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

    Summary
    EudraCT number
    		 2014-004584-20
    Trial protocol
    		 BE   SK   HU   PL  
    Global end of trial date
    20 Feb 2018

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ESKETINTRD3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02417064
    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
    20 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of switching adult subjects with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they had not responded) to intranasal esketamine (56 milligram [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. Safety evaluations included monitoring of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital sign’s (temperature, pulse/heart rate, respiratory rate, blood pressure [BP]), physical examinations (height, body weight, and neck circumference), electrocardiograms (ECG's), pulse oximetry, nasal examinations and nasal symptom questionnaire, columbia-suicide severity rating scale (C-SSRS), clinician administered dissociative states scale (CADSS), four-item positive symptom subscale of the 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), computerized cognitive battery, hopkins verbal learning testrevised (HVLT-R), university of pennsylvania smell identification test (UPSIT), and smell threshold test.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 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: 30
    Country: Number of subjects enrolled
    Brazil: 57
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Mexico: 45
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    United States: 137
    Worldwide total number of subjects
    346
    EEA total number of subjects
    87
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    346
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 346 subjects with treatment-resistant depression (TRD) were randomly assigned to receive treatment- intranasal esketamine (Esk) 56 mg+oral AD (117 subjects), intranasal Esk 84 mg+oral AD (116 subjects), or oral AD+intranasal placebo (113 subjects), out of which 111, 97 and 107 subjects completed the double-blind phase respectively.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant
    Arm description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    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 56 mg of esketamine, twice per week for 4 Weeks in double-blind induction phase.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received duloxetine 60 mg/day daily during Weeks 1 to 4 in double-blind induction phase. Subjects that have in the past shown increased sensitivity towards SSRIs/SNRIs could be started on a 30 mg dose and up‑titrated into the therapeutic range of 60 mg by the start of Week 2.

    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 escitalopram 10 mg/day during Week 1 and 20 mg/day during Weeks 2 to 4 daily in 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 venlafaxine extended release (XR) 75 mg/day during Week 1, 150 mg/day during Week 2, 225 mg/day during Weeks 3 and 4 daily in double-blind induction phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sertraline 50 mg/day during Week 1, 100 mg/day during Week 2, 150 mg/day during Week 3 and 200 mg/day during Week 4 daily in double-blind induction phase.

    Arm title
    		 Intranasal Esketamine 84 mg Plus Oral AD
    Arm description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    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 56 mg of esketamine on Day 1 and then 84 mg of esketamine from Day 4 onwards, twice per week for 4 Weeks in double-blind induction phase.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received duloxetine 60 mg/day daily during Weeks 1 to 4 in double-blind induction phase. Subjects that have in the past shown increased sensitivity towards selective serotonin reuptake inhibitors (SSRI)/serotonin and norepinephrine reuptake inhibitors (SNRI) could be started on a 30 mg dose and up‑titrated into the therapeutic range of 60 mg by the start of Week 2.

    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 escitalopram 10 mg/day during Week 1 and 20 mg/day during Weeks 2 to 4 daily in double-blind induction phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sertraline 50 mg/day during Week 1, 100 mg/day during Week 2, 150 mg/day during Week 3 and 200 mg/day during Week 4 daily in 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 venlafaxine XR 75 mg/day during Week 1, 150 mg/day during Week 2, 225 mg/day during Weeks 3 and 4 daily in double-blind induction phase.

    Arm title
    		 Oral AD Plus Intranasal Placebo
    Arm description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    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 matching placebo twice per week for 4 Weeks in double-blind Induction Phase.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received duloxetine 60 mg/day daily during Weeks 1 to 4 in double-blind induction phase. Subjects that have in the past shown increased sensitivity towards SSRIs/SNRIs could be started on a 30 mg dose and up‑titrated into the therapeutic range of 60 mg by the start of Week 2.

    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 escitalopram 10 mg/day during Week 1 and 20 mg/day during Weeks 2 to 4 daily in double-blind induction phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sertraline 50 mg/day during Week 1, 100 mg/day during Week 2, 150 mg/day during Week 3 and 200 mg/day during Week 4 daily in 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 venlafaxine XR 75 mg/day during Week 1, 150 mg/day during Week 2, 225 mg/day during Weeks 3 and 4 daily in double-blind induction phase.

