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    Clinical Trial Results:
    Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Subjects with Treatment-resistant Depression.

    Summary
    EudraCT number
    2014-004588-19
    Trial protocol
    SE   BE   ES   GB   LT   FI   BG   IT  
    Global end of trial date
    10 Aug 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Aug 2018
    First version publication date
    22 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESKETINTRD3005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02422186
    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
    10 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to evaluate the efficacy of switching elderly subjects with Treatment-Resistant Depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly-dosed intranasal esketamine (28 milligram (mg), 56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.
    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. The safety assessments included Physical Examinations, Electrocardiograms (ECG's), Nasal Examinations, Nasal Symptom Questionnaire, Cognition Testing, Clinical Laboratory Tests (hematology, serum chemistry, and urinalysis), Pulse Oximetry, Columbia-Suicide Severity Rating Scale (C-SSRS), Clinician Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS+), Modified Observer’s Assessment of Alertness/Sedation (MOAA/S), Clinical Global Assessment of Discharge Readiness (CGADR), Physician Withdrawal Checklist-20-item (PWC-20), Bladder Pain / Interstitial Cystitis Symptom Score (BPIC-SS), Cognition testing [Computerized Cognitive Battery and Hopkins Verbal Learning Test-Revised (HVLT-R)], University of Pennsylvania Smell Identification Test (UPSIT).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Aug 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: 6
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United States: 70
    Country: Number of subjects enrolled
    South Africa: 7
    Worldwide total number of subjects
    138
    EEA total number of subjects
    59
    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)
    0
    From 65 to 84 years
    137
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 148 subjects were planned and 138 subjects with Major Depressive Disorder (MDD) were enrolled and randomly assigned to treatments with either intranasal esketamine plus oral antidepressant (72 subjects) or oral antidepressant plus intranasal placebo (66 subjects) following results from a planned interim analysis in this 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
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD)
    Arm description
    Subjects self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in Double-Blind(DB) Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Subjects self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3, and 4 with minimum dose allowed for tolerability of 30 mg/Day) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Escitalopram (10 mg/day) during Weeks 1-4 with minimum dose allowed for tolerability of 5 mg/Day during Double-Blind Induction Phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Weeks 3 and 150 mg/Day during Week 4, with minimum dose allowed for tolerability of 25 mg/Day) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Venlafaxine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2 and 150 mg/day during weeks 3 and 4 with minimum dose allowed for tolerability of 75 mg/Day during Double- Blind Induction Phase.

    Arm title
    Oral AD Plus Intranasal Placebo
    Arm description
    Subjects self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in the Double-Blind Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Subjects self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3, and 4 with minimum dose allowed for tolerability of 30 mg/Day) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Escitalopram (10 mg/day) during Weeks 1-4 with minimum dose allowed for tolerability of 5 mg/Day during Double-Blind Induction Phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Weeks 3 and 150 mg/Day during Week 4, with minimum dose allowed for tolerability of 25 mg/Day) during Double-Blind Induction Phase.

    Investigational medicinal product name
    Venlafaxine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an open-label antidepressant (AD) Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2 and 150 mg/day during weeks 3 and 4 with minimum dose allowed for tolerability of 75 mg/Day during Double- Blind Induction Phase.

    Number of subjects in period 1
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Started
    72
    66
    Safety Analysis
    72
    65
    Completed
    62
    60
    Not completed
    10
    6
         Protocol deviation
    -
    1
         Other
    1
    -
         Lack of efficacy
    3
    1
         Adverse event, non-fatal
    4
    2
         Consent withdrawn by subject
    1
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD)
    Reporting group description
    Subjects self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in Double-Blind(DB) Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Reporting group title
    Oral AD Plus Intranasal Placebo
    Reporting group description
    Subjects self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in the Double-Blind Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Reporting group values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo Total
    Number of subjects
    72 66 138
    Title for AgeCategorical
    Units: subjects
        From 65 to 84 years
    71 66 137
        85 years and over
    1 0 1
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    70.6 ± 4.79 69.6 ± 4.44 -
    Title for Gender
    Units: subjects
        Female
    45 41 86
        Male
    27 25 52

    End points

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    End points reporting groups
    Reporting group title
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD)
    Reporting group description
    Subjects self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in Double-Blind(DB) Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Reporting group title
    Oral AD Plus Intranasal Placebo
    Reporting group description
    Subjects self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in the Double-Blind Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Primary: Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score up to End of 4-Week (Day 28) Double-blind Induction Phase

