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    Clinical Trial Results:
    A Randomized, Double-blind, Multicenter, Active-controlled Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression

    Summary
    EudraCT number
    2014-004586-24
    Trial protocol
    DE   BE   PL   ES   HU   CZ   SK   IT  
    Global end of trial date
    15 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Mar 2019
    First version publication date
    03 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESKETINTRD3003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02493868
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg, 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to assess the efficacy of intranasal esketamine + oral antidepressant compared with an oral antidepressant + intranasal placebo in delaying relapse of depressive symptoms in subjects with treatment-resistant depression (TRD) who were in stable remission after an induction and optimization course of intranasal esketamine + oral antidepressant.
    Protection of trial subjects
    The 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.The safety assessments included clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital sign measurements (temperature, pulse/heart rate, respiratory rate, and blood pressure), physical examinations, height, body weight, and neck circumference, electrocardiograms (ECGs), pulse oximetry, nasal examination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Oct 2015
    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
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 64
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Czech Republic: 99
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Mexico: 35
    Country: Number of subjects enrolled
    Poland: 132
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Turkey: 53
    Country: Number of subjects enrolled
    United States: 190
    Worldwide total number of subjects
    705
    EEA total number of subjects
    358
    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)
    705
    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 of 705 subjects were enrolled. Out of which 437 (direct entry [DE] subjects) entered in induction (IND) phase and 268 subjects (150 transferred-entry [TE] subjects from study ESKETINTRD3001 [NCT02417064] and 118 subjects from study ESKETINTRD3002 [NCT02418585]) entered in this study in optimization (OP) phase.

    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
    No

    Arm title
    IND: Intranasal Esketamine + Oral AD (DE Subjects)
    Arm description
    Subjects in open-label induction (IND) phase received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) once daily for 4 weeks. Subjects who completed IND phase and met predefined response criteria entered optimization (OP) phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received 56 or 84 mg intranasal esketamine solution twice weekly.

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    Arm title
    OP: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Arm description
    Subjects received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. Subjects who completed and met the predefined remission/response criteria entered maintenance (MA) phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received 56 or 84 mg intranasal esketamine solution once per week for first 4 weeks, then once per week/once every other week.

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    Arm title
    OP: Oral AD + Intranasal Placebo (TE Subjects)
    Arm description
    Optimization phase (transferred-entry subjects): Subjects received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Subjects who completed and met the predefined remission/response criteria entered MA phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    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 received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week.

    Arm title
    MA: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Arm description
    MA phase (DE+TE): subjects were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on severity of depressive symptoms and continued same oral AD from IND phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received 56 or 84 mg intranasal esketamine solution once weekly or once every other week.

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily

    Arm title
    MA: Oral AD + Intranasal Placebo (DE+TE Subjects)
    Arm description
    Maintenance phase (DE+TE subjects): Subjects (including randomized subjects from intranasal esketamine arm after OP phase and TE subjects who continued from previous phase in this group) to receive intranasal esketamine placebo with oral AD.
    Arm type
    Placebo

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    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 received intranasal esketamine placebo once weekly or once every other week.

    Arm title
    FU: Intranasal Esketamine + Oral AD
    Arm description
    Follow-up (FU) phase: subjects received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Subjects who were non-responders at the end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    Arm title
    FU: Oral AD + Intranasal Placebo
    Arm description
    FU Phase: subjects received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Subjects who were non-responders in IND phase and who were in OP and MA phase at study termination proceeded directly to FU phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Oral Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one of duloxetine/escitalopram/sertraline/venlafaxine XR oral antidepressant once daily.

