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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
    		 2016-003992-23
    Trial protocol
    		 BE   PL   CZ   AT   LT   FR   ES  
    Global end of trial date
    11 Apr 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Oct 2020
    First version publication date
    19 Apr 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    54135419SUI3002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03097133
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    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
    11 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the 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 were 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 evaluation included adverse events, clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital sign measurements (temperature, pulse/heart rate, respiratory rate, blood pressure [BP]), physical examinations, height, body weight, electrocardiograms (ECGs), pulse oximetry, and nasal examinations. Other safety evaluations included: Modified observer’s assessment of alertness/sedation (MOAA/S) to measure treatment-emergent sedation, clinician-administered dissociative states scale (CADSS) to assess dissociative symptoms, and the columbia classification algorithm for suicide assessment (C-CASA) to classify potentially suicide-related events based on responses to the suicide ideation and behavior assessment tool (SIBAT).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 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
    Argentina: 17
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 36
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    United States: 66
    Worldwide total number of subjects
    230
    EEA total number of subjects
    87
    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)
    230
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 230 subjects were randomly assigned to 1 of 2 treatment groups (esketamine and placebo) in a 1:1 ratio. Out of which 114 and 113 subjects received treatment in esketamine and placebo group respectively. Total 166 subjects completed the study.

    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 + Standard of Care (SOC)
    Arm description
    		 Subjects self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Subjects self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 in the double-blind treatment phase.

    Arm title
    		 Esketamine 84 mg + SOC
    Arm description
    		 Subjects self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 and continued for duration of DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a subject was unable to tolerate intranasal esketamine 84 mg dose. Subjects for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    JNJ-54135419
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Subjects self-administered esketamine 84 mg (1 spray containing esketamine 14 mg in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 in the double-blind treatment phase.

    Number of subjects in period 1
    		Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Started
    115
    115
    Treated
    113
    114
    Completed
    85
    81
    Not completed
    30
    34
         Consent withdrawn by subject
    2
    5
         Adverse event, non-fatal
    1
    -
         Unspecified
    3
    2
         Lost to follow-up
    3
    2
         Discontinued from DB phase, not entered FU Phase
    21
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Standard of Care (SOC)
    Reporting group description
    		 Subjects self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase.

    Reporting group title
    Esketamine 84 mg + SOC
    Reporting group description
    		 Subjects self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 and continued for duration of DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a subject was unable to tolerate intranasal esketamine 84 mg dose. Subjects for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase.

    Reporting group values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC Total
    Number of subjects
    		 115 115 230
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 115 115 230
        From 65 to 84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.3 ± 13.38 40.4 ± 12.75 -
    Title for Gender
    Units: subjects
        Female
    		 68 70 138
        Male
    		 47 45 92

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Standard of Care (SOC)
    Reporting group description
    		 Subjects self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase.

    Reporting group title
    Esketamine 84 mg + SOC
    Reporting group description
    		 Subjects self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 and continued for duration of DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a subject was unable to tolerate intranasal esketamine 84 mg dose. Subjects for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase.

    Primary: Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours Post First Dose (Last Observation Carried Forward [LOCF] Data): Double-blind (DB) Treatment Phase

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    End point title
    		 Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours Post First Dose (Last Observation Carried Forward [LOCF] Data): Double-blind (DB) Treatment Phase
    End point description
    MADRS is clinician-rated scale designed to used in subjects with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. It evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic and suicidal thoughts. Instrument consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms), for total possible score of 0 to 60. Higher scores represent 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 DB treatment phase and had both baseline and post baseline evaluation for 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 + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    113
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -12.4 ± 10.43
    -15.7 ± 11.56
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Standard of Care (SOC) v Esketamine 84 mg + SOC
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Difference (Diff.) of Least Square Means
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 -1.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39

    Secondary: Change From Baseline in Clinical Global Impression-Severity of Suicidality - revised Scale at 24 Hours Post First Dose (LOCF Data): DB Treatment Phase

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    End point title
    		 Change From Baseline in Clinical Global Impression-Severity of Suicidality - revised Scale at 24 Hours Post First Dose (LOCF Data): DB Treatment Phase
    End point description
    CGI-SS-R is revised version of the clinical global impression severity scale (CGI-S). The CGI-SS-R summarizes the clinician’s overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects), based on the totality of information available to the clinician. Analysis was performed on full efficacy analysis set. Negative change in score indicates improvement. 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 + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    113
    Units: Units on a scale
        median (full range (min-max))
    -1.0 (-5 to 2)
    -1.0 (-6 to 2)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Remission of Major Depressive Disorder (MADRS Less Than or Equal to [<=] 12): DB Treatment Phase

