4 (n=110, 110)
    -1.0 (-5 to 2)
    -2.0 (-5 to 2)
        Day 8 (n=108, 105)
    -2.0 (-5 to 2)
    -2.0 (-6 to 1)
        Day 11 (n=102,101)
    -2.0 (-5 to 1)
    -2.0 (-6 to 1)
        Day 15 (n=99, 105)
    -2.0 (-5 to 2)
    -3.0 (-5 to 2)
        Day 18 (n=94, 103)
    -3.0 (-5 to 1)
    -3.0 (-5 to 2)
        Day 22 (n=91,105)
    -3.0 (-5 to 1)
    -3.0 (-6 to 1)
        Day 25 (n=93, 96)
    -3.0 (-5 to 2)
    -3.0 (-6 to 1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Day 8 and 25 During Double-blind Phase

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    End point title
    Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Day 8 and 25 During Double-blind Phase
    End point description
    BHS is a self-reported measure consists of 20 true-false items. 9 are keyed false and 11 are keyed true. These items fall within 3 domains: feelings about the future; loss of motivation; future expectations. For every statement, each response was assigned a score of 0 or 1. Total score is a sum of item responses. Ranges from 0-20. Total scores 0-3 are normal range, 4-8 identify mild hopelessness, 9-14 identify moderate hopelessness, greater than 14 identify severe hopelessness. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Day 8 (n=108, 111)
    -4.4 ± 6.03
    -5.3 ± 6.06
        Day 25 (n=98, 105)
    -6.6 ± 6.63
    -6.9 ± 6.92
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Health Status Index

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    End point title
    Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Health Status Index
    End point description
    EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, Level 5-extreme problems). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health), a lower score indicates worse health. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 2, 11 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Day 2 (n=110, 111)
    0.096 ± 0.1785
    0.156 ± 0.1944
        Day 11 (n=107, 106)
    0.169 ± 0.2139
    0.206 ± 0.2043
        Day 25 (n=97, 104)
    0.189 ± 0.2336
    0.227 ± 0.2078
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: EQ-VAS

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    End point title
    Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: EQ-VAS
    End point description
    EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). EQ-VAS score from 0 (worst health) to 100 (best health), positive change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Day 2 (n=110, 111)
    7.8 ± 17.32
    13.5 ± 20.78
        Day 11 (n=107, 106)
    16.3 ± 22.27
    17.9 ± 24.55
        Day 25 (n=97, 104)
    20.0 ± 23.49
    21.4 ± 26.71
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Sum Score

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    End point title
    Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Sum Score
    End point description
    EQ-5D-5L measures health outcome. It consists of EQ-5D-5L system and EQ-VAS. EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). Sum score=(sum of the scores from the 5 dimensions minus 5)*5”. Higher score indicates a more severe problem. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Day 2 (n= 110, 111)
    -6.1 ± 12.28
    -11.2 ± 14.87
        Day 11 (n= 107, 106)
    -12.3 ± 16.23
    -15.2 ± 15.75
        Day 25 (n= 97, 104)
    -13.4 ± 18.05
    -16.8 ± 16.30
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score Through Double-blind Phase

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    End point title
    Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score Through Double-blind Phase
    End point description
    The QLDS is a disease specific patient-reported outcome designed to assess health related quality of life in subjects with major depressive disorder (MDD). The instrument has a recall period of "at the moment", contains 34-items with "yes"/"no" or “true”/“not true” response options and takes approximately 5-10 minutes to complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Negative change indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 2, 11 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Day 2 (n=110, 112)
    -2.5 ± 4.55
    -3.1 ± 5.14
        Day 11 (n=107, 106)
    -4.4 ± 5.93
    -5.6 ± 5.92
        Day 25 (n= 97, 104)
    -5.6 ± 5.99
    -6.8 ± 5.97
    No statistical analyses for this end point

    Secondary: Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score Through Double-blind Phase