    Number of subjects in period 1
    IND: Intranasal Esketamine + Oral AD (DE Subjects) OP: Intranasal Esketamine + Oral AD (DE+TE Subjects) OP: Oral AD + Intranasal Placebo (TE Subjects) MA: Intranasal Esketamine + Oral AD (DE+TE Subjects) MA: Oral AD + Intranasal Placebo (DE+TE Subjects) FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo
    Started
    437
    455
    86
    152
    199
    481
    64
    Completed
    273
    297
    54
    139
    177
    470
    62
    Not completed
    164
    158
    32
    13
    22
    11
    2
         Protocol deviation
    2
    4
    1
    1
    1
    -
    -
         PI Decision
    -
    -
    -
    -
    -
    5
    1
         Non Compliance with Study Drug
    -
    -
    -
    -
    1
    -
    -
         Lack of efficacy
    2
    8
    -
    -
    -
    -
    -
         Pregnancy
    -
    -
    -
    1
    -
    -
    -
         Unspecified
    8
    10
    2
    4
    9
    2
    1
         Consent withdrawn by subject
    15
    8
    3
    5
    7
    3
    -
         Adverse Event
    22
    5
    -
    1
    4
    -
    -
         MADRS >= 22 for 2 Consecutive Visit
    -
    14
    5
    -
    -
    -
    -
         Subject did not meet crit for next phase
    114
    107
    20
    -
    -
    -
    -
         Lost to follow-up
    1
    2
    1
    1
    -
    1
    -

    Baseline characteristics

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

    Reporting group values
    Overall Study Total
    Number of subjects
    705 705
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    705 705
        From 65 to 84 years
    0 0
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    46.1 ± 11.10 -
    Title for Gender
    Units: subjects
        Female
    457 457
        Male
    248 248

    End points

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    End points reporting groups
    Reporting group title
    IND: Intranasal Esketamine + Oral AD (DE Subjects)
    Reporting group description
    Subjects in open-label induction (IND) phase received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) once daily for 4 weeks. Subjects who completed IND phase and met predefined response criteria entered optimization (OP) phase.

    Reporting group title
    OP: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Reporting group description
    Subjects received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. Subjects who completed and met the predefined remission/response criteria entered maintenance (MA) phase.

    Reporting group title
    OP: Oral AD + Intranasal Placebo (TE Subjects)
    Reporting group description
    Optimization phase (transferred-entry subjects): Subjects received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Subjects who completed and met the predefined remission/response criteria entered MA phase.

    Reporting group title
    MA: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Reporting group description
    MA phase (DE+TE): subjects were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on severity of depressive symptoms and continued same oral AD from IND phase.

    Reporting group title
    MA: Oral AD + Intranasal Placebo (DE+TE Subjects)
    Reporting group description
    Maintenance phase (DE+TE subjects): Subjects (including randomized subjects from intranasal esketamine arm after OP phase and TE subjects who continued from previous phase in this group) to receive intranasal esketamine placebo with oral AD.

    Reporting group title
    FU: Intranasal Esketamine + Oral AD
    Reporting group description
    Follow-up (FU) phase: subjects received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Subjects who were non-responders at the end of IND phase or who were early terminated at any phase proceeded directly to FU phase.

    Reporting group title
    FU: Oral AD + Intranasal Placebo
    Reporting group description
    FU Phase: subjects received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Subjects who were non-responders in IND phase and who were in OP and MA phase at study termination proceeded directly to FU phase.

    Subject analysis set title
    Stable Remitters :Intranasal Esketamine + Oral AD
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were in stable remission at the end of the optimization phase and who received at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the maintenance phase.

    Subject analysis set title
    Stable Remitters: Oral AD + Intranasal Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were in stable remission at the end of the optimization phase and who received at least 1 dose of intranasal placebo and 1 dose of oral antidepressant during the maintenance phase.

    Subject analysis set title
    Stable Responders: Intranasal Esketamine + Oral AD
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were stable responders (but not stable remitters) at the end of the optimization phase and who received at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the maintenance phase.

    Subject analysis set title
    Stable Responders: Oral AD + Intranasal Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were stable responders (but not stable remitters) at the end of the optimization phase and who received at least 1 dose of intranasal placebo and 1 dose of oral antidepressant during the maintenance phase.