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    End point title
    		 Number of Subjects With Remission of Major Depressive Disorder (MADRS Less Than or Equal to [<=] 12): DB Treatment Phase
    End point description
    MADRS is clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. It evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic and suicidal thoughts. Scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms), summed for total possible score of 0 to 60. Higher scores represent more severe condition. Negative change in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Days 1 (4 hours [h] postdose), 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4h postdose)
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
        Day 1: 4 hours post dose
    4
    12
        Day 2
    12
    25
        Day 4
    20
    26
        Day 8
    23
    28
        Day 11
    26
    32
        Day 15
    29
    36
        Day 18
    32
    29
        Day 22
    37
    42
        Day 25: Predose
    31
    49
        Day 25: 4 hours postdose
    42
    54
    No statistical analyses for this end point

    Secondary: Change From Baseline in MADRS Total Score at 4 Hours Post First Dose on Day 1 and Up to the end of the DB Treatment Phase: DB Treatment Phase

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    End point title
    		 Change From Baseline in MADRS Total Score at 4 Hours Post First Dose on Day 1 and Up to the end of the DB Treatment Phase: DB Treatment Phase
    End point description
    MADRS is a clinician-rated scale designed to be used in subjects with MDD to measure depression severity and detect changes due to antidepressant treatment. MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The instrument 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 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Analysis was performed on full efficacy analysis set. Here ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, predose), Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4h postdose)
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 1: 4 hours postdose (n= 112, 112)
    -8.2 ± 7.62
    -12.2 ± 9.87
        Change at Day 2 (n= 111, 110)
    -12.4 ± 10.51
    -16.0 ± 11.52
        Change at Day 4 (n= 111, 107)
    -15.7 ± 11.50
    -17.7 ± 11.94
        Change at Day 8 (n= 105, 99)
    -17.4 ± 11.29
    -20.1 ± 11.47
        Change at Day 11 (n= 99, 95)
    -19.5 ± 11.60
    -21.3 ± 11.45
        Change at Day 15 (n= 99, 91)
    -20.0 ± 12.54
    -23.4 ± 10.62
        Change at Day 18 (n= 90, 84)
    -21.4 ± 12.90
    -23.1 ± 11.39
        Change at Day 22 (n= 94, 90)
    -22.0 ± 12.12
    -24.5 ± 11.57
        Change at Day 25: Predose (n= 88, 85)
    -22.5 ± 12.23
    -26.2 ± 11.09
        Change at Day 25: 4 hours postdose (n= 87, 83)
    -26.4 ± 11.18
    -28.7 ± 10.88
    No statistical analyses for this end point

    Secondary: Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose on Day 1 and up to the End of the DB Treatment Phase

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    End point title
    		 Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose on Day 1 and up to the End of the DB Treatment Phase
    End point description
    CGI-SS-R is revised version of the CGI-S. The CGI-SS-R summarizes the clinician’s overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects), based on the totality of information available to the clinician. 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 DB treatment phase and 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 evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, predose), Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    median (full range (min-max))
        Change at Day 1: 4 hours postdose (n= 112, 112)
    -1.0 (-4 to 1)
    -1.0 (-6 to 1)
        Change at Day 2 (n= 111, 108)
    -1.0 (-5 to 2)
    -1.0 (-6 to 2)
        Change at Day 4 (n= 111, 107)
    -2.0 (-5 to 2)
    -2.0 (-6 to 1)
        Change at Day 8 (n= 105, 99)
    -2.0 (-5 to 2)
    -2.0 (-5 to 2)
        Change at Day 11 (n= 99, 95)
    -2.0 (-6 to 2)
    -3.0 (-6 to 1)
        Change at Day 15 (n= 99, 91)
    -3.0 (-5 to 2)
    -3.0 (-6 to 0)
        Change at Day 18 (n= 90, 84)
    -3.0 (-6 to 1)
    -3.0 (-5 to 0)
        Change at Day 22 (n= 95, 90)
    -3.0 (-5 to 3)
    -3.0 (-5 to 0)
        Change at Day 25 (n= 88, 85)
    -3.0 (-6 to 4)
    -3.0 (-6 to 0)
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase

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    End point title
    		 Number of Subjects Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase
    End point description
    CGI-SS-R is revised version of the CGI-S. The CGI-SS-R summarizes the clinician’s overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects), based on the totality of information available to the clinician. A subject was considered to have achieved 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). Subjects who did not met such criterion or discontinued prior to the time point for any reason were not considered to have resolution of suicidality. Analysis was performed on full efficacy analysis set.
    End point type
    Secondary
    End point timeframe
    Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
        Day 1: 4 hours postdose
    20
    38
        Day 2
    35
    36
        Day 4
    51
    52
        Day 8
    54
    53
        Day 11
    58
    62
        Day 15
    58
    65
        Day 18
    59
    62
        Day 22
    65
    68
        Day 25
    66
    69
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at 4 Hours Post First Dose and up to the end of the DB Treatment Phase

