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    Clinical Trial Results:
    A Double-blind, Randomized, Psychoactive Placebo-controlled, Study to Evaluate the Efficacy and Safety of 3 Fixed Doses (28 mg, 56 mg and 84 mg) of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Pediatric Subjects Assessed to be at Imminent Risk for Suicide

    Summary
    EudraCT number
    		 2016-004422-42
    Trial protocol
    		 HU   ES   BE   PL   IT   BG   FR   Outside EU/EEA  
    Global end of trial date
    31 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2023
    First version publication date
    15 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ESKETINSUI2002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03185819
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001428-PIP03-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal esketamine (28 milligrams [mg], 56 mg, and 84 mg) compared with psychoactive placebo (oral midazolam) in rapidly reducing the symptoms of major depressive disorder (MDD), including suicidal ideation, in subjects 12 to less than (<) 18 years of age who were assessed to be at imminent risk for suicide.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 2018
    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
    Brazil: 11
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    147
    EEA total number of subjects
    49
    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)
    147
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 147 subjects were randomised, of which 146 subjects (safety analysis set) were involved in the analysis.

    Period 1
    Period 1 title
    Double Blind Period (25 Days)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Midazolam + SOC
    Arm description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received placebo nasal spray along with psychoactive oral midazolam 0.125 milligrams per kilogram (mg/kg) solution 2 times per week for 4 weeks. As local standard of care (SOC), subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received placebo nasal spray 2 times per week for 4 weeks.

    Investigational medicinal product name
    Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC antidepressant (either fluoxetine, escitalopram or sertraline) based on treating physician(s) clinical judgment daily at least through Day 25.

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received midazolam 0.125 mg/kg oral solution 2 times per week for 4 weeks.

    Arm title
    		 Esketamine 28 mg + Placebo + SOC
    Arm description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 28 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    JNJ-54135419
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received Esketamine 28 mg nasal spray 2 times per week for 4 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received oral placebo solution 2 times per week for 4 weeks.

    Investigational medicinal product name
    Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC antidepressant (either fluoxetine, escitalopram or sertraline) based on treating physician(s) clinical judgment daily at least through Day 25.

    Arm title
    		 Esketamine 56 mg + Placebo + SOC
    Arm description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 56 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    JNJ-54135419
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Subject received Esketamine 56 mg nasal spray 2 times per week for 4 weeks.

    Investigational medicinal product name
    Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC antidepressant (either fluoxetine, escitalopram or sertraline) based on treating physician(s) clinical judgment daily at least through Day 25.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received oral placebo solution 2 times per week for 4 weeks.

    Arm title
    		 Esketamine 84 mg + Placebo + SOC
    Arm description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 84 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine
    Investigational medicinal product code
    Other name
    JNJ-54135419
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received Esketamine 84 mg nasal spray 2 times per week for 4 weeks.

    Investigational medicinal product name
    Antidepressant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC antidepressant (either fluoxetine, escitalopram or sertraline) based on treating physician(s) clinical judgment daily at least through Day 25.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oral placebo solution 2 times per week for 4 weeks.

    Number of subjects in period 1 [1]
    		Placebo + Midazolam + SOC Esketamine 28 mg + Placebo + SOC Esketamine 56 mg + Placebo + SOC Esketamine 84 mg + Placebo + SOC
    Started
    63
    29
    31
    23
    Completed
    59
    29
    29
    21
    Not completed
    4
    0
    2
    2
         Adverse Event
    1
    -
    -
    -
         Unspecified
    1
    -
    1
    -
         Subject refused further study treatment
    -
    -
    -
    1
         Withdrawal by parent/guardian
    -
    -
    -
    1
         Lack of efficacy
    2
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 147 subjects were enrolled, of which 146 subjects received the drug and were included in the analysis.
    Period 2
    Period 2 title
    Follow up Phase (6 months)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Midazolam + SOC
    Arm description
    		 Subjects received Standard of Care (SOC) per clinical judgment. Subjects were followed for 6 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC per clinical judgment and were followed for 6 months.

    Arm title
    		 Esketamine 28 mg + Placebo + SOC
    Arm description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC per clinical judgment and were followed for 6 months.

    Arm title
    		 Esketamine 56 mg + Placebo + SOC
    Arm description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC per clinical judgment and were followed for 6 months.