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    End point title
    Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score up to End of 4-Week (Day 28) Double-blind Induction Phase
    End point description
    The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items (to evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel [interest level], pessimistic thoughts, and suicidal thoughts), 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 range of 0-60. Higher scores represent a more severe condition. The full analysis set was defined as all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using Last Observation Carried Forward (LOCF) method.
    End point type
    Primary
    End point timeframe
    Baseline up to End of Double-blind Induction Phase (Week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    71
    64
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -9.3 ± 12.28
    -5.6 ± 9.11
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) v Oral AD Plus Intranasal Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.026
    Method
    Weighted Combination Test Statistics
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.16
         upper limit
    -0.03

    Secondary: Percentage of Subjects Who Achieved >=50% Reduction from Baseline in MADRS Total Score

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    End point title
    Percentage of Subjects Who Achieved >=50% Reduction from Baseline in MADRS Total Score
    End point description
    A subject is defined as a responder at a given time point if the percent improvement from baseline in MADRS total score is at least 50%. The percent of participants with greater than or equal to (>=50) percent (%) improvement from baseline is reported. The full analysis set was defined as all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method.
    End point type
    Secondary
    End point timeframe
    End of Double-Blind Induction Phase (Week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    71
    64
    Units: Percentage of Subjects
        number (not applicable)
    23.9
    12.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Remission (MADRS<=12) at the End of Double-Blind Induction Phase

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    End point title
    Percentage of Subjects in Remission (MADRS<=12) at the End of Double-Blind Induction Phase
    End point description
    Remission is defined as subjects who have a MADRS total score <=12. All randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. The full analysis set was defined as all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method.
    End point type
    Secondary
    End point timeframe
    End of Double-Blind Induction Phase (Week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    71
    64
    Units: Percentage of Subjects
        number (not applicable)
    15.5
    6.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at End of Double-Blind Induction Phase (Week 4)

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    End point title
    Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at End of Double-Blind Induction Phase (Week 4)
    End point description
    The CGI-S provides an overall clinician-determined summary measure of the severity of the subject’s illness including subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the subject’s ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, a subject is assessed on severity of mental illness at the time of rating according to: 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 the most extremely ill patients. The full analysis set was defined as all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Double-blind Induction Phase (Week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    71
    65
    Units: Units on a scale
        median (full range (min-max))
    -1.0 (-4 to 1)
    0.0 (-4 to 3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Response to The EuroQoL Group 5 Dimension 5-Level Self-Report Questionnaire (EQ-5D-5L)

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    End point title
    Percentage of Subjects With a Response to The EuroQoL Group 5 Dimension 5-Level Self-Report Questionnaire (EQ-5D-5L)
    End point description
    The EQ-5D-5L questionnaire is a brief, generic health related quality of life assessment (HRQOL) that can also be used to incorporate subject preferences into health economic evaluations. The EQ-5D-5L descriptive system comprises the following 5 dimensions with 5 levels (level 1 indicates no problem to level 5 indicates extreme problem): mobility, self-care, usual activities, pain/discomfort and anxiety/depression and as overall health using a "thermometer" visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). The full analysis set was defined as all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind induction phase. Here, N (Number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    End of Double-blind Induction Phase (Week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral antidepressant (AD) Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    70
    64
    Units: Percentage of Subjects
    number (not applicable)
        Mobility: Level 1
    68.6
    60.9
        Mobility: Level 2
    20.0
    23.4
        Mobility: Level 3
    8.6
    14.1
        Mobility: Level 4
    2.9
    1.6
        Mobility: Level 5
    0
    0
        Self-care: Level 1
    67.1
    71.9
        Self-care: Level 2
    18.6
    14.1
        Self-care: Level 3
    8.6
    12.5
        Self-care: Level 4
    5.7
    1.6
        Self-care: Level 5
    0
    0
        Usual activities: Level 1
    31.4
    20.3
        Usual activities: Level 2
    15.7
    17.2
        Usual activities: Level 3
    27.1
    29.7
        Usual activities: Level 4
    21.4
    29.7
        Usual activities: Level 5
    4.3
    3.1
        Pain/discomfort: Level 1
    31.4
    39.1
        Pain/discomfort: Level 2
    34.3
    23.4
        Pain/discomfort: Level 3
    21.4
    31.3
        Pain/discomfort: Level 4
    5.7
    4.7
        Pain/discomfort: Level 5
    7.1
    1.6
        Anxiety/depression: Level 1
    12.9
    7.8
        Anxiety/depression: Level 2
    20.0
    12.5
        Anxiety/depression: Level 3
    27.1
    45.3
        Anxiety/depression: Level 4
    31.4
    25.0
        Anxiety/depression: Level 5
    8.6
    9.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately up to 2 years
    Adverse event reporting additional description
    The safety analysis set included all randomized subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Oral antidepressant (AD) + Intranasal Placebo
    Reporting group description
    Subjects self-administered esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in the Double-Blind Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Reporting group title
    Intranasal Esketamine (Esk) + Oral antidepressant (AD)
    Reporting group description
    Subjects self-administered esketamine 28 milligram (mg) or 56 mg or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 11, 15, 18, 22 and 25) as determined by investigator based on efficacy and tolerability in Double-Blind(DB) Induction Phase. Subjects simultaneously initiated titration schedule for open-label Oral antidepressant (AD) with one of the following four oral AD that was not used in current depression episode: [Duloxetine (30 mg/day during Week 1 and 60 mg/day during Weeks 2, 3 and 4 with minimum dose for tolerability at 30 mg/day); Escitalopram (10 mg/day during Weeks 1-4 with minimum dose for tolerability at 5 mg/day); Sertraline (25 mg/day during Week 1, 50 mg/day during Week 2, 100 mg/day during Week 3 and 150 mg/day during Week 4 with minimum dose for tolerability of 25 mg/Day) or Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2, and 150 mg/day during Weeks 3 and 4 with minimum dose for tolerability of 75 mg/day) during DB Induction Phase.