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    End point title
    		 Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at 4 Hours Post First Dose and up to the end of the DB Treatment 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: where’ 0 (no imminent suicide risk); 1 (minimal imminent suicide risk), 2 (mild imminent suicide risk), 3 (moderate imminent suicide risk), 4 (marked imminent suicide risk), 5 (severely imminent suicide risk), 6 (extreme imminent suicide risk). Higher score indicates a more severe condition. Negative change in score indicates improvement. Analysis was performed on full efficacy analysis set. Here ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, predose), Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    median (full range (min-max))
        Change at Day 1: 4 hours postdose (n= 112, 112)
    0.0 (-4 to 2)
    -1.0 (-6 to 3)
        Change at Day 2 (n= 111, 108)
    -1.0 (-4 to 2)
    -1.0 (-6 to 2)
        Change at Day 4 (n= 111, 107)
    -2.0 (-5 to 2)
    -2.0 (-6 to 1)
        Change at Day 8 (n= 105, 98)
    -2.0 (-5 to 2)
    -2.0 (-5 to 2)
        Change at Day 11 (n= 99, 95)
    -2.0 (-5 to 1)
    -2.0 (-6 to 2)
        Change at Day 15 (n= 99, 91)
    -3.0 (-5 to 2)
    -2.0 (-6 to 1)
        Change at Day 18 (n= 90, 84)
    -3.0 (-5 to 2)
    -3.0 (-5 to 1)
        Change at Day 22 (n= 95, 90)
    -3.0 (-5 to 2)
    -3.0 (-5 to 0)
        Change at Day 25 (n= 88, 85)
    -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 in DB Treatment Phase

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    End point title
    		 Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Day 8 and 25 in DB Treatment Phase
    End point description
    BHS is a self-reported measure to assess one’s level of negative expectations or pessimism regarding future. It consists of 20 true-false items that examine respondent’s attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. For every statement, each response was assigned score of 0 or 1. Total BHS score is sum of item responses, ranged from 0-20, where higher score represented higher level of hopelessness. Analysis was performed on full efficacy analysis set. Here ‘N’ (number of subjects analyzed) signifies number of subjects evaluable for this endpoint and ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    112
    112
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 8 (n= 108, 104)
    -6.3 ± 6.31
    -6.1 ± 6.17
        Change at Day 25 (n= 96, 91)
    -7.0 ± 6.47
    -8.0 ± 6.31
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Sum Score up to the end of the DB Treatment Phase

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    End point title
    		 Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Sum Score up to the end of the DB Treatment Phase
    End point description
    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (no problem, slight, moderate, severe and extreme problems). Subject selects answer for each of 5 dimensions considering response that best matches his/her health "today”. Responses were used to generate Health Status Index (HSI). HSI ranges from 0-1.00 (dead-full health). EQ-VAS self-rating records respondent’s own assessment of his/her overall health status at time of completion, on a scale of 0 (worst imaginable health)-100 (best imaginable health). Sum score ranges from 0 -100. Higher score indicates worse health state. Analysis was performed on full efficacy analysis set. Here ‘N’ (number of subjects analyzed) = subjects evaluable for this endpoint and ‘n’ (number analyzed) = subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    112
    113
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 2 (n= 111, 107)
    -9.0 ± 12.30
    -11.8 ± 14.45
        Change at Day 11 (n= 103, 103)
    -15.1 ± 16.32
    -15.0 ± 15.51
        Change at Day 25 (n = 95, 92)
    -15.3 ± 15.78
    -18.8 ± 16.96
    No statistical analyses for this end point

    Secondary: Change From Baseline in EQ Visual Analogue Scale Score up to the end of the DB Treatment Phase

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    End point title
    		 Change From Baseline in EQ Visual Analogue Scale Score up to the end of the DB Treatment Phase
    End point description
    EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). Analysis was performed on full efficacy analysis set. Here ‘N’ (number of subjects analyzed) signifies number of subjects evaluable for this endpoint and ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    112
    113
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 2 (n = 111, 107)
    9.7 ± 15.57
    13.4 ± 22.58
        Change at Day 11 (n = 103, 103)
    17.6 ± 24.87
    21.4 ± 26.95
        Change at Day 25 (n = 95, 92)
    18.6 ± 25.39
    27.0 ± 27.54
    No statistical analyses for this end point

    Secondary: Change From Baseline in EQ-5D-5L Health Status Index up to the end of the DB Treatment Phase