    Number of subjects in period 1
    		Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Started
    117
    116
    113
    Full Analysis Set
    115
    114
    113
    Safety Analysis Set
    115
    116
    113
    Completed
    111
    97
    107
    Not completed
    6
    19
    6
         Consent withdrawn by subject
    1
    5
    1
         Adverse event, non-fatal
    1
    7
    2
         Unspecified
    1
    4
    2
         Lost to follow-up
    -
    1
    -
         Lack of efficacy
    1
    1
    -
         Protocol deviation
    2
    1
    1
    Period 2
    Period 2 title
    Follow-up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intranasal Esketamine 56 mg Plus Oral AD
    Arm description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Intranasal Esketamine 84 mg Plus Oral AD
    Arm description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Oral AD Plus Intranasal Placebo
    Arm description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Intranasal Esketamine 56 mg Plus Oral AD Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Started
    47
    52
    69
    Completed
    8
    10
    18
    Not completed
    39
    42
    51
         Consent withdrawn by subject
    3
    9
    2
         PI decision
    34
    29
    44
         Unspecified
    2
    2
    3
         Lost to follow-up
    -
    2
    1
         Protocol deviation
    -
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects in follow-up phase included subjects who were not eligible or who chose to not participate in the maintenance of effect study(ESKETINTRD3003) and therefore number of subjects starting the period is not consistent with the number completing the preceding period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intranasal Esketamine 56 mg Plus Oral Antidepressant
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Intranasal Esketamine 84 mg Plus Oral AD
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Oral AD Plus Intranasal Placebo
    Reporting group description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo Total
    Number of subjects
    		 117 116 113 346
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 117 116 113 346
        From 65 to 84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.5 ( 11.12 ) 45.7 ( 11.02 ) 46.8 ( 11.36 ) -
    Title for Gender
    Units: subjects
        Female
    		 82 80 81 243
        Male
    		 35 36 32 103

    End points

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    End points reporting groups
    Reporting group title
    Intranasal Esketamine 56 mg Plus Oral Antidepressant
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Intranasal Esketamine 84 mg Plus Oral AD
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Oral AD Plus Intranasal Placebo
    Reporting group description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.
    Reporting group title
    Intranasal Esketamine 56 mg Plus Oral AD
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Intranasal Esketamine 84 mg Plus Oral AD
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

    Reporting group title
    Oral AD Plus Intranasal Placebo
    Reporting group description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug.

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

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    End point title
    		 Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint Double-blind Induction Phase (Day 28)
    End point description
    MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), for total possible score of 0 to 60. Higher scores represent more severe condition. Full analysis set (FAS): all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during double-blind induction phase. Here 'N' (number of subjects analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Primary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    115
    113
    113
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -18.3 ( 14.21 )
    -17.4 ( 14.25 )
    -14.3 ( 15.00 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Intranasal Esketamine 84 mg Plus Oral AD v Oral AD Plus Intranasal Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 ANCOVA
    Parameter type
    		 Difference of Least Square (LS) Means
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.52
         upper limit
    		 1.42
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Intranasal Esketamine 56 mg Plus Oral Antidepressant v Oral AD Plus Intranasal Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference of Least Square (LS) Means
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.53
         upper limit
    		 -0.6

    Secondary: Percentage of Subjects with Onset of Clinical Response by Day 2 and Day 8