    Serious adverse events
    Oral antidepressant (AD) + Intranasal Placebo Intranasal Esketamine (Esk) + Oral antidepressant (AD)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 72 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip Fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait Disturbance
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety Disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeling of Despair
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Oral antidepressant (AD) + Intranasal Placebo Intranasal Esketamine (Esk) + Oral antidepressant (AD)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 65 (32.31%)
    44 / 72 (61.11%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    3 / 65 (4.62%)
    9 / 72 (12.50%)
         occurrences all number
    6
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 65 (6.15%)
    15 / 72 (20.83%)
         occurrences all number
    6
    43
    Headache
         subjects affected / exposed
    2 / 65 (3.08%)
    9 / 72 (12.50%)
         occurrences all number
    2
    15
    Dysgeusia
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 72 (5.56%)
         occurrences all number
    9
    12
    Hypoaesthesia
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 72 (5.56%)
         occurrences all number
    1
    5
    Paraesthesia
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 72 (5.56%)
         occurrences all number
    2
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 65 (7.69%)
    9 / 72 (12.50%)
         occurrences all number
    6
    15
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 65 (3.08%)
    8 / 72 (11.11%)
         occurrences all number
    10
    24
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 72 (2.78%)
         occurrences all number
    9
    2
    Dissociation
         subjects affected / exposed
    1 / 65 (1.54%)
    9 / 72 (12.50%)
         occurrences all number
    1
    40
    Dysphoria
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    0
    4
    Insomnia
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 72 (5.56%)
         occurrences all number
    6
    4
    Gastrointestinal disorders
    Hypoaesthesia Oral
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 72 (6.94%)
         occurrences all number
    0
    11
    Nausea
         subjects affected / exposed
    3 / 65 (4.62%)
    13 / 72 (18.06%)
         occurrences all number
    4
    18
    Vomiting
         subjects affected / exposed
    1 / 65 (1.54%)
    5 / 72 (6.94%)
         occurrences all number
    1
    5
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 65 (1.54%)
    6 / 72 (8.33%)
         occurrences all number
    1
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2015
    The overall reason for the amendment is to allow for a 28 mg dose throughout the study, based on pharmacokinetic data from study ESKETINTRD1012 in elderly subjects.
    10 Jan 2016
    The overall reason for the amendment is to update and/or clarify protocol content based on ongoing feedback received during study initiation activities.
    18 Jul 2016
    The overall reason for the amendment is to improve recruitment while maintaining the integrity of the study. Changes are made that relate to the elderly population specifically (which differ in some aspects from younger patients) not included in the original protocol.

    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.
    The use of remote raters to administer the MADRS assessment may have reduced the sensitivity of detecting early change. There was limited numbers of subjects 75 years of age and older limiting the generalizability of the results in this population.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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