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    End point title
    		 Change From Baseline in EQ-5D-5L Health Status Index up to the end of the DB Treatment Phase
    End point description
    EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Subject selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health). Analysis was performed on full efficacy analysis set. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 2 ( n = 111, 107)
    0.129 ± 0.1732
    0.160 ± 0.1872
        Change at Day 11 (n = 103, 103)
    0.194 ± 0.2173
    0.202 ± 0.2051
        Change at Day 25 (n = 95, 92)
    0.194 ± 0.2149
    0.235 ± 0.2228
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life in Depression Scale (QLDS) Score up to the end of the DB Treatment Phase

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    End point title
    		 Change From Baseline in Quality of Life in Depression Scale (QLDS) Score up to the end of the DB Treatment Phase
    End point description
    The QLDS is a disease-specific patient-reported outcome designed to assess health-related quality of life in patients with MDD, it captures the impact of depression and its treatment from the subject’s perspective. The instrument has a recall period of "at the moment" and contains 34 items with “true”/“not true” response options. 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. Analysis was performed on full efficacy analysis set. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 2, 11 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Day 2 (n = 111, 107)
    -2.5 ± 3.93
    -3.5 ± 4.93
        Change at Day 11 (n = 103, 103)
    -5.2 ± 5.55
    -5.1 ± 6.16
        Change at Day 25 (n = 95, 92)
    -5.5 ± 6.03
    -6.3 ± 6.26
    No statistical analyses for this end point

    Secondary: Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score: DB Treatment Phase

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    End point title
    		 Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score: DB Treatment Phase
    End point description
    The TSQM-9 is a 9-item generic patient-reported outcome instrument to assess subjects’ satisfaction with medication. It covers domains of effectiveness, convenience, and global satisfaction. The TSQM-9 domain scores were calculated as recommended by the instrument authors. (i) Effectiveness = [(item 1 + item 2 + item 3) - 3]/18*100, (ii) Convenience = [(item 4 + item 5 + item 6) - 3]/18*100 and (iii) Global satisfaction = [(item 7 + item 8 + item 9) - 3]/14*100. Each domain score can be calculated only if all the three items considered in the calculation of that score are not missing. The TSQM-9 domain scores range from 0 to 100, with higher scores representing higher satisfaction. Analysis was performed on full efficacy analysis. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point for each specified category.
    End point type
    Secondary
    End point timeframe
    Days 15 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Effectiveness: Day 15 (n= 97, 101)
    55.3 ± 27.93
    63.5 ± 26.05
        Effectiveness: Day 25 (n= 113, 90)
    54.8 ± 28.84
    68.8 ± 25.41
        Convenience: Day 15 (n= 113, 114)
    77.2 ± 16.73
    71.3 ± 18.38
        Convenience: Day 25 (n= 113, 90)
    76.9 ± 17.92
    77.0 ± 18.66
        Global Satisfaction: Day 15 (n= 113, 114)
    59.7 ± 27.12
    63.6 ± 27.69
        Global Satisfaction: Day 25 (n=113, 90)
    56.8 ± 28.31
    71.5 ± 24.85
    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 (Subject-Reported Frequency of Suicidal Thinking) Score: DB Treatment 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 (Subject-Reported Frequency of Suicidal Thinking) Score: DB Treatment Phase
    End point description
    SIBAT is an assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT is organized into 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Patient-reported section has modules of demographics and suicide history, risk/protective factors, suicidal thinking, suicide behavior, and suicide risk. Question 3 from Module 5 asks subjects to describe their thinking about suicide right now from 5 response options ranging from 0 (I have no suicidal thoughts) to 4 (I have suicidal thoughts all of time). Analysis was performed on full efficacy analysis set. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    median (full range (min-max))
        Change at Day 1: 4 hours (n= 111, 109)
    -1.0 (-3 to 1)
    -1.0 (-4 to 2)
        Change at Day 2 (n= 110, 106)
    -1.0 (-4 to 1)
    -1.0 (-4 to 2)
        Change at Day 4 (n= 109, 107)
    -1.0 (-4 to 1)
    -1.0 (-4 to 4)
        Change at Day 8 (n= 105, 98)
    -2.0 (-4 to 1)
    -2.0 (-4 to 4)
        Change at Day 11 (n= 97, 96)
    -2.0 (-4 to 1)
    -2.0 (-4 to 4)
        Change at Day 15 (n= 96, 87)
    -2.0 (-4 to 0)
    -2.0 (-4 to 1)
        Change at Day 18 (n= 89, 92)
    -2.0 (-4 to 1)
    -2.0 (-4 to 3)
        Change at Day 22 (n= 96, 83)
    -2.0 (-4 to 1)
    -2.0 (-4 to 3)
        Change at Day 25 (n= 88, 90)
    -2.0 (-4 to 1)
    -2.0 (-4 to 4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score: DB Treatment Phase