    Primary: Time to Relapse in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Time to Relapse in Subjects with Stable Remission (Maintenance Phase)
    End point description
    Relapse (any of following): MADRS total score >= 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression/any clinical event suggestive of relapse of depressive illness such as suicide attempt/completed suicide/hospitalization to prevent suicide; If hospitalized, start date of hospitalization will be date of relapse, if not then date of event will be used. Stable remission: MADRS total score <= 12 for at least 3 of last 4 weeks of OP phase, with 1 excursion total score > 12 or 1 missing assessment at OP week 13/14. FAS (stable remitters) = all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. ‘99999’ = for esketamine arm that median time to relapse (time point at which cumulative survival function equals 0.5 or 50%) was not estimable, as group never reached 50%; 99999 (placebo arm) = upper limit of CI could not be estimated due to insufficient data.
    End point type
    Primary
    End point timeframe
    Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    90
    86
    Units: Days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    273.0 (97.0 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Stable Remitters :Intranasal Esketamine + Oral AD v Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.83

    Secondary: Time to Relapse in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Time to Relapse in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    Relapse (any of following): MADRS total score >= 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression/any clinical event suggestive of relapse of depressive illness such as suicide attempt/completed suicide/hospitalization to prevent suicide; If hospitalized, start date of hospitalization will be date of relapse, if not then date of event will be used. MADRS: scale to measure depression severity and to detect changes due to AD treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), total score =60. Higher scores: more severe condition. Stable response: >= 50% reduction in MADRS total score from baseline (Day 1: IND phase [before first dose]) in each of last 2 weeks of OP phase, but no stable remission. FAS Stable responders: all randomized subjects who were stable responders (not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    62
    59
    Units: Days
        median (confidence interval 95%)
    635.0 (264.0 to 635.0)
    88.0 (46.0 to 196.0)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Montgomery-asberg Depression Rating Scale (MADRS) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in Montgomery-asberg Depression Rating Scale (MADRS) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    MADRS: scale to measure depression severity and to detect changes due to AD treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), total score = 60. Higher scores: more severe condition. The change from baseline in MADRS total score (last observation carried forward [LOCF] data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint. FAS Stable remitters included all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    89
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    7.5 ± 11.59
    12.5 ± 13.63
    No statistical analyses for this end point

    Secondary: Change from Baseline in MADRS Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in MADRS Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    MADRS: scale to measure depression severity and to detect changes due to AD treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), total score = 60. Higher scores: more severe condition. The change from baseline in MADRS total score (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint. FAS Stable responders included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    62
    59
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4.4 ± 11.38
    11.4 ± 12.00
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day). The subject’s item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint. FAS Stable remitters included all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    89
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3.3 ± 5.58
    5.9 ± 7.09
    No statistical analyses for this end point

    Secondary: Change from Baseline in PHQ-9 Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in PHQ-9 Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day). The subject’s item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint. FAS (Stable responders) included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    61
    58
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.7 ± 5.02
    4.7 ± 5.48
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    CGI-S: clinician-determined summary measure of severity of subject’s illness that considers all available information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on a scale of 0-7. Subject is assessed on severity of mental illness at time of rating as: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. Change from baseline in CGI-S score, (LOCF data) at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable remitters) included all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    89
    86
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-3 to 4)
    1.0 (-2 to 5)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Global Impression-Severity Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in Clinical Global Impression-Severity Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    CGI-S: clinician-determined summary measure of severity of subject’s illness that considers information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on a scale of 0-7. Subject is assessed on severity of mental illness at time of rating as: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. Change from baseline in CGI-S score, (LOCF data) at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable responders): all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    62
    58
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-2 to 4)
    1.0 (-3 to 5)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Generalized Anxiety Disorder-7 Items (GAD-7) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in Generalized Anxiety Disorder-7 Items (GAD-7) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    GAD-7 is brief and validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4-point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, 3=nearly every day. Item responses are summed to yield total score with range of 0-21, higher scores indicate more anxiety. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). Item responses are summed for total score (range of 0-21), higher scores indicating more anxiety. Change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable remitters) included all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    89
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.2 ± 4.45
    4.0 ± 5.93
    No statistical analyses for this end point