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    End point title
    		 Percentage of Subjects with Onset of Clinical Response by Day 2 and Day 8
    End point description
    A subject was defined as having a clinical response if there was at least 50% improvement (decrease) from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. Subjects were allowed one excursion (non-response) on Days 8, 15 or 22, however the score must show at least 25% improvement. Subjects who did not meet these criteria, or discontinued during the study before Day 28 were considered as non-responders and were assigned the value of 0 (that is no). FAS: 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.
    End point type
    Secondary
    End point timeframe
    Day 2 and Day 8
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    115
    114
    113
    Units: Percentage of subjects
    number (not applicable)
        Day 2
    10.4
    8.8
    1.8
        Day 8
    13.0
    11.4
    3.5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint Double-blind Induction Phase (Day 28)
    End point description
    The SDS is a subject-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1) work/school, 2) social life, and 3) family life/home responsibilities using 0-10 rating scale. Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment. FAS: 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 analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    91
    99
    95
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -10.7 ( 9.39 )
    -10.2 ( 10.00 )
    -8.1 ( 9.57 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Item Total Score up to Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Item Total Score up to Endpoint Double-blind Induction Phase (Day 28)
    End point description
    PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. Higher score indicates greater severity of depression. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). The recall period is 2 weeks. FAS: all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of subjects analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    113
    112
    113
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -10.9 ( 8.26 )
    -10.9 ( 7.81 )
    -8.9 ( 8.37 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved >=50% Reduction from Baseline in MADRS Total Score at the Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Percentage of Subjects who Achieved >=50% Reduction from Baseline in MADRS Total Score at the Endpoint Double-blind Induction Phase (Day 28)
    End point description
    A subject is defined as a responder (yes=1 and no=0) at a given time point if the percent improvement from baseline in MADRS total score is at >= 50 percentage(%). The percentage of subjects with greater than or equal to (>=) 50% improvement from baseline is reported. FAS: 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 analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using last observed carried forward (LOCF) method and the last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    At Day 28 (Double-blind Endpoint)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    115
    113
    113
    Units: Percentage of subjects
        number (not applicable)
    53.0
    47.8
    37.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Remission (MADRS<=12) at the Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Percentage of Subjects in Remission (MADRS<=12) at the Endpoint Double-blind Induction Phase (Day 28)
    End point description
    Subjects who had a MADRS total score of less than or equal to (=<) 12 were considered as remitters. FAS: 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 analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using last observed carried forward (LOCF) method and the last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    At Day 28 (Double-blind Endpoint)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    115
    113
    113
    Units: Percentage of subjects
        number (not applicable)
    34.8
    35.4
    29.2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint Double-blind Induction Phase (Day 28)
    End point description
    CGI-S provides measure of severity of subject’s illness including subject’s history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, subject is assessed on severity of mental illness 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 most extremely ill patients (a decrease in score indicates improvement). FAS: all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during double-blind induction phase. Here 'N' (number of subjects analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using LOCF method and last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    115
    113
    113
    Units: Units on a scale
        median (full range (min-max))
    -2.0 (-5 to 1)
    -2.0 (-5 to 1)
    -1.0 (-6 to 3)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Generalized Anxiety Disorder-7 item (GAD-7) Total Score up to Endpoint Double-blind Induction Phase (Day 28)

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    End point title
    		 Change From Baseline in Generalized Anxiety Disorder-7 item (GAD-7) Total Score up to Endpoint Double-blind Induction Phase (Day 28)
    End point description
    GAD-7 is a brief and validated 7-item self-reported assessment of overall anxiety. Subjects responded to each item using a 4 point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15-21). FAS: 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 analysed) signifies number of subjects who were evaluable for this endpoint. Missing data was imputed using last observed carried forward (LOCF) method and the last post baseline observation during the phase was carried forward as “End Point (Day 28 LOCF)” for that phase.
    End point type
    Secondary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    111
    109
    111
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -7.4 ( 5.94 )
    -7.7 ( 5.72 )
    -6.0 ( 6.01 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-related Quality of Life and Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28)

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    End point title
    		 Change From Baseline in Health-related Quality of Life and Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28)
    End point description
    EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ visual analogue scale (EQ-VAS), and EQ-5D-5L descriptive system. It comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health). EQ-VAS self-rating records the respondent’s own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). FAS: all randomized subjects who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during double-blind induction phase. Here 'N' (number of subjects analysed) signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Double-blind Endpoint (Day 28)
    End point values
    		 Intranasal Esketamine 56 mg Plus Oral Antidepressant Intranasal Esketamine 84 mg Plus Oral AD Oral AD Plus Intranasal Placebo
    Number of subjects analysed
    113
    112
    112
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Health Status Index
    0.224 ( 0.2481 )
    0.243 ( 0.2395 )
    0.181 ( 0.2495 )
        EQ VAS Score
    20.9 ( 25.04 )
    19.1 ( 26.86 )
    14.9 ( 27.15 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to follow up phase (up to 35 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    DB Phase: Intranasal Esketamine 56 mg Plus Oral Antidepressant
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, subjects simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 milligram [mg]/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.

    Reporting group title
    DB Phase: Intranasal Esketamine 84 mg Plus Oral AD
    Reporting group description
    		 Subjects self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.

    Reporting group title
    DB Phase: Oral AD Plus Intranasal Placebo
    Reporting group description
    		 Subjects self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, subjects simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose [MTD] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase.

    Reporting group title
    FU Phase: Intranasal Esketamine 56 mg Plus Oral AD
    Reporting group description
    		 Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the subject’s major depressive episode over a 24-week period.

    Reporting group title
    FU Phase: Intranasal Esketamine 84 mg Plus Oral AD
    Reporting group description
    		 Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the subject’s major depressive episode over a 24-week period.

    Reporting group title
    FU Phase: Oral AD Plus Intranasal Placebo
    Reporting group description
    		 Subjects who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks to assess safety and tolerability including withdrawal symptoms of study drug and for collection of additional informative data to assess the course of the subject’s major depressive episode over a 24-week period.