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    End point title
    		 Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score: DB Treatment Phase
    End point description
    SIBAT is assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT has 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Clinician-rated section has modules for semi-structured interview, clinical global impressions of current severity of suicidality and imminent suicide risk, clinical global impression of long-term suicide risk, and clinical judgment of optimal suicide management. Module 7-FoST score ranges from 0-5; higher score indicates more severe condition. Negative change in score indicates improvement. Analysis was performed on full efficacy analysis set. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1 (4h postdose), 2, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Units on a scale
    median (full range (min-max))
        Change at Day 1: 4 hours (n= 112, 112)
    -1.0 (-4 to 2)
    -1.0 (-5 to 1)
        Change at Day 2 (n= 111, 108)
    -1.0 (-5 to 1)
    -1.0 (-5 to 1)
        Change at Day 4 (n= 111, 107)
    -2.0 (-5 to 1)
    -2.0 (-5 to 1)
        Change at Day 8 (n= 105, 99)
    -2.0 (-4 to 1)
    -2.0 (-5 to 1)
        Change at Day 11 (n= 99, 95)
    -2.0 (-5 to 2)
    -2.0 (-5 to 1)
        Change at Day 15 (n= 99, 91)
    -2.0 (-5 to 2)
    -3.0 (-5 to 0)
        Change at Day 18 (n= 90, 84)
    -2.0 (-5 to 1)
    -3.0 (-5 to 1)
        Change at Day 22 (n= 95, 90)
    -2.0 (-5 to 2)
    -3.0 (-5 to 2)
        Change at Day 25 (n= 88, 85)
    -2.0 (-5 to 4)
    -3.0 (-5 to 2)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse events (TEAEs): DB Treatment Phase

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse events (TEAEs): DB Treatment Phase
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. A TEAE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to study agent. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
    87
    104
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinical Laboratory Abnormal Findings: DB Treatment Phase

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    End point title
    		 Number of Subjects With Clinical Laboratory Abnormal Findings: DB Treatment Phase
    End point description
    Low/high abnormal values are as follows:ALT-high=200 Units per liter(U/L); ALP-high=250U/L; aspartate aminotransferase(AST)-high=250U/L; gamma glutamyl transferase(GGT)=300U/L;Albumin(24-60 g/L); Bicarbonate(15.1-34.9 millimoles per liter [mmol/L]);Bilirubin(high=51.3micromol/L[mcm/L]);Calcium(1.5-3mmol/L);Chloride(94-112mmol/L); CK(high=990U/L);Creatinine(high=265.2 mcm/L); Eosinophils(high=10%);Erythrocytes(3.0*10^12/L-6.4*10^12/L);Glucose(2.2-16.7mmol/L); Hemoglobin(80-190g/L);Hematocrit(0.28-0.55 fraction);LD(high=500U/L);Leukocytes(2.5*10^9/L-15.5*10^9/L);Lymphocytes(10-60%);Monocytes(high=20%);Neutrophils(30-90%);Phosphate(0.7-2.6mmol/L);Platelet count(100*10^9/L-600*10^9/L];Potassium(3.0-5.8 mmol/L]; Protein(low=50 g/L);Sodium(125-155 mmol/L);Urate(89.2-594.8 mcm/L);Urine(high=8.0 pH).Analysis was done on safety analysis set. N’ (number of subjects analyzed) signifies number of subjects evaluable for this endpoint. ‘n’ (number analyzed)= subjects evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    101
    101
    Units: Subjects
        Alanine aminotransferase(ALT): ALT>3*ULN(n= 92,97)
    2
    2
        ALT: Abnormal High (n= 92, 97)
    0
    0
        Albumin: Abnormal High (n= 101, 101)
    0
    0
        Albumin: Abnormal Low (n= 101, 101)
    0
    0
        Alkaline phosphatase(ALP):Abnormal High(n=99,99)
    0
    0
        AST: AST>3*ULN (90, 97)
    0
    0
        AST: Abnormal High (90, 97)
    0
    0
        Bicarbonate: Abnormal High (n= 91, 96)
    0
    0
        Bicarbonate: Abnormal Low (n= 91, 96)
    0
    0
        Bilirubin: Abnormal High (n= 92, 97)
    0
    0
        Calcium: Abnormal High (n= 99, 99)
    0
    0
        Calcium: Abnormal Low (n= 99, 99)
    0
    0
        Chloride: Abnormal High (n= 99, 99)
    0
    0
        Chloride: Abnormal Low (n= 99, 99)
    0
    0
        Creatine Kinase (CK): Abnormal High (n= 92, 97)
    0
    0
        Creatinine: Abnormal High (n= 99, 99)
    0
    0
        GGT: Abnormal High (n= 99, 99)
    3
    1
        Glucose: Abnormal High (n= 92, 97)
    0
    1
        Glucose: Abnormal Low (n= 92, 97)
    0
    0
        ALT>3*ULN or AST>3*ULN and BILI>2*ULN (n= 92, 97)
    0
    0
        Lactate Dehydrogenase: Abnormal High (n= 86, 89)
    0
    0
        Phosphate: Abnormal High (n= 101, 101)
    0
    0
        Phosphate: Abnormal Low (n= 101, 101)
    0
    1
        Potassium: Abnormal High (n= 99, 99)
    1
    0
        Potassium: Abnormal Low (n= 99, 99)
    0
    0
        Protein: Abnormal Low (n= 99, 99)
    0
    0
        Sodium: Abnormal High (n= 99, 99)
    0
    0
        Sodium: Abnormal Low (n= 99, 99)
    0
    0
        Urate: Abnormal High (n= 99, 99)
    0
    0
        Urate: Abnormal Low (n= 99, 99)
    0
    0
        Basophils: Abnormal High (n= 87, 94)
    0
    0
        Eosinophils: Abnormal High (n= 87, 94)
    0
    0
        Erythrocytes: Abnormal High (n= 87, 94)
    0
    1
        Erythrocytes: Abnormal Low (n= 87, 94)
    0
    0
        Hematocrit: Abnormal High (n= 86, 92)
    0
    2
        Hematocrit: Abnormal Low (n= 86, 92)
    0
    0
        Hemoglobin (Hb): Abnormal High (n= 87, 94)
    0
    1
        Hemoglobin: Abnormal Low (n= 87, 94)
    0
    0
        Leukocytes: Abnormal High (n= 87, 94)
    1
    0
        Leukocytes: Abnormal Low (n= 87, 94)
    0
    0
        Lymphocytes: Abnormal High (n= 87, 94)
    0
    0
        Lymphocytes: Abnormal Low (n= 87, 94
    2
    1
        Monocytes: Abnormal High (n= 87, 94)
    0
    0
        Neutrophils: Abnormal High (n= 87, 94)
    0
    0
        Neutrophils: Abnormal Low (n= 87, 94)
    0
    1
        Platelets: Abnormal High (n= 87, 94)
    0
    0
        Platelets: Abnormal Low (n= 87, 94)
    0
    1
        Urine pH: Abnormal High (n= 96, 97)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Nasal Examinations at Day 25: DB Treatment Phase