    Secondary: Change from Baseline in Generalized Anxiety Disorder-7 Items Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in Generalized Anxiety Disorder-7 Items Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    GAD-7 is brief and validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4-point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, 3=nearly every day. Item responses are summed to yield total score with range of 0-21, higher score means more anxiety. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Item responses are summed for total score (range of 0-21), higher scores indicating more anxiety. Change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable responders) included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    61
    58
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.4 ± 3.76
    2.6 ± 4.26
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Sum Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Sum Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels of perceived problems (1-no problem; 2-slight; 3-moderate; 4-severe; 5-extreme problems). Responses from all 5 dimensions answered by subject as per his/her health “today” were used to generate HIS, range=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, scale range=0-100 (worst health-best health). Sum score range=0-100. sum score= (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state. FAS (Stable remitters) included all randomized subjects in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    88
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    7.5 ± 11.87
    10.9 ± 14.74
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ Visual Analogue Scale (EQ VAS) Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in EQ Visual Analogue Scale (EQ VAS) Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    EQ VAS self-rating records respondent’s own assessment of his/her overall health status at time of completion, scale range = 0-100 (worst health-best health). FAS (Stable remitters) included all randomized subjects who were in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    88
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -10.4 ± 20.29
    -16.1 ± 21.80
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D-5L Health Status Index (HSI) at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in EQ-5D-5L Health Status Index (HSI) at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels of perceived problems (1-no problem; 2-slight; 3-moderate; 4-severe; 5-extreme problems). Responses from all 5 dimensions answered by subject as per his/her health “today” were used to generate HSI. HSI range: 0-1.00 (dead-full health). FAS (Stable remitters) included all randomized subjects in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) included number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    88
    86
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.067 ± 0.1180
    -0.096 ± 0.1484
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol-5 Dimension-5 Level Sum Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in EuroQol-5 Dimension-5 Level Sum Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. Descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels of perceived problems (1-no problem; 2-slight; 3-moderate; 4-severe; 5-extreme problems). Responses from all 5 dimensions answered by subject as per his/her health “today” were used to generate HIS, range: 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, scale range=0-100 (worst health-best health). Sum score range=0-100. sum score= (sum score of 5 dimensions minus 5) *5. Higher score: worst health state. FAS (Stable responders): all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    61
    58
    Units: Units on scale
        arithmetic mean (standard deviation)
    3.0 ± 8.13
    8.4 ± 13.55
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D-5L EQ Visual Analogue Scale Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in EQ-5D-5L EQ Visual Analogue Scale Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    EQ VAS self-rating records respondent’s own assessment of his/her overall health status at time of completion, scale range=0-100 (worst health-best health). FAS (Stable responders) included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    61
    58
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -1.3 ± 15.55
    -13.8 ± 19.81
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D-5L Health Status Index at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in EQ-5D-5L Health Status Index at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels of perceived problems (1-no problem; 2-slight; 3-moderate; 4-severe; 5-extreme problems). Responses from all 5 dimensions answered by subject as per his/her health “today” were used to generate HSI. HSI range: 0-1.00 (dead-full health). FAS (Stable responders) included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    61
    58
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.023 ± 0.0753
    -0.073 ± 0.1383
    No statistical analyses for this end point

    Secondary: Change from Baseline in Sheehan Disability Scale (SDS) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)