    Arm title
    		 Esketamine 84 mg + Placebo + SOC
    Arm description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received SOC per clinical judgment and were followed for 6 months.

    Number of subjects in period 2
    		Placebo + Midazolam + SOC Esketamine 28 mg + Placebo + SOC Esketamine 56 mg + Placebo + SOC Esketamine 84 mg + Placebo + SOC
    Started
    59
    29
    29
    21
    Completed
    48
    24
    21
    18
    Not completed
    11
    5
    8
    3
         Consent withdrawn by subject
    3
    3
    2
    -
         Physician decision
    2
    -
    2
    -
         Adverse Event
    -
    1
    -
    -
         Death
    1
    -
    -
    -
         Requires treatment with ECT, TMS, ketamine
    1
    -
    -
    -
         Unspecified
    1
    -
    3
    1
         Lost to follow-up
    2
    1
    -
    2
         Withdrawal by parent/guardian
    1
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Midazolam + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received placebo nasal spray along with psychoactive oral midazolam 0.125 milligrams per kilogram (mg/kg) solution 2 times per week for 4 weeks. As local standard of care (SOC), subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 28 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 28 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 56 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 56 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 84 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 84 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group values
    		 Placebo + Midazolam + SOC Esketamine 28 mg + Placebo + SOC Esketamine 56 mg + Placebo + SOC Esketamine 84 mg + Placebo + SOC Total
    Number of subjects
    		 63 29 31 23 146
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 63 29 31 23 146
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65 to 84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ( 1.45 ) 14.9 ( 1.33 ) 14.8 ( 1.52 ) 14.3 ( 1.43 ) -
    Title for Gender
    Units: subjects
        Female
    		 48 24 25 17 114
        Male
    		 15 5 6 6 32

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Midazolam + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received placebo nasal spray along with psychoactive oral midazolam 0.125 milligrams per kilogram (mg/kg) solution 2 times per week for 4 weeks. As local standard of care (SOC), subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 28 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 28 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 56 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 56 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    Esketamine 84 mg + Placebo + SOC
    Reporting group description
    		 In double blind period, subjects with MDD who were at imminent risk for suicide received Esketamine 84 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.
    Reporting group title
    Placebo + Midazolam + SOC
    Reporting group description
    		 Subjects received Standard of Care (SOC) per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    Esketamine 28 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    Esketamine 56 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    Esketamine 84 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Subject analysis set title
    Placebo + Midazolam + SOC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with MDD who were at imminent risk for suicide received placebo nasal spray along with psychoactive oral midazolam 0.125 milligrams per kilogram (mg/kg) solution 2 times per week for 4 weeks. As SOC, Subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects were followed for 6 months.

    Subject analysis set title
    Esketamine 28 mg + Placebo + SOC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with MDD who were at imminent risk for suicide received Esketamine 28 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects were followed for 6 months.

    Subject analysis set title
    Esketamine 56 mg + Placebo + SOC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with MDD who were at imminent risk for suicide received Esketamine 56 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects were followed for 6 months.

    Subject analysis set title
    Esketamine 84 mg + Placebo + SOC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with MDD who were at imminent risk for suicide received Esketamine 84 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects were followed for 6 months.

    Subject analysis set title
    Pooled Esketamine 56 mg + Esketamine 84 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Pooled data of 'Esketamine 56 mg + Placebo + SOC' arm and 'Esketamine 84 mg + Placebo + SOC' arm was analysed.

    Primary: Change From Baseline in Children’s Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose

