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    Clinical Trial Results:
    An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression. Safety and Sustenance of Esketamine Treatment Response with Repeated Doses at Intervals Determined by Symptom Severity (SUSTAIN-2)

    Summary
    EudraCT number
    2014-004587-38
    Trial protocol
    SE   BE   DE   ES   GB   AT   PL   BG   LT   FI   IT  
    Global end of trial date
    28 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Nov 2018
    First version publication date
    10 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESKETINTRD3004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02497287
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Janssen-Cilag International NV, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International NV, Clinical Registry Group, 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
    28 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the long-term safety and tolerability of intranasal esketamine plus a newly initiated oral antidepressant in subjects with treatment resistant depression (TRD), with special attention to the following: potential effects on cognitive function; potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms; potential withdrawal and/or rebound symptoms following cessation of intranasal esketamine treatment.
    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. Screening safety evaluation included the following clinical laboratory tests: hematology, serum chemistry, urinalysis, lipid panel, serum and urine pregnancy testing (for women of childbearing potential only), urine drug screen, alcohol breath test, thyroid-stimulating hormone (TSH), free thyroxine (FT4), creatinine clearance, glycated hemoglobin (HbA1c) test, serum follicle stimulating hormone (FSH) level test. Safety assessments in the study included single, 12-lead electrocardiogram (ECG), vital signs, pulse oximetry, physical examination, height, body weight and neck circumference, nasal examinations, nasal symptom questionnaire, columbia suicide severity rating scale (C-SSRS), clinician administered dissociative states scale (CADSS), 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), cognition testing.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 106
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 94
    Country: Number of subjects enrolled
    Brazil: 52
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Malaysia: 19
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Sweden: 90
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    Taiwan: 33
    Country: Number of subjects enrolled
    United States: 147
    Country: Number of subjects enrolled
    South Africa: 64
    Worldwide total number of subjects
    802
    EEA total number of subjects
    291
    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)
    624
    From 65 to 84 years
    176
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 802 subjects were enrolled in this study. Direct-entry subjects (691) and transferred-entry subjects (111) from study ESKETINTRD3005 were assigned to esketamine plus oral antidepressant.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Arm description
    Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study.
    Arm type
    Experimental

    Investigational medicinal product name
    Esketamine Intranasal Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    In the Induction phase, direct-entry subjects and non-responders from the TRD3005 study self-administered Esk twice per week for 4 weeks as a flexible dose regimen (56 or 84 mg for those less than [<]65 years; 28 mg, 56 mg or 84 mg for those greater than or equal to [>]=65 years old until Day 11 and 15, respectively, after which the dose remained to be stable for the remainder of the study. The transfer-entry responder subjects from TRD3005 joined the study in the OP/MA phase and received Esk at the starting dose of 28 mg which could be further up-titrated until week 8; from week 9, the dose remained stable until the end of the study. Subjects in OP/MA Phase received the weekly sessions of intranasal Esk for week 5 to 8 and received either weekly or every other week dosing depending on the MADRS score which was assessed monthly from week 9 to 52.

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Direct entry subjects who were < 65 years old, administered duloxetine at a dose of 60mg/day during of the study period. Subjects >=65 years old administered duloxetine at a dose of 30 mg/day with a maximum dose of 60mg/day.

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Direct entry subjects who were < 65 years old, administered Escitalopram at a dose of 10 mg/day during Week 1 of the Induction Phase, and from Week 2 to Week 52 of the study administered Escitalopram at a dose of 20 mg/day. Subjects >=65 years old administered Escitalopram at a dose of 10 mg/day during the entire Induction and Optimization/Maintenance phase.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Direct entry subjects <65 years old received 50 mg during week 1, 100 mg during Week 2 and 150 mg during Week 3 and 4 of the Induction Phase and during Optimization/Maintenance phase. Transferred entry subjects received 150 mg dose during their entire participation in the study. The dose could be reduced due to tolerability.

    Investigational medicinal product name
    Venlafaxine XR Extended Release
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Direct entry subjects who were < 65 years old received AD Venlafaxine XR at increasing doses during the Induction Phase (75 mg/day during Week 1, 150 mg/day during week 2, and 225 mg/day during week 3 and 4 of the Induction phase) and continued to administer 225 mg/day during the Optimization/Maintenance phase. Subjects who were >=65 years old received 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) during open-label Induction Phase. All subjects continued to administer Venlafaxine XR at a dose of 225 mg/day during the OP/MA phase.