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    End point title
    Change from Baseline in Sheehan Disability Scale (SDS) Total Score at Endpoint in Subjects with Stable Remission (Maintenance Phase)
    End point description
    SDS: 5-item questionnaire used for assessment of functional impairment and associated disability. First 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities on a 0-10 rating scale. It has 1 item for each day lost from school/work and when underproductive. First 3 items scores are summed to make total score of 0-30, higher score: greater impairment. Recall period is 7 days. Response: scores <=4 for each item, <=12 for total score. Remission: scores <=2 for each item, <=6 for total score. Change from baseline in SDS total Score, (LOCF data), at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable remitters) included all randomized subjects in stable remission at end of OP phase and received at least 1 dose of study drug and oral AD in MA phase. 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Remitters :Intranasal Esketamine + Oral AD Stable Remitters: Oral AD + Intranasal Placebo
    Number of subjects analysed
    82
    77
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4.7 ± 7.34
    7.2 ± 10.44
    No statistical analyses for this end point

    Secondary: Change from Baseline in Sheehan Disability Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)

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    End point title
    Change from Baseline in Sheehan Disability Total Score at Endpoint in Subjects with Stable Response (but not in Stable Remission) (Maintenance Phase)
    End point description
    SDS: 5-item questionnaire for assessment of functional impairment and associated disability. First 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities on a 0-10 rating scale. It has 1 item for each day lost from school/work and when underproductive. First 3 items sum score gives total score of 0-30, higher score: greater impairment. Recall period is 7 days. Response: scores <=4 for each item, <=12 for total score. Remission: scores <=2 for each item, <=6 for total score. Change from baseline in SDS total Score, (LOCF data) at endpoint was reported. Last post baseline observation was carried forward as endpoint. FAS (Stable responders) included all randomized subjects who were stable responders (but not stable remitters) at end of OP phase and who received at least 1 dose of intranasal study drug and oral AD in MA phase. 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Up to 92 Weeks)
    End point values
    Stable Responders: Intranasal Esketamine + Oral AD Stable Responders: Oral AD + Intranasal Placebo
    Number of subjects analysed
    58
    53
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.2 ± 6.63
    6.8 ± 7.64
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 2.4 years
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in respective phase (Induction, Optimization, Maintenance). Follow-up analysis set included all subjects who entered the follow-up phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    IND: DE Subjects: Intranasal Esketamine + Oral AD
    Reporting group description
    Subjects in open-label induction (IND) phase received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) once daily for 4 weeks.

    Reporting group title
    MA: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Reporting group description
    Maintenance (MA) phase (both direct-entry and transferred-entry subjects): received 56 mg or 84 mg intranasal esketamine solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily until relapse or study termination.

    Reporting group title
    OP: Intranasal Esketamine + Oral AD (DE+TE Subjects)
    Reporting group description
    Subjects received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks.

    Reporting group title
    MA: Oral AD + Intranasal Placebo (DE+TE Subjects)
    Reporting group description
    Maintenance phase (both direct-entry and transferred-entry subjects): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), until relapse or study termination.

    Reporting group title
    FU: Intranasal Esketamine + Oral AD
    Reporting group description
    Subjects (who were non-responders in IND phase and who were in OP and MA phase at study termination) who received at least 1 dose of 56 mg or 84 mg intranasal esketamine participated in the follow-up (FU) phase. No intranasal esketamine was administered during FU phase. Subjects received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate.

    Reporting group title
    FU: Oral AD + Intranasal Placebo
    Reporting group description
    Subjects (who were non-responders in IND phase and who were in OP and MA phase at study termination) who received intranasal esketamine matching placebo with oral AD participated in the FU phase. Subjects received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate.

    Reporting group title
    OP_TES: Oral AD + Intranasal Placebo
    Reporting group description
    OP phase (transferred-entry subjects [TES]): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks.

    Reporting group title
    MA_TES: Oral AD + Intranasal Placebo
    Reporting group description
    Maintenance phase (transferred-entry subjects): Subjects were randomized (at the end of optimization phase) to intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR).