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    End point title
    		 Change From Baseline in Children’s Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose
    End point description
    The CDRS-R is a validated 17- item, clinician-rated instrument developed to assess depressive symptomatology in children that measures the severity of a patient’s depressive symptoms. The 17-item included 14 best description items that were determined by CDRS-R raters based on their scores from interviewing of the subject and caregiver, and 3 nonverbal behaviour ratings. The item scores ranged from 1 to 5 or 1 to 7, with a possible total score ranging from 17 to 113. A higher score represented a more severe condition. Full efficacy analysis set for DB phase was defined as all randomized subjects who received at least 1 dose of double-blind study medication during the DB phase and have both a baseline and a post dose evaluation for the CDRS-R total score. Follow-up analysis set for follow-up phase was defined as all subjects who completed the double-blind phase and either entered the follow-up phase or have provided adverse event data after the double-blind phase.
    End point type
    Primary
    End point timeframe
    Baseline (predose) on Day 1 to 24 hours post first dose
    End point values
    		 Placebo + Midazolam + SOC Esketamine 28 mg + Placebo + SOC Esketamine 56 mg + Placebo + SOC Esketamine 84 mg + Placebo + SOC Pooled Esketamine 56 mg + Esketamine 84 mg
    Number of subjects analysed
    63
    28
    31
    23
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -26.2 ( 16.72 )
    -29.6 ( 18.15 )
    -31.8 ( 12.92 )
    -30.3 ( 17.48 )
    -31.2 ( 14.90 )
    Statistical analysis title
    		 Pooled Esketamine Vs Midazolam + SOC
    Comparison groups
    Pooled Esketamine 56 mg + Esketamine 84 mg v Placebo + Midazolam + SOC
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.19
         upper limit
    		 -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.74
    Statistical analysis title
    		 Esketamine 28 mg + SOC Vs Midazolam + SOC
    Comparison groups
    Placebo + Midazolam + SOC v Esketamine 28 mg + Placebo + SOC
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference of LS Means
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.08
         upper limit
    		 4.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.35
    Statistical analysis title
    		 Esketamine 56 mg + SOC Vs Midazolam + SOC
    Comparison groups
    Placebo + Midazolam + SOC v Esketamine 56 mg + Placebo + SOC
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.072
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Mean
    Point estimate
    -5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.25
         upper limit
    		 0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.23
    Statistical analysis title
    		 Esketamine 84 mg + Placebo VS Midazolam + SOC
    Comparison groups
    Placebo + Midazolam + SOC v Esketamine 84 mg + Placebo + SOC
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.123
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Mean
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.91
         upper limit
    		 1.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.65

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double Blind Period: Until Day 25; Follow-up period: Up to 6 months
    Adverse event reporting additional description
    Safety analysis set for DB period included all randomized subjects who received at least 1 dose of study medication during the double-blind period. Follow-up analysis set for follow-up period included subjects who completed the double-blind treatment period and either entered the follow-up period or provided AE data after the DB treatment period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    DB: Placebo + Midazolam + SOC
    Reporting group description
    		 In double blind (DB) period, subjects with MDD who were at imminent risk for suicide received placebo nasal spray along with psychoactive oral midazolam 0.125 milligrams per kilogram (mg/kg) solution 2 times per week for 4 weeks. As local standard of care (SOC), subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up (FU) period.

    Reporting group title
    DB: Esketamine 28 mg + Placebo + SOC
    Reporting group description
    		 In DB period, subjects with MDD who were at imminent risk for suicide received Esketamine 28 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    DB: Esketamine 56 mg + Placebo + SOC
    Reporting group description
    		 In DB period, subjects with MDD who were at imminent risk for suicide received Esketamine 56 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    DB: Esketamine 84 mg + Placebo + SOC
    Reporting group description
    		 In DB period, subjects with MDD who were at imminent risk for suicide received Esketamine 84 mg nasal spray along with oral placebo solution 2 times per week for 4 weeks. As local SOC, subjects were hospitalized initially for recommended 5 days and received antidepressant (either fluoxetine, escitalopram or sertraline) daily at least through Day 25 and evidence-based psychological therapy for at least 81 days and close outpatient follow-up based on treating physician(s) clinical judgment. Subjects who completed the double-blind period entered the follow-up period.

    Reporting group title
    FU: Placebo + Midazolam + SOC
    Reporting group description
    		 Subjects received Standard of Care (SOC) per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    FU: Esketamine 28 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    FU: Esketamine 56 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Reporting group title
    FU: Esketamine 84 mg + Placebo + SOC
    Reporting group description
    		 Subjects received SOC per clinical judgment. Subjects were followed for 6 months.