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    End point title
    		 Number of Subjects With Abnormal Nasal Examinations at Day 25: DB Treatment Phase
    End point description
    Number of subjects with abnormal nasal examination were reported. Nasal examination of visual inspection of the nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis was performed. Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase. Here, ‘n’ (number analyzed) signifies number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    at Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    105
    104
    Units: Subjects
        Epistaxis: Mild
    1
    1
        Epistaxis: Moderate
    0
    0
        Epistaxis: Severe
    0
    0
        Nasal Crusts: Mild
    0
    1
        Nasal Crusts: Moderate
    0
    0
        Nasal Crusts: Severe
    0
    0
        Nasal Discharge: Mild
    0
    1
        Nasal Discharge: Moderate
    0
    0
        Nasal Discharge: Severe
    0
    0
        Nasal Erythema: Mild
    1
    4
        Nasal Erythema: Moderate
    1
    0
        Nasal Erythema: Severe
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase

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    End point title
    		 Number of Subjects With Treatment-emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase
    End point description
    Number of subjects with treatment emergent abnormal ECG values for variables including heart rate (abnormally low refers to less than or equal to [<=] 50 beats per minute [bpm] , abnormally high refers greater than or equal to [>=] 100 bpm) , pulse rate interval (abnormally high refers to >= 210 milliseconds [msec]), QRS interval (abnormally Low refers to <= 50, abnormally high refers to >= 120 msec) and QT interval (abnormally low refers to <= 200, abnormally high >= 500 msec) were reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase. Here ‘N’ (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    112
    Units: Subjects
        Heart Rate <= 50 bpm
    9
    2
        Heart Rate >= 100 bpm
    3
    2
        PR Duration >= 210 msec
    2
    2
        QRS Duration <= 50 msec
    0
    0
        QRS Duration >= 120 msec
    1
    0
        QT Duration <= 200 msec
    0
    0
        QT Duration >= 500 msec
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Abnormal Arterial Oxygen Saturation (SpO2) Levels (less than [<] 93%) as Assessed by Pulse Oximetry at Any Time: DB Treatment Phase