    Number of subjects in period 1
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Started
    802
    Induction phase (IND)
    779
    Optimization/maintenance phase
    603
    Follow-up phase
    357
    Completed
    150
    Not completed
    652
         Protocol deviation
    4
         Lack of efficacy
    46
         Adverse event, serious fatal
    2
         Study terminated by sponsor
    331
         Consent withdrawn by subject
    52
         Other
    34
         Non-compliance with study drug
    2
         Did not meet criteria to enter op/ma phase
    84
         Pregnancy
    2
         Missed assessment
    3
         Adverse event, non-fatal
    61
         Adverse event, serious non-fatal
    16
         Lost to follow-up
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Reporting group description
    Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study.

    Reporting group values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) Total
    Number of subjects
    802 802
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    624 624
        From 65 to 84 years
    176 176
        85 years and over
    2 2
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    52.2 ± 13.69 -
    Title for Gender
    Units: subjects
        Female
    502 502
        Male
    300 300

    End points

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    End points reporting groups
    Reporting group title
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Reporting group description
    Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study.

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event is any untoward medical occurrence in a clinical study which subject administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. A TEAE defined as an event that was new in onset or increased in severity following treatment initiation. The TEAEs for the induction (IND) phase were those events with an onset date/time on or after the start of study medication, which occurred on or before the end of the IND phase and for the optimization/maintenance (OP/MA) phase were those events with an onset date/time on or after the start of OP/MA study medication, which occurred on or before the end of the optimization/maintenance phase. All enrolled analysis set include all transferred-entry and direct-entry subjects who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
    End point type
    Primary
    End point timeframe
    Screening up to Follow up period (Maximum 60 Weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    802
    Units: percentage of subjects
        number (not applicable)
    90.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Cystitis, Urinary Tract Infections, Urinary Tract Symptom, Renal and Urinary Disorders

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    End point title
    Percentage of Subjects With Cystitis, Urinary Tract Infections, Urinary Tract Symptom, Renal and Urinary Disorders [2]
    End point description
    Percentage of subjects with cystitis, urinary tract infections, urinary tract symptom, renal and urinary disorders was evaluated. Cystitis and urinary tract infections are selected MedDRA preferred terms, "urinary tract symptoms" refers to any preferred term (PT) in the group of selected PTs; and "renal and urinary disorders" refers to a MedDRA System Organ Class (SOC). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication.
    End point type
    Primary
    End point timeframe
    Screening to follow up phase (Maximum 60 Weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    802
    Units: percentage of subjects
    number (not applicable)
        Cystitis
    0.6
        Urinary tract infections
    8.1
        Renal and urinary disorders
    10.5
        Urinary tract symptoms
    17.0
    No statistical analyses for this end point

    Primary: Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score

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    End point title
    Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score [3]
    End point description
    The DET is a measure of psychomotor function and uses a well-validated simple reaction time. Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] period)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    561
    Units: log10 millisecond (msec)
        arithmetic mean (standard deviation)
    -0.0028 ± 0.12744
    No statistical analyses for this end point

    Primary: Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score

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    End point title
    Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score [4]
    End point description
    IDN test is a measure of visual attention, uses a validated choice reaction time and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    561
    Units: log10 msec
        arithmetic mean (standard deviation)
    -0.0083 ± 0.09656
    No statistical analyses for this end point

    Primary: Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score

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    End point title
    Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score [5]
    End point description
    OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses. Higher score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    561
    Units: Arcsine ([sqrt] proportion of CR)
        arithmetic mean (standard deviation)
    0.0502 ± 0.13149
    No statistical analyses for this end point

    Primary: Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score

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    End point title
    Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score [6]
    End point description
    The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    563
    Units: log10 msec
        arithmetic mean (standard deviation)
    0.0177 ± 0.10026
    No statistical analyses for this end point

    Primary: Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score

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    End point title
    Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score [7]
    End point description
    GMLT measures executive function; maze/sequencing test, scored for total number of errors. Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set: all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005and received at least 1 dose of oral AD medication. 'N' (number of subjects analysed); subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    506
    Units: Number of Errors
        arithmetic mean (standard deviation)
    6.9 ± 25.36
    No statistical analyses for this end point

    Primary: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall

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    End point title
    Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall [8]
    End point description
    HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), and a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, and recognition scores. HVLT-R is a well-validated and widely used measure of verbal episodic memory. HVLT-R Score (Total Recall) is used to measure the verbal learning. Higher score indicate better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    569
    Units: Number correct
        arithmetic mean (standard deviation)
    2.8 ± 4.74
    No statistical analyses for this end point

