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    Clinical Trial Results:
    Intravenous ketamine for Treatment Resistant Depression: Exploring biomarkers of response and relapse A double-blind, randomized controlled trial

    Summary
    EudraCT number
    		 2016-001715-21
    Trial protocol
    		 BE  
    Global end of trial date
    29 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Feb 2020
    First version publication date
    12 Feb 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    S59102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Carmen Schiweck, UZ Leuven, +32 016346798, stephan.claes@uzleuven.be
    Scientific contact
    Carmen Schiweck, UZ Leuven, +32 0465273027, carmen.schiweck@kuleuven.be
    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
    Interim
    Date of interim/final analysis
    29 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To replicate efficacy of intravenous ketamine in Treatment resistant depressed patients in a Belgian sample
    Protection of trial subjects
    availability of emergency medication at study site, minitoring of vital signs, constant supervision during drug administration and 4h post administration; follow-up of adverse events and report to the eudravigilance database
    Background therapy
    		 general antidepressant medication as described by current psychiatrist or physician; other medication not prohibited by the study protocol
    Evidence for comparator
    		 The placebo is approximately 0.9 percent solution of sodium chloride and is used to compare to the study drug, it has proven successful in previous clinical trials with ketamine
    Actual start date of recruitment
    21 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    52
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment has been ongoing since end december 2016. Recruitment was slow and we did not achieve the initial number of participants. The final inclusion was 29 patients and 26 controls.

    Pre-assignment
    Screening details
    		 Before screening patients need to have stable medication for 4 weeks. Patients excluded for participation in the study show symptoms of psychosis, alcohol abuse, other physical disease or are not interested to participate. The requirement for stable medication for at least 4 weeks limits inclusion by treating physicians.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Assessor, Subject
    Blinding implementation details
    At baseline patients have a one week period of data collection. All patients are following their usual treatment and no study drug is administered. No person involved knows the group membership up to this point.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 patients who will receive ketamine during randomization
    Arm type
    		 Experimental

    Investigational medicinal product name
    ketalar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infusion of 0.5mg/kg of bodyweight over 40 minutes

    Arm title
    		 Placebo
    Arm description
    		 patients who will recieve placebo during randomization
    Arm type
    		 Placebo

    Investigational medicinal product name
    0,9% sodium chloride solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    0,9% sodium chloride solution administered over 40 min intraveneously

    Number of subjects in period 1 [1]
    		Ketamine Placebo
    Started
    21
    7
    Completed
    21
    7
    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: 26 healthy controls completed the baseline but did not continue to randomization, as foreseenin the protocol
    Period 2
    Period 2 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    All involved study personnel is blinded to the study drug membership ( placebo/ketamine). Only the pharmacist knows the content of the provided study medication and is not to reveal its content to the study personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 1/3 of the patients receive placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    0,9% sodium chloride solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    0,9% sodium chloride solution administered over 40 min intraveneously

    Arm title
    		 Ketamine
    Arm description
    		 2/3 of participants receive ketamine
    Arm type
    		 Experimental

    Investigational medicinal product name
    ketalar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infusion of 0.5mg/kg of bodyweight over 40 minutes

    Number of subjects in period 2
    		Placebo Ketamine
    Started
    7
    21
    Completed
    7
    21
    Period 3
    Period 3 title
    Follow Up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    idem to before

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 This period is the follow up of the randomization phase, no medication was administered
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo
    Arm description
    		 Follow-Up of Placebo arm
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Ketamine Placebo
    Started
    21
    7
    Completed
    20
    7
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ketamine
    Reporting group description
    		 patients who will receive ketamine during randomization

    Reporting group title
    Placebo
    Reporting group description
    		 patients who will recieve placebo during randomization

    Reporting group values
    		 Ketamine Placebo Total
    Number of subjects
    		 21 7 28
    Age categorical
    Subjects are all above 18 and younger than 85 at this stage of inclusion
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 7 26
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.95 ( 14.72 ) 45.43 ( 10.77 ) -
    Gender categorical
    Both male an female particpants are being collected
    Units: Subjects
        Female
    		 13 4 17
        Male
    		 8 3 11
    SMOKER
    Current Smoking Status of Subjects
    Units: Subjects
        SMOKER
    		 4 1 5
        NONSMOKER
    		 17 6 23
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Depression severity
    Depression Severity as measured by the Hamilton Depression Rating Scale
    Units: points
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Subject analysis sets

    Subject analysis set title
    Depressed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    patients who are depressed and received ketamine