    Serious adverse events
    		 DB: Placebo + Midazolam + SOC DB: Esketamine 28 mg + Placebo + SOC DB: Esketamine 56 mg + Placebo + SOC DB: Esketamine 84 mg + Placebo + SOC FU: Placebo + Midazolam + SOC FU: Esketamine 28 mg + Placebo + SOC FU: Esketamine 56 mg + Placebo + SOC FU: Esketamine 84 mg + Placebo + SOC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 63 (14.29%)
    4 / 29 (13.79%)
    7 / 31 (22.58%)
    1 / 23 (4.35%)
    19 / 59 (32.20%)
    10 / 29 (34.48%)
    8 / 29 (27.59%)
    7 / 21 (33.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status Migrainosus
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression Suicidal
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    3 / 59 (5.08%)
    2 / 29 (6.90%)
    1 / 29 (3.45%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Bipolar Disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    3 / 63 (4.76%)
    3 / 29 (10.34%)
    2 / 31 (6.45%)
    0 / 23 (0.00%)
    4 / 59 (6.78%)
    5 / 29 (17.24%)
    3 / 29 (10.34%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
    0 / 0
    0 / 4
    0 / 10
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Self-Injury
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    2 / 59 (3.39%)
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    5 / 63 (7.94%)
    1 / 29 (3.45%)
    5 / 31 (16.13%)
    1 / 23 (4.35%)
    9 / 59 (15.25%)
    3 / 29 (10.34%)
    5 / 29 (17.24%)
    4 / 21 (19.05%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 5
    0 / 1
    0 / 11
    0 / 3
    0 / 11
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hiv Infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Food Refusal
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DB: Placebo + Midazolam + SOC DB: Esketamine 28 mg + Placebo + SOC DB: Esketamine 56 mg + Placebo + SOC DB: Esketamine 84 mg + Placebo + SOC FU: Placebo + Midazolam + SOC FU: Esketamine 28 mg + Placebo + SOC FU: Esketamine 56 mg + Placebo + SOC FU: Esketamine 84 mg + Placebo + SOC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 63 (90.48%)
    26 / 29 (89.66%)
    30 / 31 (96.77%)
    23 / 23 (100.00%)
    48 / 59 (81.36%)
    21 / 29 (72.41%)
    19 / 29 (65.52%)
    14 / 21 (66.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    9
    1
    2
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    3 / 59 (5.08%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    1
    0
    Feeling Drunk
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    6
    0
    3
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    2 / 23 (8.70%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    9
    4
    0
    3
    2
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    1 / 23 (4.35%)
    4 / 59 (6.78%)
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    1 / 21 (4.76%)
         occurrences all number
    6
    0
    1
    1
    9
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 29 (6.90%)
    3 / 31 (9.68%)
    1 / 23 (4.35%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    5
    3
    2
    1
    0
    0
    2
    Nasal Congestion
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 29 (0.00%)
    2 / 31 (6.45%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    2
    0
    1
    0
    1
    2
    Nasal Discomfort
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 29 (6.90%)
    3 / 31 (9.68%)
    3 / 23 (13.04%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    2
    5
    9
    0
    0
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 63 (4.76%)
    2 / 29 (6.90%)
    1 / 31 (3.23%)
    2 / 23 (8.70%)
    2 / 59 (3.39%)
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    4
    1
    2
    2
    3
    0
    1
    Pharyngeal Hypoaesthesia
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    3
    3
    0
    0
    0
    0
    0
    Sneezing
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    1 / 31 (3.23%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    1
    4
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    8 / 63 (12.70%)
    1 / 29 (3.45%)
    1 / 31 (3.23%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    8
    1
    1
    0
    0
    0
    0
    0
    Throat Irritation
         subjects affected / exposed
    3 / 63 (4.76%)
    2 / 29 (6.90%)
    3 / 31 (9.68%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    4
    3
    3
    0
    0
    0
    0
    Psychiatric disorders
    Disinhibition
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 29 (6.90%)
    0 / 31 (0.00%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    8
    0
    2
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    2 / 59 (3.39%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    2
    0
    0
    0
    3
    1
    0
    5
    Confusional State
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    12
    2
    2
    1
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    10 / 63 (15.87%)
    3 / 29 (10.34%)
    4 / 31 (12.90%)
    2 / 23 (8.70%)
    7 / 59 (11.86%)