    Primary: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall

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    End point title
    Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall [9]
    End point description
    HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. HVLT-R is a well-validated and widely used measure of verbal episodic memory. The test measure total number of words recalled after a 20 minute delay. Higher score indicate better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    569
    Units: Number correct
        arithmetic mean (standard deviation)
    0.8 ± 2.31
    No statistical analyses for this end point

    Primary: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: True Positives

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    End point title
    Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: True Positives [10]
    End point description
    HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. The HVLT-R is a well-validated and widely used measure of verbal episodic memory. The test measures total number of true positives (words recognized) after a 20 minute delay. Higher score indicate better performance. Higher change from baseline is better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral AD medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    568
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.3 ± 2.83
    No statistical analyses for this end point

    Primary: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index

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    End point title
    Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index [11]
    End point description
    HVLT-R, a measure of verbal learning, memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions, word lists aloud, recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. HVLT-R is a well-validated and measures verbal episodic memory. Test measures total number of true positives (words recognized) minus total number of false positives after a 20 minute delay. Higher score indicates better performance. Higher change from baseline is better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral AD medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses.
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    568
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.5 ± 3.16
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase

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    End point title
    Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase
    End point description
    MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), total possible score of 60. Mean change (standard deviation [SD]) in MADRS total score from baseline to endpoint was evaluated. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder subjects). 'N' (number of subjects analysed); subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    756
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -16.4 ± 8.76
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase

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    End point title
    Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase
    End point description
    MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), a total possible score of 60. The mean change (SD) in MADRS total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    603
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.3 ± 8.12
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase

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    End point title
    Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase
    End point description
    PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The mean change (SD) in PHQ-9 total score from baseline (IND) to the endpoint (4 weeks) was evaluated. A higher score indicates greater severity of depression. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    746
    Units: Unit on a Scale
        arithmetic mean (standard deviation)
    -8.9 ± 6.67
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase

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    End point title
    Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase
    End point description
    PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The mean change (SD) in PHQ-9 total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. A higher score indicates greater severity of depression. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (OP/MA) analysis set include all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    603
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -0.2 ± 5.65
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase

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    End point title
    Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase
    End point description
    CGI-S measures severity of subject’s illness that include knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on subject’s ability to function. Scale ranges from 0 - 7, were 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. Median change (range) in CGI-S score from baseline (IND) to endpoint (4 weeks) was evaluated. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    763
    Units: Units on a Scale
        median (full range (min-max))
    -2.0 (-6 to 2)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase

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    End point title
    Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase
    End point description
    The CGI-S measures the severity of the subject’s illness that include knowledge of the 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, where 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 median change (range) in CGI-S score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    603
    Units: Units on a Scale
        median (full range (min-max))
    0.0 (-3 to 4)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase

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    End point title
    Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase
    End point description
    GAD-7 is brief, validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0-21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Mean change (SD) in GAD-7 total score from baseline (IND) to endpoint (4 weeks) was evaluated. Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as “End Point”. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed): subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    724
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -5.9 ± 5.85
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase

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    End point title
    Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase
    End point description
    GAD-7 is brief and validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score ranges from 0-21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Mean change (SD) in GAD-7 total score from baseline (OP/MA) to endpoint (52 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    574
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.2 ± 4.23
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase

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    End point title
    Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase
    End point description
    EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ visual analogue scale (EQ VAS), 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). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health), EQ-VAS score from 0 (worst health you can imagine) to 100 (best health you can imagine), Sum score from 0 - 100, Sum score=(sum of scores from 5 dimensions minus 5)*5”. Mean change (SD) in EQ-5D health status index score from baseline (IND) to endpoint (4 weeks) was evaluated. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder subjects). 'n' signifies those subjects who were evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    746
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Health Status Index (n= 745)
    0.190 ± 0.2138
        EQ VAS Score (n= 746)
    17.0 ± 21.69
        Sum Score (n= 745)
    -15.3 ± 16.26
    No statistical analyses for this end point

    Secondary: Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as EQ 5D-5L During OP/MA Phase

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    End point title
    Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as EQ 5D-5L During OP/MA Phase
    End point description
    EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ visual analogue scale (EQ VAS), 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). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health), EQ-VAS score from 0 (worst health) to 100 (best health), Sum score from 0-100, Sum score=(sum of the scores from the 5 dimensions minus 5)*5”. Mean change (SD) in EQ-5D health status index score from baseline (OP/MA) to endpoint (52 weeks) was evaluated. Full (OP/MA) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase. 'N' (number of subjects analysed) signifies: subjects who were evaluable for this endpoint, 'n' signifies those subjects who were evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    603
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Health Status Index
    -0.009 ± 0.1411
        EQ VAS Score
    1.6 ± 18.51
        Sum Score
    -0.7 ± 13.19
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase