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    End point title
    Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score Through Double-blind Phase
    End point description
    The TSQM-9 is a 9-item generic patient-reported outcome instrument to assess subject’s satisfaction with medication. It covers three domains (effectiveness, convenience, and global satisfaction) were each scored from 0 to 100 with a higher score indicating higher satisfaction and a lower score indicates lower satisfaction. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Days 15 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Effectiveness: Day 15 (n=105, 108)
    51.7 ± 25.74
    63.5 ± 23.72
        Effectiveness: Day 25 (n=96, 102)
    57.6 ± 24.66
    65.8 ± 25.23
        Convenience: Day 15 (n=105, 108)
    70.9 ± 19.57
    70.5 ± 20.75
        Convenience: Day 25 (n=96, 102)
    74.0 ± 19.38
    71.3 ± 19.69
        Global Satisfaction: Day 15 (n=105, 108)
    52.2 ± 28.57
    64.5 ± 24.62
        Global Satisfaction: Day 25 (n=96, 102)
    55.7 ± 27.44
    68.5 ± 25.51
    No statistical analyses for this end point

    Secondary: Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score Through Double-blind Phase

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    End point title
    Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score Through Double-blind Phase
    End point description
    SIBAT Module 5 (My Risk) Question 3, Assessment of Frequency of Suicidal Thinking (FoST), asks patients to describe their thinking about suicide right now. There are 5 response options ranging from “I have no suicidal thoughts” to “I have suicidal thoughts all of the time” and ranges from 0 to 4. A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    median (full range (min-max))
        Day 1 (n=111, 110)
    0.0 (-4 to 2)
    0.0 (-3 to 1)
        Day 2 (n=111, 110)
    -1.0 (-4 to 1)
    -1.0 (-4 to 2)
        Day 4 (n=110, 108)
    -1.0 (-4 to 2)
    -1.0 (-4 to 1)
        Day 8 (n=108, 104)
    -1.0 (-4 to 1)
    -1.0 (-4 to 1)
        Day 11 (n=103, 100)
    -1.0 (-4 to 1)
    -1.5 (-4 to 1)
        Day 15 (n=100, 104)
    -1.0 (-4 to 1)
    -2.0 (-4 to 1)
        Day 18 (n=94, 101)
    -2.0 (-4 to 1)
    -2.0 (-4 to 1)
        Day 22 (n= 92, 104)
    -2.0 (-4 to 2)
    -2.0 (-4 to 1)
        Day 25 (n=93, 96)
    -2.0 (-4 to 1)
    -2.0 (-4 to 1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 – Clinician-rated FoST Total Score During Double-blind Phase

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    End point title
    Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 – Clinician-rated FoST Total Score During Double-blind Phase
    End point description
    SIBAT Module 7 Assessment of frequency of suicidal thinking (FoST) is a clinician-reported global impression with response options of “Never”, “Rarely”, “Sometimes”, “Often”, “Most of the time”, and “All of the time.” The score ranges from 0 to 5. A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    Placebo Plus SOC Antidepressant treatment Esketamine 84 mg Plus SOC Antidepressant Treatment
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    median (full range (min-max))
        Day 1 (n=112, 109)
    -1.0 (-5 to 2)
    -1.0 (-5 to 1)
        Day 2 (n=112, 111)
    -1.0 (-5 to 1)
    -1.0 (-5 to 1)
        Day 4 (n=110, 109)
    -1.0 (-5 to 1)
    -2.0 (-5 to 2)
        Day 8 (n=108, 104)
    -2.0 (-5 to 2)
    -2.0 (-5 to 1)
        Day 11 (n=102, 100)
    -2.0 (-5 to 2)
    -2.0 (-5 to 2)
        Day 15 (n=99, 104)
    -2.0 (-5 to 0)
    -2.0 (-5 to 1)
        Day 18 (n=94, 102)
    -2.0 (-5 to 1)
    -2.0 (-5 to 1)
        Day 22 (n=91, 104
    -2.0 (-5 to 1)
    -2.0 (-5 to 1)
        Day 25 (n=93, 95)
    -2.0 (-5 to 1)
    -3.0 (-5 to 1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 13 Weeks
    Adverse event reporting additional description
    Safety analysis set included all randomized subjects who received at least 1 dose of study agent in the double-blind treatment phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Esketamine 84 mg Plus SOC Antidepressant Treatment
    Reporting group description
    Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus SOC antidepressant treatment which was initiated on Day 1.

    Reporting group title
    Placebo Plus SOC Antidepressant treatment (Placebo)
    Reporting group description
    Subjects self-administered placebo intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus standard of care (SOC) antidepressant treatment which was initiated on Day 1.