    Subject analysis set title
    Healthy control
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy controls not receiving ketamine

    Subject analysis sets values
    		 Depressed Healthy control
    Number of subjects
    28
    26
    Age categorical
    Subjects are all above 18 and younger than 85 at this stage of inclusion
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    26
    26
        From 65-84 years
    2
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.07 ( 13.65 )
    42.69 ( 11.80 )
    Gender categorical
    Both male an female particpants are being collected
    Units: Subjects
        Female
    17
    13
        Male
    11
    13
    SMOKER
    Current Smoking Status of Subjects
    Units: Subjects
        SMOKER
    5
    3
        NONSMOKER
    23
    23
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    28.47 ( 5.06 )
    24.54 ( 3.94 )
    Depression severity
    Depression Severity as measured by the Hamilton Depression Rating Scale
    Units: points
        arithmetic mean (standard deviation)
    21.07 ( 3.68 )
    2.0 ( 1.83 )

    End points

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    End points reporting groups
    Reporting group title
    Ketamine
    Reporting group description
    		 patients who will receive ketamine during randomization

    Reporting group title
    Placebo
    Reporting group description
    		 patients who will recieve placebo during randomization
    Reporting group title
    Placebo
    Reporting group description
    		 1/3 of the patients receive placebo

    Reporting group title
    Ketamine
    Reporting group description
    		 2/3 of participants receive ketamine
    Reporting group title
    Ketamine
    Reporting group description
    		 This period is the follow up of the randomization phase, no medication was administered

    Reporting group title
    Placebo
    Reporting group description
    		 Follow-Up of Placebo arm

    Subject analysis set title
    Depressed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    patients who are depressed and received ketamine

    Subject analysis set title
    Healthy control
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy controls not receiving ketamine

    Primary: Depression score change Day 8

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    End point title
    		 Depression score change Day 8
    End point description
    Depression scores on the Hamilton depression scale and the quick inventory of depressive symptomatology. Severity scores for the HAMD can be found below: 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression. Depressions cores are used as continuous variables.
    End point type
    Primary
    End point timeframe
    Depression score per group on Day 8 (4H post Ketamine)
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: points
        arithmetic mean (standard deviation)
    19.57 ( 4.86 )
    18.86 ( 4.67 )
    Statistical analysis title
    		 Day 8 depression difference groups
    Statistical analysis description
    t test between placebo and ketamine groups to estimate a significant difference between both. Similar analysis are performed for day 9, day 15 and follow-up.
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7409
    Method
    		 t-test, 2-sided
    Parameter type
    		 t value
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.396
         upper limit
    		 3.968

    Primary: Depression score Day 9

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    End point title
    		 Depression score Day 9
    End point description
    This is the score 24 h post ketamine
    End point type
    Primary
    End point timeframe
    Day 9 (24h post ketamine)
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: points
        arithmetic mean (standard deviation)
    13.29 ( 5.35 )
    15.81 ( 5.37 )
    Statistical analysis title
    		 Day 9 Depression Severity change
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.304
    Method
    		 t-test, 2-sided
    Parameter type
    		 t value
    Point estimate
    1.0805
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6557
         upper limit
    		 7.7034

    Primary: Depression Score change Day 15

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    End point title
    		 Depression Score change Day 15
    End point description
    End point type
    Primary
    End point timeframe
    Depression Score on Day 15 (7 days post ketamine)
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    20
    Units: points
        arithmetic mean (standard deviation)
    14.71 ( 6.73 )
    19.3 ( 6.33 )
    Statistical analysis title
    		 D15 depression severity between groups
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1462
    Method
    		 t-test, 2-sided
    Parameter type
    		 t value
    Point estimate
    1.576
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.898
         upper limit
    		 11.07

    Primary: Depression change score Day 21

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    End point title
    		 Depression change score Day 21
    End point description
    End point type
    Primary
    End point timeframe
    Depression change score follow up ( 2 weeks post ketamine)
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: points
        arithmetic mean (standard deviation)
    16 ( 6.32 )
    18.81 ( 6.06 )
    Statistical analysis title
    		 FU comparison depression severity
    Statistical analysis description
    depression severity between groups at FU
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3281
    Method
    		 t-test, 2-sided
    Parameter type
    		 T value
    Point estimate
    1.0283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.282
         upper limit
    		 8.901