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    End point title
    Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase
    End point description
    SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0-10 rating scale. Score for the first three items are summed to create a total score of 0-30, higher score indicates greater impairment and a negative change in score indicates improvement. Mean change (SD) in SDS total score from baseline (IND) to the endpoint (4 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    626
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -9.3 ± 7.86
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Impairment and Associated Disability Using Sheehan Disability Scale Total Score During OP/MA Phase

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    End point title
    Change From Baseline in Functional Impairment and Associated Disability Using Sheehan Disability Scale Total Score During OP/MA Phase
    End point description
    SDS was a subject-reported outcome measure and was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment and a negative change in score indicates improvement. The mean change (SD) in SDS total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    541
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -1.6 ± 8.25
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Response Rate Over Time Who Achieved Greater Than or Equal to (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score During IND Phase

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    End point title
    Percentage of Subjects With Response Rate Over Time Who Achieved Greater Than or Equal to (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score During IND Phase
    End point description
    Response rate over time is defined as percentage of subjects with >= 50 % reduction from baseline (IND phase) in the MADRS total score. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 8, 15, 22 and End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    756
    Units: Percentage of subjects
    number (not applicable)
        Day 8 (n=739)
    11.6
        Day 15 (n=751)
    25.0
        Day 22 (n=753)
    42.8
        End point (n=756)
    78.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Response Rate Over Time Who Achieved >= 50 % Reduction From Baseline in PHQ-9 Total Score During IND Phase

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    End point title
    Percentage of Subjects With Response Rate Over Time Who Achieved >= 50 % Reduction From Baseline in PHQ-9 Total Score During IND Phase
    End point description
    Response rate over time is defined as percentage of subjects with >= 50 % reduction from baseline (IND phase) in PHQ-9 total score. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set include all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to the End-point (last post-baseline assessment value during 4 Week IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    746
    Units: percentage of subjects
    number (not applicable)
        Day 15 (n=724)
    37.2
        End point (n=744)
    62.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Remission Rate Over Time With MADRS Total Score Less Than or Equal to (<=) 12 During IND Phase

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    End point title
    Percentage of Subjects With Remission Rate Over Time With MADRS Total Score Less Than or Equal to (<=) 12 During IND Phase
    End point description
    Remission rate over time is defined as percentage of subjects with MADRS total score <= 12. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 8, 15, 22 and End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    756
    Units: percentage of subjects
    number (not applicable)
        Day 8 (n=739)
    7.3
        Day 15 (n=751)
    15.6
        Day 22 (n=753)
    27.2
        End point (n=756)
    47.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Remission Rate Over Time With PHQ-9 Total Score <= 4 During IND Phase

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    End point title
    Percentage of Subjects With Remission Rate Over Time With PHQ-9 Total Score <= 4 During IND Phase
    End point description
    Remission rate over time is defined as percentage of subjects with PHQ-9 total score less than or equals to 4. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 15 and End-point (last post-baseline assessment value during 4 weeks of IND period)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    746
    Units: percentage of subjects
    number (not applicable)
        Day 15 (n=726)
    12.7
        Endpoint (n=746)
    26.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) During IND Phase

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    End point title
    Percentage of Subjects With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) During IND Phase
    End point description
    The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization, derealization, and amnesia. Subjects responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline of each dosing session (predose) , up to the last post-dose measurement (1.5 hours) from the start of Induction Phase to End of Induction phase (week 4)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    775
    Units: percentage of subjects
        number (not applicable)
    92.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Increase Score From Predose at Any Time in CADSS During OP/MA Phase

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    End point title
    Percentage of Subjects With an Increase Score From Predose at Any Time in CADSS During OP/MA Phase
    End point description
    The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization, derealization, and amnesia. Subjects responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline of each dosing session (predose) , up to the last post-dose measurement (1.5 hours) from the start of Induction Phase to End of Optimization/Maintenance Phase (week 52)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    603
    Units: percentage of subjects
        number (not applicable)
    86.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases

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    End point title
    Percentage of Subjects With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases
    End point description
    Percentage of subjects with treatment-emergent acute hypertension (Systolic Blood Pressure >= 180 mm Hg or Diastolic Blood Pressure >= 110 mm Hg) during IND and OP/MA Phases was evaluated. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication.
    End point type
    Secondary
    End point timeframe
    Screening up to OP/MA phase (Week 52)
    End point values
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Number of subjects analysed
    802
    Units: percentage of subjects
    number (not applicable)
        Systolic BP >=180
    2.2
        Diastolic BP >=110
    2.4
    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 (Week 60)
    Adverse event reporting additional description
    There were 2 deaths resulting from adverse events.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Reporting group description
    Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study.

