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    Clinical Trial Results:
    Ketamine as an adjunctive therapy for Major Depression - a randomised controlled pilot trial: The KARMA-Dep Trial

    Summary
    EudraCT number
    		 2016-004764-18
    Trial protocol
    		 IE  
    Global end of trial date
    21 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2020
    First version publication date
    21 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    01-17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03256162
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St Patrick's Mental Health Services
    Sponsor organisation address
    James Street, Dublin, Ireland,
    Public contact
    Bronagh Gallagher, St Patrick’s Mental Health Services, 00353 12493385, bgallag@tcd.ie
    Scientific contact
    Bronagh Gallagher, St Patrick’s Mental Health Services, 00353 12493385, bgallag@tcd.ie
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study was to conduct a pragmatic randomised controlled patient- and rater-blinded pilot trial of a four-week course of once-weekly infusions of ketamine compared to midazolam as an adjunctive therapy for depression. The main objective of this pilot trial was to assess trial procedures to inform a future definitive trial, including rates of recruitment, dropout and completion of follow-up assessments.
    Protection of trial subjects
    Independent ethics approval was sought and informed consent procedures were followed as per the trial protocol. Interventions were designed to minimise the potential for distress and participants were accompanied by researchers at all times during interventions.
    Background therapy
    		 Participants continued on usual therapy throughout the trial including medication changes and multi-disciplinary team input.
    Evidence for comparator
    		 Ketamine is a competitive glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist with a half-life of 2-3 hours. Ketamine has a rapid antidepressant effect when given as single sub-anaesthetic doses (usually a 40 minute 0.5 mg/kg intravenous infusion). It was chosen as the investigative medicinal product as an adjunctive treatment in depressive episode. An active comparator, midazolam, was chosen as previously used by others in controlling for ketamine’s potential psychotomimetic effects. Midazolam is a psychoactive medication which may theoretically improve blinding by controlling for some of the effects of the investigative medicinal product, ketamine.
    Actual start date of recruitment
    06 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    19
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who were admitted to St Patrick’s University Hospital for treatment of a depressive episode between September 2017 and June 2018 and who met eligibility criteria for the trial were approached by the research team within 10 days of admission.

    Pre-assignment
    Screening details
    		 Clinical notes of newly admitted patients were screened for exclusion criteria. Eligible patients were then approached by the research team and baseline assessments were completed.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor
    Blinding implementation details
    Block randomisation was performed by another researcher within St Patrick’s University Hospital and who was not otherwise associated with the Karma-Dep pilot trial. Randomisation was done in blocks of two and four.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ketamine
    Arm description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ketamine hydrochloride
    Investigational medicinal product code
    ket
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ketamine Hydrochloride 10 mg/ml infusion at 0.5mg/kg (Pfizer Healthcare Ireland) made up as 50ml colourless saline solution and administered intravenously over 40 minutes via syringe driver pump.

    Arm title
    		 midazolam
    Arm description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Midazolam Hydrochloride
    Investigational medicinal product code
    mid
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Midazolam Hydrochloride (Hypnovel) 10mg/5ml solution at 0.045mg/kg (Roche Products Ireland Ltd) made up as 50ml colourless saline solution and administered intravenously over 40 minutes via syringe driver pump.

    Number of subjects in period 1
    		ketamine midazolam
    Started
    13
    12
    Completed
    8
    8
    Not completed
    5
    4
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ketamine
    Reporting group description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.

    Reporting group title
    midazolam
    Reporting group description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.

    Reporting group values
    		 ketamine midazolam Total
    Number of subjects
    		 13 12 25
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 48.8 ± 13.1 52.3 ± 12.5 -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 13
        Male
    		 5 7 12

    End points

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    End points reporting groups
    Reporting group title
    ketamine
    Reporting group description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.

    Reporting group title
    midazolam
    Reporting group description
    		 Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.

    Primary: Adherence

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    End point title
    		 Adherence [1]
    End point description
    A total of 16 participants (64%) completed all four infusions, eight in each group.
    End point type
    Primary
    End point timeframe
    Recruitment took place over a nine-month period between September 2017 and June 2018 and follow-up assessments were completed by September 2018.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this is a pilot trial, it is not adequately powered to detect statistically significant differences between the two groups.
    End point values
    		 ketamine midazolam
    Number of subjects analysed
    8
    8
    Units: participants
    8
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    ketamine
    Reporting group description
    		 Participants were randomly allocated to four once-weekly ketamine infusions (0.5 mg/kg over 40 minutes) compared to midazolam infusions (0.045 mg/kg over 40 minutes) as an adjunctive therapy in hospitalised depression.

    Reporting group title
    midazolam
    Reporting group description
    		 Participants were randomly allocated to four once-weekly ketamine infusions (0.5 mg/kg over 40 minutes) compared to midazolam infusions (0.045 mg/kg over 40 minutes) as an adjunctive therapy in hospitalised depression.

    Serious adverse events
    		 ketamine midazolam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ketamine midazolam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    General disorders and administration site conditions
    Nightmare
    Additional description: One participant experienced nightmares during the infusion period
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Dissociation
    Additional description: Two participants experienced dissociation side-effects which were unpleasant
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    As this is a pilot trial, it is not adequately powered to detect statistically significant differences between the depression scores of the two groups.
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    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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