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    End point title
    		 Number of Subjects with Abnormal Arterial Oxygen Saturation (SpO2) Levels (less than [<] 93%) as Assessed by Pulse Oximetry at Any Time: DB Treatment Phase
    End point description
    Pulse oximetry was used to measure arterial SpO2 levels. On each dosing day, the device was attached to the finger, toe, or ear, and SpO2 was monitored and documented. If oxygen saturation levels were less than (<) 93% at any time during the 1.5 hour postdose interval, pulse oximetry was recorded every 5 minutes until levels return to >= 93% or until the subject is referred for appropriate medical care, if clinically indicated. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
    2
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Vital Signs Abnormalities: DB Treatment Phase

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    End point title
    		 Number of Subjects With Treatment-emergent Vital Signs Abnormalities: DB Treatment Phase
    End point description
    Number of subjects with treatment-emergent vital signs abnormalities (pulse rate [abnormally low = a decrease from baseline of >= 15 to a value <= 50; abnormally high = an increase from baseline of >=15 to a value >=100] , systolic blood pressure [SBP] [abnormally low = a decrease from baseline of >= 20 to a value <= 90; abnormally high = an increase from baseline of >= 20 to a value >= 180], and diastolic blood pressure [DBP] [abnormally low= a decrease from baseline of >=15 to a value <= 50; abnormally high = an increase from baseline of >= 15 to a value >= 105) were reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
        Pulse rate: Decrease of >=15 to <=50
    2
    1
        Pulse rate: Increase of >=15 to >=100
    11
    12
        SBP: decrease of >=20 to <=90
    5
    2
        SBP: increase of >=20 to >=180
    2
    3
        DBP: Decrease of >=15 to <=50
    4
    4
        DBP: Increase of >=15 to >=105
    3
    6
    No statistical analyses for this end point

    Secondary: Number of Sedated Subjects as Assessed by Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) Score at any Time: DB Treatment Phase

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    End point title
    		 Number of Sedated Subjects as Assessed by Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) Score at any Time: DB Treatment Phase
    End point description
    MOAA/S was used to measure treatment-emergent sedation with correlation to levels of sedation defined by the american society of anesthesiologists (ASA) continuum. The MOAA/S scores range from 0 to 5 where,0 = no response to painful stimulus; ASA continuum = general anesthesia, 1 = responds to trapezius squeeze; ASA continuum = deep sedation, 2 = purposeful response to mild prodding or mild shaking; ASA continuum = moderate sedation, 3 = responds after name called loudly or repeatedly; ASA continuum = moderate sedation, 4 = lethargic response to name spoken in normal tone; ASA continuum = moderate sedation and 5 = readily responds to name spoken in normal tone (awake); ASA continuum = minimal sedation. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
    End point type
    Secondary
    End point timeframe
    Up to Day 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    113
    114
    Units: Subjects
        Score <=2: Yes
    0
    4
        Score <=3: Yes
    3
    21
        Score <=4: Yes
    20
    65
    No statistical analyses for this end point

    Secondary: Number of Subjects With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score: DB Treatment Phase

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    End point title
    		 Number of Subjects With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score: DB Treatment Phase
    End point description
    The CADSS is an instrument for the measurement of present-state dissociative symptoms and was administered to assess treatment-emergent dissociative symptoms. The CADSS consists of 23 subjective items, divided into 3 components: depersonalization, derealization, and amnesia. Subject’s responses were coded on a 5-point scale (0 = not at all to 4 = extremely). Number of subjects with an increase in CADSS total score (increase based on maximum CADSS total score change from predose of > 0) was reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase. Here, ‘n’ (number analyzed) signifies number of subjects evaluable for each specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 4, 8, 11, 15, 18, 22 and 25
    End point values
    		 Placebo + Standard of Care (SOC) Esketamine 84 mg + SOC
    Number of subjects analysed
    112
    113
    Units: Subjects
        Day 1 (n= 111, 113)
    28
    106
        Day 4 (n= 105, 104)
    21
    86
        Day 8 (n= 106, 98)
    16
    75
        Day 11 (n= 96, 90)
    8
    68
        Day 15 (n= 96, 91)
    11
    68
        Day 18 (n= 88, 80)
    8
    53
        Day 22 (n= 93, 89)
    7
    58
        Day 25 (n= 88, 85)
    4
    56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening up to Day 25
    Adverse event reporting additional description
    Safety analysis set included all randomized subjects who received at least 1 dose of study drug 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 + SOC
    Reporting group description
    		 Subjects self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 and continued for duration of DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a subject was unable to tolerate intranasal esketamine 84 mg dose. Subjects for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase.

    Reporting group title
    Placebo + Standard of Care (SOC)
    Reporting group description
    		 Subjects self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase.