    Serious adverse events
    IND: DE Subjects: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD (DE+TE Subjects) OP: Intranasal Esketamine + Oral AD (DE+TE Subjects) MA: Oral AD + Intranasal Placebo (DE+TE Subjects) FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TES: Oral AD + Intranasal Placebo MA_TES: Oral AD + Intranasal Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 437 (2.97%)
    4 / 152 (2.63%)
    11 / 455 (2.42%)
    1 / 145 (0.69%)
    3 / 481 (0.62%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    1 / 54 (1.85%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural Pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus Tachycardia
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic Nervous System Imbalance
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar Stroke
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Simple Partial Seizures
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic Pregnancy
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 152 (0.66%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    1 / 481 (0.21%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 437 (0.69%)
    2 / 152 (1.32%)
    1 / 455 (0.22%)
    1 / 145 (0.69%)
    1 / 481 (0.21%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 152 (0.66%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    1 / 481 (0.21%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic Attack
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal Fissure
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    1 / 481 (0.21%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    1 / 455 (0.22%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    IND: DE Subjects: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD (DE+TE Subjects) OP: Intranasal Esketamine + Oral AD (DE+TE Subjects) MA: Oral AD + Intranasal Placebo (DE+TE Subjects) FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TES: Oral AD + Intranasal Placebo MA_TES: Oral AD + Intranasal Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    306 / 437 (70.02%)
    114 / 152 (75.00%)
    279 / 455 (61.32%)
    45 / 145 (31.03%)
    14 / 481 (2.91%)
    1 / 64 (1.56%)
    40 / 86 (46.51%)
    37 / 54 (68.52%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    34 / 437 (7.78%)
    10 / 152 (6.58%)
    26 / 455 (5.71%)
    5 / 145 (3.45%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    99
    40
    97
    11
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal Discomfort
         subjects affected / exposed
    29 / 437 (6.64%)
    11 / 152 (7.24%)
    26 / 455 (5.71%)
    4 / 145 (2.76%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    95
    94
    98
    19
    0
    0
    0
    0
    Throat Irritation
         subjects affected / exposed
    26 / 437 (5.95%)
    8 / 152 (5.26%)
    16 / 455 (3.52%)
    1 / 145 (0.69%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    100
    75
    97
    7
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    97 / 437 (22.20%)
    31 / 152 (20.39%)
    61 / 455 (13.41%)
    7 / 145 (4.83%)
    0 / 481 (0.00%)
    1 / 64 (1.56%)
    6 / 86 (6.98%)
    0 / 54 (0.00%)
         occurrences all number
    347
    170
    241
    13
    0
    1
    0
    0
    Dizziness Postural
         subjects affected / exposed
    33 / 437 (7.55%)
    10 / 152 (6.58%)
    26 / 455 (5.71%)
    3 / 145 (2.07%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    188
    98
    168
    6
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    90 / 437 (20.59%)
    41 / 152 (26.97%)
    79 / 455 (17.36%)
    10 / 145 (6.90%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    8 / 86 (9.30%)
    8 / 54 (14.81%)
         occurrences all number
    429
    494
    529
    125
    0
    0
    67
    144
    Headache
         subjects affected / exposed
    60 / 437 (13.73%)
    27 / 152 (17.76%)
    57 / 455 (12.53%)
    14 / 145 (9.66%)
    8 / 481 (1.66%)
    0 / 64 (0.00%)
    16 / 86 (18.60%)
    12 / 54 (22.22%)
         occurrences all number
    86
    77
    91
    23
    11
    0
    40
    24
    Hypoaesthesia
         subjects affected / exposed
    30 / 437 (6.86%)
    9 / 152 (5.92%)
    24 / 455 (5.27%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    102
    179
    115
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    48 / 437 (10.98%)
    11 / 152 (7.24%)
    23 / 455 (5.05%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    161
    82
    85
    0
    0
    0
    0
    0
    Sedation
         subjects affected / exposed