    Serious adverse events
    		 DB Phase: Intranasal Esketamine 56 mg Plus Oral Antidepressant DB Phase: Intranasal Esketamine 84 mg Plus Oral AD DB Phase: Oral AD Plus Intranasal Placebo FU Phase: Intranasal Esketamine 56 mg Plus Oral AD FU Phase: Intranasal Esketamine 84 mg Plus Oral AD FU Phase: Oral AD Plus Intranasal Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    2 / 47 (4.26%)
    2 / 52 (3.85%)
    1 / 69 (1.45%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    2 / 47 (4.26%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 116 (0.00%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DB Phase: Intranasal Esketamine 56 mg Plus Oral Antidepressant DB Phase: Intranasal Esketamine 84 mg Plus Oral AD DB Phase: Oral AD Plus Intranasal Placebo FU Phase: Intranasal Esketamine 56 mg Plus Oral AD FU Phase: Intranasal Esketamine 84 mg Plus Oral AD FU Phase: Oral AD Plus Intranasal Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 115 (80.87%)
    92 / 116 (79.31%)
    64 / 113 (56.64%)
    7 / 47 (14.89%)
    4 / 52 (7.69%)
    7 / 69 (10.14%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    8 / 115 (6.96%)
    11 / 116 (9.48%)
    5 / 113 (4.42%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    24
    36
    5
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    32 / 115 (27.83%)
    26 / 116 (22.41%)
    10 / 113 (8.85%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    1 / 69 (1.45%)
         occurrences all number
    111
    86
    12
    0
    1
    1
    Dizziness Postural
         subjects affected / exposed
    7 / 115 (6.09%)
    7 / 116 (6.03%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    28
    28
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    17 / 115 (14.78%)
    20 / 116 (17.24%)
    17 / 113 (15.04%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    63
    56
    81
    0
    0
    0
    Headache
         subjects affected / exposed
    23 / 115 (20.00%)
    24 / 116 (20.69%)
    19 / 113 (16.81%)
    4 / 47 (8.51%)
    2 / 52 (3.85%)
    3 / 69 (4.35%)
         occurrences all number
    42
    38
    34
    4
    2
    3
    Hypoaesthesia
         subjects affected / exposed
    14 / 115 (12.17%)
    16 / 116 (13.79%)
    2 / 113 (1.77%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences all number
    33
    48
    2
    0
    1
    0
    Lethargy
         subjects affected / exposed
    7 / 115 (6.09%)
    5 / 116 (4.31%)
    1 / 113 (0.88%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    18
    13
    3
    0
    0
    0
    Mental Impairment
         subjects affected / exposed
    6 / 115 (5.22%)
    3 / 116 (2.59%)
    1 / 113 (0.88%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    13
    9
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    19 / 115 (16.52%)
    11 / 116 (9.48%)
    3 / 113 (2.65%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    48
    31
    9
    0
    0
    0
    Sedation
         subjects affected / exposed
    6 / 115 (5.22%)
    8 / 116 (6.90%)
    1 / 113 (0.88%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    31
    22
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    24 / 115 (20.87%)
    21 / 116 (18.10%)
    13 / 113 (11.50%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    55
    87
    23
    0
    0
    0
    Tremor
         subjects affected / exposed
    4 / 115 (3.48%)
    6 / 116 (5.17%)
    2 / 113 (1.77%)
    1 / 47 (2.13%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    5
    8
    4
    1
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 115 (10.43%)
    8 / 116 (6.90%)
    5 / 113 (4.42%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    20
    13
    5
    0
    0
    1
    Feeling Drunk
         subjects affected / exposed
    7 / 115 (6.09%)
    3 / 116 (2.59%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    19
    10
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    24 / 115 (20.87%)
    24 / 116 (20.69%)
    2 / 113 (1.77%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    86
    102
    5
    0
    0
    0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    8 / 115 (6.96%)
    9 / 116 (7.76%)
    0 / 113 (0.00%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    18
    11
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 115 (6.96%)
    5 / 116 (4.31%)
    3 / 113 (2.65%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    2 / 69 (2.90%)
         occurrences all number
    8
    5
    3
    0
    1
    2
    Hypoaesthesia Oral
         subjects affected / exposed
    16 / 115 (13.91%)
    12 / 116 (10.34%)
    2 / 113 (1.77%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    61
    56
    7
    0
    0
    0
    Nausea
         subjects affected / exposed
    31 / 115 (26.96%)
    37 / 116 (31.90%)
    12 / 113 (10.62%)
    2 / 47 (4.26%)
    1 / 52 (1.92%)
    1 / 69 (1.45%)
         occurrences all number
    73
    72
    12
    3
    2
    1
    Paraesthesia Oral
         subjects affected / exposed
    9 / 115 (7.83%)
    1 / 116 (0.86%)