    Serious adverse events
    		 Esketamine 84 mg + SOC Placebo + Standard of Care (SOC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 114 (4.39%)
    6 / 113 (5.31%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depersonalisation/Derealisation Disorder
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 114 (0.88%)
    2 / 113 (1.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    3 / 114 (2.63%)
    3 / 113 (2.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         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 + SOC Placebo + Standard of Care (SOC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 114 (85.96%)
    73 / 113 (64.60%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    7 / 114 (6.14%)
    3 / 113 (2.65%)
         occurrences all number
    18
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    47 / 114 (41.23%)
    21 / 113 (18.58%)
         occurrences all number
    177
    41
    Dizziness Postural
         subjects affected / exposed
    9 / 114 (7.89%)
    1 / 113 (0.88%)
         occurrences all number
    20
    1
    Dysgeusia
         subjects affected / exposed
    29 / 114 (25.44%)
    18 / 113 (15.93%)
         occurrences all number
    123
    58
    Headache
         subjects affected / exposed
    25 / 114 (21.93%)
    26 / 113 (23.01%)
         occurrences all number
    32
    56
    Hypoaesthesia
         subjects affected / exposed
    12 / 114 (10.53%)
    1 / 113 (0.88%)
         occurrences all number
    27
    5
    Paraesthesia
         subjects affected / exposed
    23 / 114 (20.18%)
    7 / 113 (6.19%)
         occurrences all number
    53
    11
    Sedation
         subjects affected / exposed
    16 / 114 (14.04%)
    3 / 113 (2.65%)
         occurrences all number
    47
    11
    Somnolence
         subjects affected / exposed
    26 / 114 (22.81%)
    12 / 113 (10.62%)
         occurrences all number
    69
    19
    General disorders and administration site conditions
    Feeling Drunk
         subjects affected / exposed
    6 / 114 (5.26%)
    1 / 113 (0.88%)
         occurrences all number
    17
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 114 (6.14%)
    0 / 113 (0.00%)
         occurrences all number
    18
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    9
    0
    Vision Blurred
         subjects affected / exposed
    17 / 114 (14.91%)
    6 / 113 (5.31%)
         occurrences all number
    26
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 114 (6.14%)
    9 / 113 (7.96%)
         occurrences all number
    7
    11
    Dry Mouth
         subjects affected / exposed
    8 / 114 (7.02%)
    5 / 113 (4.42%)
         occurrences all number
    14
    9
    Hypoaesthesia Oral
         subjects affected / exposed
    7 / 114 (6.14%)
    2 / 113 (1.77%)
         occurrences all number
    13
    10
    Nausea
         subjects affected / exposed
    38 / 114 (33.33%)
    16 / 113 (14.16%)
         occurrences all number
    63
    31
    Paraesthesia Oral
         subjects affected / exposed
    14 / 114 (12.28%)
    3 / 113 (2.65%)
         occurrences all number
    32
    5
    Vomiting
         subjects affected / exposed
    18 / 114 (15.79%)
    5 / 113 (4.42%)
         occurrences all number
    21
    5
    Respiratory, thoracic and mediastinal disorders
    Nasal Discomfort
         subjects affected / exposed
    10 / 114 (8.77%)
    9 / 113 (7.96%)
         occurrences all number
    22
    28
    Oropharyngeal Pain
         subjects affected / exposed
    6 / 114 (5.26%)
    3 / 113 (2.65%)
         occurrences all number
    6
    3
    Throat Irritation
         subjects affected / exposed
    6 / 114 (5.26%)
    4 / 113 (3.54%)
         occurrences all number
    14
    9
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    6 / 114 (5.26%)
    3 / 113 (2.65%)
         occurrences all number
    8
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    17 / 114 (14.91%)
    7 / 113 (6.19%)
         occurrences all number
    28
    7
    Depersonalisation/Derealisation Disorder
         subjects affected / exposed
    9 / 114 (7.89%)
    0 / 113 (0.00%)
         occurrences all number
    23
    0
    Dissociation
         subjects affected / exposed
    44 / 114 (38.60%)
    9 / 113 (7.96%)
         occurrences all number
    202
    28
    Euphoric Mood
         subjects affected / exposed
    13 / 114 (11.40%)
    1 / 113 (0.88%)
         occurrences all number
    26
    1
    Insomnia
         subjects affected / exposed
    9 / 114 (7.89%)
    11 / 113 (9.73%)
         occurrences all number
    11
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.
    31 Jan 2018
    The overall reason for the amendment was to remove the interim analysis from the protocol; to clarify that Module 3 suicide ideation and behavior assessment tool (SIBAT) is 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 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’s known characteristic effects such as dissociative symptoms, sedation, and elevation of blood pressure may have impact on blinding, to minimize this bias, protocol specified that different raters perform efficacy and safety assessments.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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