    Serious adverse events
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 802 (6.86%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian Cancer
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcohol Abuse
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 802 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Delusion
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    8 / 802 (1.00%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Depression Suicidal
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Major Depression
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional Self-Injury
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    6 / 802 (0.75%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    6 / 802 (0.75%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Costochondral Separation
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot Fracture
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Transaminases Increased
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Psychomotor Hyperactivity
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Anal Incontinence
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis Microscopic
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal Ulcer
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Stress Urinary Incontinence
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vesical Fistula
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Synovial Cyst
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dengue Fever
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 802 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 802 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    653 / 802 (81.42%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    75 / 802 (9.35%)
         occurrences all number
    219
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    264 / 802 (32.92%)
         occurrences all number
    1663
    Dizziness Postural
         subjects affected / exposed
    67 / 802 (8.35%)
         occurrences all number
    532
    Dysgeusia
         subjects affected / exposed
    95 / 802 (11.85%)
         occurrences all number
    602
    Headache
         subjects affected / exposed
    200 / 802 (24.94%)
         occurrences all number
    480
    Paraesthesia
         subjects affected / exposed
    58 / 802 (7.23%)
         occurrences all number
    176
    Hypoaesthesia
         subjects affected / exposed
    95 / 802 (11.85%)
         occurrences all number
    592
    Sedation
         subjects affected / exposed
    71 / 802 (8.85%)
         occurrences all number
    280
    Somnolence
         subjects affected / exposed
    134 / 802 (16.71%)
         occurrences all number
    708
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    60 / 802 (7.48%)
         occurrences all number
    199
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    63 / 802 (7.86%)
         occurrences all number
    97
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    88 / 802 (10.97%)
         occurrences all number
    516
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    63 / 802 (7.86%)
         occurrences all number
    105
    Dissociation
         subjects affected / exposed
    221 / 802 (27.56%)
         occurrences all number
    1466
    Anxiety
         subjects affected / exposed
    70 / 802 (8.73%)
         occurrences all number
    125
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    60 / 802 (7.48%)
         occurrences all number
    79
    Hypoaesthesia Oral
         subjects affected / exposed
    73 / 802 (9.10%)
         occurrences all number
    251
    Nausea
         subjects affected / exposed
    201 / 802 (25.06%)
         occurrences all number
    422
    Vomiting
         subjects affected / exposed
    87 / 802 (10.85%)
         occurrences all number
    144
    Infections and infestations
    Influenza
         subjects affected / exposed
    43 / 802 (5.36%)
         occurrences all number
    47
    Urinary Tract Infection
         subjects affected / exposed
    65 / 802 (8.10%)
         occurrences all number
    89
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    82 / 802 (10.22%)
         occurrences all number
    120

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2015
    The overall reason for the amendment was to allow for the use of a 28 milligram (mg) dose throughout the study, based on pharmacokinetic data from study ESKETINTRD1012 in elderly subjects.
    17 Feb 2016
    The overall reason for this amendment was to update and/or clarify protocol content based on ongoing feedback received during the study initiation activities. In addition, key protocol entry criteria for direct entry subjects have been added for transferred entry subjects, in order to confirm that subject’s, who completed ESKETINTRD3005, continue to meet the criteria at entry to the ESKETINTRD3004 study.
    06 Jun 2016
    The overall reason for the amendment was to modify entry criteria with respect to PR interval based on Phase 1 and Phase 2 data, to add the information about the long-term safety study 54135419TRD3008; to implement changes and align language being applied across all Phase 3 studies in the esketamine development program; to correct errors and make minor clarifications in the text of the inclusion and exclusion criteria.
    06 Jul 2016
    The overall reason for the amendment was to remove the exclusion criteria for subjects aged ≥ 65 years with first degree AV block.

    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 treatment was open-label with no comparator group. Based on predefined criteria related to achieving the required number of exposures at 6 and 12 months, not all enrolled subjects completed the full planned duration of the study.
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