    3 / 29 (10.34%)
    4 / 29 (13.79%)
    3 / 21 (14.29%)
         occurrences all number
    15
    3
    5
    6
    16
    6
    4
    11
    Agitation
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    1 / 31 (3.23%)
    1 / 23 (4.35%)
    1 / 59 (1.69%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    3
    4
    4
    1
    1
    0
    1
    Aggression
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    3 / 59 (5.08%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Dissociation
         subjects affected / exposed
    11 / 63 (17.46%)
    12 / 29 (41.38%)
    12 / 31 (38.71%)
    11 / 23 (47.83%)
    1 / 59 (1.69%)
    1 / 29 (3.45%)
    1 / 29 (3.45%)
    0 / 21 (0.00%)
         occurrences all number
    24
    46
    51
    58
    1
    1
    4
    0
    Euphoric Mood
         subjects affected / exposed
    6 / 63 (9.52%)
    6 / 29 (20.69%)
    5 / 31 (16.13%)
    5 / 23 (21.74%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    12
    17
    22
    24
    1
    0
    0
    0
    Time Perception Altered
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    0
    0
    Suicidal Ideation
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    4 / 59 (6.78%)
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    0
    0
    6
    3
    0
    2
    Intentional Self-Injury
         subjects affected / exposed
    12 / 63 (19.05%)
    6 / 29 (20.69%)
    6 / 31 (19.35%)
    5 / 23 (21.74%)
    21 / 59 (35.59%)
    7 / 29 (24.14%)
    3 / 29 (10.34%)
    7 / 21 (33.33%)
         occurrences all number
    19
    9
    12
    7
    33
    19
    3
    17
    Insomnia
         subjects affected / exposed
    8 / 63 (12.70%)
    4 / 29 (13.79%)
    2 / 31 (6.45%)
    2 / 23 (8.70%)
    1 / 59 (1.69%)
    4 / 29 (13.79%)
    2 / 29 (6.90%)
    0 / 21 (0.00%)
         occurrences all number
    16
    4
    7
    3
    1
    4
    3
    0
    Initial Insomnia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 29 (3.45%)
    1 / 31 (3.23%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    1 / 29 (3.45%)
    2 / 29 (6.90%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    3
    0
    Illusion
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    2 / 31 (6.45%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    2
    3
    0
    0
    0
    0
    Hallucination, Visual
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 29 (3.45%)
    1 / 31 (3.23%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    7
    1
    1
    2
    0
    0
    0
    0
    Investigations
    Weight Increased
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    5 / 59 (8.47%)
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    0
    0
    5
    2
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    2 / 31 (6.45%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    0
    0
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    3 / 31 (9.68%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    3
    4
    2
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    15 / 63 (23.81%)
    10 / 29 (34.48%)
    8 / 31 (25.81%)
    9 / 23 (39.13%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    53
    57
    33
    39
    0
    0
    0
    0
    Memory Impairment
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 29 (3.45%)
    3 / 31 (9.68%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    6
    1
    3
    1
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    2 / 63 (3.17%)
    5 / 29 (17.24%)
    8 / 31 (25.81%)
    4 / 23 (17.39%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    12
    24
    7
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    18 / 63 (28.57%)
    10 / 29 (34.48%)
    13 / 31 (41.94%)
    7 / 23 (30.43%)
    12 / 59 (20.34%)
    10 / 29 (34.48%)
    7 / 29 (24.14%)
    3 / 21 (14.29%)
         occurrences all number
    33
    17
    34
    18
    20
    14
    11
    6
    Dizziness
         subjects affected / exposed
    27 / 63 (42.86%)
    16 / 29 (55.17%)
    16 / 31 (51.61%)
    16 / 23 (69.57%)
    3 / 59 (5.08%)
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 21 (0.00%)
         occurrences all number
    44
    76
    88
    58
    5
    0
    2
    0
    Sedation
         subjects affected / exposed
    9 / 63 (14.29%)
    2 / 29 (6.90%)
    4 / 31 (12.90%)
    2 / 23 (8.70%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    45
    2
    7
    4
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    24 / 63 (38.10%)
    10 / 29 (34.48%)
    9 / 31 (29.03%)
    8 / 23 (34.78%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 21 (0.00%)
         occurrences all number
    123
    36
    34
    25
    2
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 29 (10.34%)
    2 / 31 (6.45%)
    2 / 23 (8.70%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    4
    2
    2
    3
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    1 / 23 (4.35%)
    3 / 59 (5.08%)
    1 / 29 (3.45%)
    1 / 29 (3.45%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    1