    Primary: Baseline Depression Scores Placebo Ketamine

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    End point title
    		 Baseline Depression Scores Placebo Ketamine
    End point description
    Baseline Depression Score
    End point type
    Primary
    End point timeframe
    Baseline depression scores
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: points
        arithmetic mean (standard deviation)
    21.86 ( 4.56 )
    20.81 ( 3.43 )
    Statistical analysis title
    		 Baseline difference Placebo Ketamine
    Statistical analysis description
    T test of depression severity difference between placebo and Ketamine
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 t value
    Point estimate
    -0.55736
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.35
         upper limit
    		 3.25

    Primary: Resp vs non Resp ket and placebo

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    End point title
    		 Resp vs non Resp ket and placebo
    End point description
    comparison of proportions between responders and non responders
    End point type
    Primary
    End point timeframe
    Responders and partial responders on day 9 compared to Baseline
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: Subjects
        non responder
    2
    13
        responder
    3
    3
        partial responder
    2
    5
    Statistical analysis title
    		 chi square responder
    Statistical analysis description
    chi square test between responder/non responder proportions per group
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.208 [1]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - The X2 is 3.1365, df=2, p value =0.2084

    Primary: Depressive sympotm change over time per group

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    End point title
    		 Depressive sympotm change over time per group
    End point description
    Here we assess a simple linear mixed model to assess the change of depressive symptoms over time. We include an interaction effect of Treatment and timepoint to see if the groups differ at any given timepoint and a random intercept. The model is as follows: Depression severity ~ timepoint*treatment condition+ random intercept
    End point type
    Primary
    End point timeframe
    spans the entire study period from baseline to follow up
    End point values
    		 Placebo Ketamine
    Number of subjects analysed
    7
    21
    Units: points
        number (not applicable)
    7
    21
    Attachments
    		 Resultas Linear Mixed Model
    Statistical analysis title
    		 Linear Mixed Model Treatment over time
    Statistical analysis description
    Treatment over time is assessed with a linear model including timepoint, treatment condition and their interaction.
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.6431 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    1.0476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.43
         upper limit
    		 5.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.25
    Notes
    [2] - Linear mixed model to determine development over time.
    [3] - We here tested whether any timepoint or group effect is significant at the p<0.05 level. The platform does not allow to fill in several p values which is required for this analysis. Therefore we here report the overall group effect of the model.

    Other pre-specified: Baseline Healthy vs Depressed Depression Severity

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    End point title
    		 Baseline Healthy vs Depressed Depression Severity
    End point description
    Comparison of Hamilton Depression Rating scale between healthy controls and entire depressed group
    End point type
    Other pre-specified
    End point timeframe
    Baseline comparison
    End point values
    		 Depressed Healthy control
    Number of subjects analysed
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    21.07 ( 3.68 )
    2 ( 1.83 )
    Statistical analysis title
    		 Difference HC and depressed
    Statistical analysis description
    Anova test comparing healthy controls and depressed patients at baseline regarding depression severity
    Comparison groups
    Depressed v Healthy control
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.65
         upper limit
    		 -17.49

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are assessed during the whole study period.
    Adverse event reporting additional description
    An independent company (The Clinical Company) reports serious adverse events to the FAGG
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SAFTEE questionnaire
    Dictionary version
    1
    Reporting groups
    Reporting group title
    depressed patients
    Reporting group description
    		 patients with depression

    Reporting group title
    healthy controls
    Reporting group description
    		 -