    Serious adverse events
    Esketamine 84 mg Plus SOC Antidepressant Treatment Placebo Plus SOC Antidepressant treatment (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 113 (3.54%)
    6 / 112 (5.36%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression Suicidal
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Esketamine 84 mg Plus SOC Antidepressant Treatment Placebo Plus SOC Antidepressant treatment (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 113 (80.53%)
    66 / 112 (58.93%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    19 / 113 (16.81%)
    6 / 112 (5.36%)
         occurrences all number
    47
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    40 / 113 (35.40%)
    10 / 112 (8.93%)
         occurrences all number
    187
    19
    Dizziness Postural
         subjects affected / exposed
    6 / 113 (5.31%)
    2 / 112 (1.79%)
         occurrences all number
    24
    2
    Dysgeusia
         subjects affected / exposed
    16 / 113 (14.16%)
    11 / 112 (9.82%)
         occurrences all number
    89
    46
    Hypoaesthesia
         subjects affected / exposed
    8 / 113 (7.08%)
    2 / 112 (1.79%)
         occurrences all number
    42
    3
    Headache
         subjects affected / exposed
    21 / 113 (18.58%)
    20 / 112 (17.86%)
         occurrences all number
    29
    33
    Somnolence
         subjects affected / exposed
    21 / 113 (18.58%)
    11 / 112 (9.82%)
         occurrences all number
    79
    32
    Sedation
         subjects affected / exposed
    7 / 113 (6.19%)
    2 / 112 (1.79%)
         occurrences all number
    16
    2
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    10 / 113 (8.85%)
    5 / 112 (4.46%)
         occurrences all number
    18
    12
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 113 (6.19%)
    1 / 112 (0.89%)
         occurrences all number
    18
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 113 (6.19%)
    7 / 112 (6.25%)
         occurrences all number
    9
    7
    Dissociation
         subjects affected / exposed
    33 / 113 (29.20%)
    4 / 112 (3.57%)
         occurrences all number
    166
    9
    Anxiety
         subjects affected / exposed
    6 / 113 (5.31%)
    10 / 112 (8.93%)
         occurrences all number
    6
    13
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    15 / 113 (13.27%)
    5 / 112 (4.46%)
         occurrences all number
    15
    5
    Vomiting
         subjects affected / exposed
    8 / 113 (7.08%)
    7 / 112 (6.25%)
         occurrences all number
    9
    9
    Nausea
         subjects affected / exposed
    23 / 113 (20.35%)
    15 / 112 (13.39%)
         occurrences all number
    38
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2017
    The overall reason for the amendment was to revise based on comments received during an initial Voluntary Harmonisation Procedure (VHP) assessment; the following changes are included: Duration of hospitalization without the need for discussion with the Sponsor updated, A remote contact at Day 35 was added to the Time and Events Schedule, Exclusion criteria were revised to explicitly specify a detailed list of important medical conditions which are exclusionary, Text was added to emphasize that subjects may participate in the study only if they have adequate capacity to give consent and after fully understanding the potential risks, benefits, and potential adverse events of the study.
    20 Apr 2017
    The overall reason for the amendment was to update and/or clarify protocol content based on feedback received during study initiation activities. Exclusion criterion was revised to clarify which potential subjects are excluded from participation in the study due to substance or alcohol use disorder, a positive urine test result; to clarify that subjects who were previously enrolled in this study or the Sponsor’s other studies in this population (54135419SUI3002 and ESKETINSUI2001) are excluded from participation in this study.
    08 Feb 2018
    The overall reason for the amendment was to remove the interim analysis from the 54135419SUI3001 protocol; to clarify that Module 3 Suicide Ideation and Behavior Assessment Tool (SIBAT) was an exploratory objective; to modify the timing of screening procedures to be consistent with the Time and Events Schedule; to clarify which potential subjects were not excluded from participation in the 54135419SUI3001 study due to having a positive screening test for prescribed psychostimulants that are permitted during the study; and updated text regarding the presentation of nasal examination data.

    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.
    Esketamine has known effects that may impact blinding, these treatment-emergent events potentially could have biased research staff. To minimize this bias, protocol specified that different raters perform efficacy, safety assessments.
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