    2 / 113 (1.77%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    17
    1
    9
    0
    0
    0
    Vomiting
         subjects affected / exposed
    7 / 115 (6.09%)
    14 / 116 (12.07%)
    2 / 113 (1.77%)
    1 / 47 (2.13%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    11
    20
    3
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal Discomfort
         subjects affected / exposed
    4 / 115 (3.48%)
    5 / 116 (4.31%)
    7 / 113 (6.19%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    10
    8
    19
    0
    0
    0
    Throat Irritation
         subjects affected / exposed
    5 / 115 (4.35%)
    9 / 116 (7.76%)
    4 / 113 (3.54%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    21
    32
    5
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 115 (8.70%)
    9 / 116 (7.76%)
    7 / 113 (6.19%)
    1 / 47 (2.13%)
    0 / 52 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    14
    20
    10
    3
    0
    3
    Dissociation
         subjects affected / exposed
    30 / 115 (26.09%)
    32 / 116 (27.59%)
    4 / 113 (3.54%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    127
    153
    21
    0
    0
    0
    Euphoric Mood
         subjects affected / exposed
    8 / 115 (6.96%)
    2 / 116 (1.72%)
    2 / 113 (1.77%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    15
    9
    3
    0
    0
    0
    Insomnia
         subjects affected / exposed
    10 / 115 (8.70%)
    8 / 116 (6.90%)
    11 / 113 (9.73%)
    0 / 47 (0.00%)
    1 / 52 (1.92%)
    0 / 69 (0.00%)
         occurrences all number
    10
    8
    11
    0
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    6 / 115 (5.22%)
    2 / 116 (1.72%)
    1 / 113 (0.88%)
    0 / 47 (0.00%)
    0 / 52 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    8
    3
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2016
    Amendment INT-1 included following changes: Revised exclusion criteria; revised inclusion criteria; removal of prohibition of concomitant medications that prolonged the QT interval/corrected QT (QTc); indicated that the severity of a subject’s depressive symptoms was also being confirmed using a Site Independent Qualification Assessment (SIQA), and the required Week 1 Montgomery-Asberg depression rating scale (MADRS) total score was added; allowed option to start at a 30 milligram (mg) dose of duloxetine in the oral antidepressant titration schedule for subjects who had increased sensitivity towards selective serotonin reuptake inhibitors (SSRI)/serotonin and norepinephrine reuptake inhibitors (SNRI); addition of an additional sheehan disability scale (SDS) assessment on Day 15 (Week 2) of the double-blind induction phase; addition of discontinuation criteria related to electrocardiogram (ECG) readings; provided the criterion for non-response at the end of the screening/prospective observational phase; clarification on the (1) mandatory use of oral antidepressant dosing titration schedule, (2) guidance on BP monitoring on intranasal treatment session days, (3) use of prestudy and concomitant therapies, (3) language regarding mandatory discontinuation of subjects who developed treatment emergent ulcerative cystitis, (4) medication(s) that were used for depression had to be discontinued after completion of the 4-week screening/ prospective observational phase, (5) statement that there were no changes to the current oral antidepressant treatment regimen for the duration of the screening/prospective observational phase, (6) definition of clinically significant ECG abnormalities as defined by QT interval corrected according to Fridericia’s formula (QTcF).
    31 May 2016
    Amendment INT-2 included following changes: Revised inclusion; deleted the exclusion for first degree atrioventricular (AV) block; revision was made to the analysis of onset of clinical response (defined as >=50% reduction in the MADRS total score by the day after taking the first dose of double-blind medication [Day 2, 24 hours] that continued through the end of the 4-week double-blind induction phase) to indicate that subjects were allowed 1 excursion; permitted use of prescribed psychostimulants for indications other than major depressive disorder (MDD) with dosing restrictions on intranasal treatment session days; addition of (1) MADRS assessment during the follow-up phase, (2) information about 54135419TRD3008, an open-label safety extension study; maximum dose of sertraline in oral antidepressant titration schedule increased from 150 mg/day to 200 mg/day; clarification of procedure to be followed if subjects withdrew from the study.

    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.
    Transient, dissociative effects of esketamine are difficult to blind, site staff who observed treatment sessions could have been biased. To ensure unbiased efficacy evaluations, independent, remote, blinded MADRS raters assessed treatment response.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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