    43 / 437 (9.84%)
    10 / 152 (6.58%)
    19 / 455 (4.18%)
    1 / 145 (0.69%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    223
    77
    86
    1
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    65 / 437 (14.87%)
    32 / 152 (21.05%)
    63 / 455 (13.85%)
    3 / 145 (2.07%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    5 / 86 (5.81%)
    4 / 54 (7.41%)
         occurrences all number
    183
    154
    240
    7
    0
    0
    13
    12
    Eye disorders
    Diplopia
         subjects affected / exposed
    16 / 437 (3.66%)
    9 / 152 (5.92%)
    10 / 455 (2.20%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    39
    31
    34
    0
    0
    0
    0
    0
    Vision Blurred
         subjects affected / exposed
    45 / 437 (10.30%)
    24 / 152 (15.79%)
    30 / 455 (6.59%)
    1 / 145 (0.69%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    148
    217
    170
    2
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    99 / 437 (22.65%)
    38 / 152 (25.00%)
    91 / 455 (20.00%)
    8 / 145 (5.52%)
    2 / 481 (0.42%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    385
    260
    406
    26
    3
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    31 / 437 (7.09%)
    12 / 152 (7.89%)
    11 / 455 (2.42%)
    5 / 145 (3.45%)
    2 / 481 (0.42%)
    0 / 64 (0.00%)
    5 / 86 (5.81%)
    0 / 54 (0.00%)
         occurrences all number
    38
    17
    19
    6
    2
    0
    9
    0
    Confusional State
         subjects affected / exposed
    13 / 437 (2.97%)
    9 / 152 (5.92%)
    9 / 455 (1.98%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    36
    53
    24
    0
    0
    0
    0
    0
    Dissociation
         subjects affected / exposed
    82 / 437 (18.76%)
    35 / 152 (23.03%)
    73 / 455 (16.04%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    333
    181
    321
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Hypoaesthesia Oral
         subjects affected / exposed
    32 / 437 (7.32%)
    20 / 152 (13.16%)
    34 / 455 (7.47%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    87
    144
    156
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    94 / 437 (21.51%)
    25 / 152 (16.45%)
    48 / 455 (10.55%)
    1 / 145 (0.69%)
    2 / 481 (0.42%)
    1 / 64 (1.56%)
    0 / 86 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    158
    60
    83
    2
    3
    1
    0
    5
    Paraesthesia Oral
         subjects affected / exposed
    16 / 437 (3.66%)
    8 / 152 (5.26%)
    13 / 455 (2.86%)
    1 / 145 (0.69%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    61
    15
    35
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    29 / 437 (6.64%)
    10 / 152 (6.58%)
    17 / 455 (3.74%)
    1 / 145 (0.69%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    39
    15
    26
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    4 / 54 (7.41%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    Spinal Pain
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    14
    Infections and infestations
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 437 (1.14%)
    11 / 152 (7.24%)
    22 / 455 (4.84%)
    12 / 145 (8.28%)
    1 / 481 (0.21%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    13 / 54 (24.07%)
         occurrences all number
    6
    16
    23
    18
    1
    0
    0
    14
    Urinary Tract Infection
         subjects affected / exposed
    0 / 437 (0.00%)
    0 / 152 (0.00%)
    0 / 455 (0.00%)
    0 / 145 (0.00%)
    0 / 481 (0.00%)
    0 / 64 (0.00%)
    0 / 86 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2016
    The overall reason for the amendment was to update and clarify the protocol based on ongoing feedback received during study initiation activities.
    09 Jun 2016
    The overall reason for the amendment was based on feedback received from investigators involved in the study, the subject entry criteria had been revised to improve recruitment.
    04 Apr 2017
    The overall reason for the amendment was to enhance the number of clinically valid subjects proceeding to the maintenance phase as stable remitters, the stable remission criteria had been revised.

    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 transient dissociative, sedative effect difficult to blind, potential for treatment -emergent symptoms to have biased site staff who observed dosing was mitigated by independent, remote, blinded MADRS raters who assessed response.
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