    Serious adverse events
    		 depressed patients healthy controls
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Acute suicidal ideation with psychological decompensation
    Additional description: the patient experinced decompensation after feeling no improvement in depressive sympotms after the ketamine/placebo infusion. The clinicians decided to hsopitalize the patient.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 depressed patients healthy controls
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 28 (89.29%)
    0 / 26 (0.00%)
    Vascular disorders
    migraine
    Additional description: not related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Nausea systematic
    Additional description: occured post infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Fatigue/tired systematic
    Additional description: reported post infusion IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Dizziness
    Additional description: 10 of them reported during infusion IMP , one post
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 28 (39.29%)
    0 / 26 (0.00%)
         occurrences all number
    11
    0
    Headache systematic
    Additional description: occured post infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Dry mouth systematic
    Additional description: both occured post infusion IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Stiffness
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Confusional state
    Additional description: occured during infusion , related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Diplopia
    Additional description: during infusion , related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Tremor systematic
    Additional description: post infusion IMP but not related
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Oral pain
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hot flush systematic
    Additional description: hot and cold flushes, pre infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    paresthesia hands
    Additional description: occured during infusion, related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    sore throat systematic
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Pruritus
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Menstruation irregular
    Additional description: bleedings between menstruation, menstruation accompanied by cramps post infusion IMP but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Somnolence
    Additional description: during infusion, related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    muscle pain
    Additional description: occured post infusion, but not related to IMP
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    fatigue/tired non-systematic
    Additional description: occured post infusion IMP, related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    headache non-systematic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    dry mouth non-systematic
    Additional description: 2 of them reported during infusion IMP, 1 post infusion. All of them related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    tremor non-systematic
    Additional description: occured during infusion, related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    hot flush non-systematic
    Additional description: during ketamin infusion reported by patient
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    sore throat non-systematic
    Additional description: not related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    worsening dizziness
    Additional description: occured during infusion IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    worsening headache
    Additional description: patient experienced this event pre infusion IMP (not related)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    worsening blurry vision
    Additional description: 1 patient experienced this event pre infusion IMP (not related) and 1 during infusion IMP (related)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    sensitive breast
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    pain breast
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    change of taste
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    increased thirst
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    decreased sense of smell
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    decreased interest in sex
    Additional description: not related to IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    pain joints
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    unstable stand on feet
    Additional description: psot infusion IMP but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    trembling
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    rigidity
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    bruising
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    excited
    Additional description: occured post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    anxiety
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    irritable
    Additional description: not related to IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    shivering
    Additional description: during infusion IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    worsening dry mouth systematic
    Additional description: during infusion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    worsening dry mouth non-systematic
    Additional description: related to IMP, during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    light-headed
    Additional description: during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    reduced awareness
    Additional description: related to IMP, during infusion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    difficulties with speaking systematic
    Additional description: post infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    difficulties with speaking non-systematic
    Additional description: during infusion, related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    insensibility/tingles
    Additional description: not related to IMP, pre infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    cardial problems
    Additional description: during infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    stiff muscles
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    allergic reaction
    Additional description: post infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    nightmares
    Additional description: post infusion IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    memory problem
    Additional description: post infusion IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    excessive sweating
    Additional description: related to IMP, post infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    sedated feeling
    Additional description: related to IMP, during infusion .One patient overall sedated feeling, another sedated feeling moth and another one sedated feeling fingers
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    paresthesia
    Additional description: related to IMP, during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    increased saliva production
    Additional description: related to IMP, during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    strange taste in mouth
    Additional description: related to IMP, during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    balance disorder
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    nervosity
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    restlegg legs
    Additional description: related to IMP, during infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    hyperventilation
    Additional description: during infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Auto-mutilation
    Additional description: occured Post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Concentration impairment
    Additional description: occured post infusion, but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Acute suicidal ideation & Psychological decompensation
    Additional description: Also added as serious advent because hospitalization was required. The mental health state of this patient did not change majorly in comparison to before the administration of study drug, but as no improvement was seen the patient was hospitalized.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Stress
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Restlessness
    Additional description: not related to IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Blood pressure fluctuation
    Additional description: occured during infusion, related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    oedema feet
    Additional description: post infusion but not related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
    Additional description: post infusion, not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred systematic
    Additional description: one pre infusion, one post infusion
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    light sensitivity
    Additional description: post administration IMP, related
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    vision blurred non-systematic
    Additional description: 3 of them occured during infusion, one post infusion IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    swollen eyes
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting
    Additional description: Patient started vomiting during ketamine/placebo infusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    stomach pain
    Additional description: after ketamin infusion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    nausea non-systematic
    Additional description: all of them occured during infusion IMP, related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    problems stomach
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    abdominal cramps
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    gastro-intestinal complaints
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    excanthema
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    increased frequency urination
    Additional description: not related to IMP
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Endocrine disorders
    elavated TSH in blood
    Additional description: pre Infusion IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gingivitis
    Additional description: post infusion but not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    chlamydia trachomatis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    oral ulcer
    Additional description: post infusion IMP, but no related
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    flu
    Additional description: not related to IMP
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    loss of appetite
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    increased appetite
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    weight gain
    Additional description: not related to IMP
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2017
    Minor improvements were made to the protocol; no major changes
    01 Aug 2017
    Correction of small mistakes in protocol that were made previously
    13 Nov 2017
    Add French speaking, Belgian participants and allow for inclusion of BPD I patients

    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.
    Covariates and transformations of data still need to be applied; similarly, immune data is not yet available and will be included at a later moment.
    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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