    4
    1
    1
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    2 / 31 (6.45%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    5
    7
    0
    1
    0
    0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    4 / 31 (12.90%)
    3 / 23 (13.04%)
    1 / 59 (1.69%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    8
    3
    7
    12
    1
    1
    0
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 63 (6.35%)
    3 / 29 (10.34%)
    2 / 31 (6.45%)
    3 / 23 (13.04%)
    7 / 59 (11.86%)
    1 / 29 (3.45%)
    2 / 29 (6.90%)
    1 / 21 (4.76%)
         occurrences all number
    5
    3
    2
    5
    8
    1
    3
    1
    Abdominal Pain
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 29 (10.34%)
    0 / 31 (0.00%)
    2 / 23 (8.70%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    0
    3
    2
    0
    1
    3
    Hypoaesthesia Oral
         subjects affected / exposed
    0 / 63 (0.00%)
    6 / 29 (20.69%)
    6 / 31 (19.35%)
    5 / 23 (21.74%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    19
    29
    7
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    1 / 23 (4.35%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    2
    1
    2
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    1 / 23 (4.35%)
    6 / 59 (10.17%)
    1 / 29 (3.45%)
    3 / 29 (10.34%)
    2 / 21 (9.52%)
         occurrences all number
    4
    0
    1
    3
    7
    1
    3
    2
    Dyspepsia
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 29 (6.90%)
    1 / 31 (3.23%)
    0 / 23 (0.00%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 63 (6.35%)
    5 / 29 (17.24%)
    7 / 31 (22.58%)
    6 / 23 (26.09%)
    4 / 59 (6.78%)
    3 / 29 (10.34%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    5
    11
    7
    5
    3
    0
    0
    Nausea
         subjects affected / exposed
    11 / 63 (17.46%)
    8 / 29 (27.59%)
    15 / 31 (48.39%)
    13 / 23 (56.52%)
    9 / 59 (15.25%)
    3 / 29 (10.34%)
    3 / 29 (10.34%)
    1 / 21 (4.76%)
         occurrences all number
    13
    19
    43
    37
    10
    3
    11
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    3
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 29 (6.90%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    2 / 23 (8.70%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    3
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 29 (3.45%)
    0 / 31 (0.00%)
    2 / 23 (8.70%)
    3 / 59 (5.08%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    2
    3
    0
    0
    0
    Muscular Weakness
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 29 (6.90%)
    0 / 31 (0.00%)
    1 / 23 (4.35%)
    0 / 59 (0.00%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    0
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 29 (3.45%)
    1 / 31 (3.23%)
    2 / 23 (8.70%)
    0 / 59 (0.00%)
    2 / 29 (6.90%)
    1 / 29 (3.45%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    1
    2
    0
    2
    1
    2
    Infections and infestations
    Covid-19
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    2 / 59 (3.39%)
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 29 (0.00%)
    2 / 31 (6.45%)
    1 / 23 (4.35%)
    2 / 59 (3.39%)
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    2
    1
    2
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 29 (0.00%)
    1 / 31 (3.23%)
    0 / 23 (0.00%)
    3 / 59 (5.08%)
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    1
    0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 29 (0.00%)
    0 / 31 (0.00%)
    0 / 23 (0.00%)
    1 / 59 (1.69%)
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 29 (10.34%)
    4 / 31 (12.90%)
    0 / 23 (0.00%)
    4 / 59 (6.78%)
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    4
    4
    0
    4
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2017
    The overall reason for the amendment was to revise the protocol to address feedback from Health Authorities, improve clarity, enhance safety, and align the protocol with currently ongoing studies in a related population.
    14 Jun 2017
    The overall reason for the amendment (1) permit the initiation of standard of care antidepressant during the first 7 days of double-blind treatment, to reflect local standard of care in regions where it was not routine to initiate two medications simultaneously; (2) remove cognitive assessment at baseline and replace the Rey Auditory Verbal Learning Test (RAVLT) with the International Shopping List Test (ISLT); (3) expand description of safety evaluations; and (4) clarify within the Time & Events schedule the different recall periods for efficacy assessments used at certain study visits.

    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 study was designed as a Phase 2 study and thus limited by the relatively small sample size per treatment arm.
    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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