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    Clinical Trial Results:
    Effects of erythropoietin (EPO) on cognitive side-effects of electroconvulsive therapy (ECT) (EPO-T)

    Summary
    EudraCT number
    		 2016-002326-36
    Trial protocol
    		 DK  
    Global end of trial date
    10 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2016-858
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mental Health Services, Capital Region of Denmark
    Sponsor organisation address
    Hovedvejen 13, Nordre Fasanvej 57, Frederiksberg, Denmark, 2000
    Public contact
    Psychiatric Centre Copenhagen, Frederiksberg Hospital, Hovedvejen 13, Nordre Fasanvej 57, Mental Health Services, Capital Region of Denmark, 3864 7087, martin.balslev.joergensen@regionh.dk
    Scientific contact
    Psychiatric Centre Copenhagen, Frederiksberg Hospital, Hovedvejen 13, Nordre Fasanvej 57, Mental Health Services, Capital Region of Denmark, 3864 7087, martin.balslev.joergensen@regionh.dk
    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
    04 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective is to investigate whether short-term add-on treatment with high dose erythropoietin (EPO) can counteract the cognitive sideeffects of ECT and if such beneficial effects are long-lasting.
    Protection of trial subjects
    Good Clinical Practice (GCP) Unit, Copenhagen, Denmark
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 2017
    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
    Denmark: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    60
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We recruited in-patients from the Mental Health Services, Capital Region of Denmark.

    Pre-assignment
    Screening details
    		 Eligible participants were 18-70 years of age, had a diagnosis of UD or BD with current moderate to severe depressive symptoms, as reflected by a HDRS-17 total score≥17. Exclusion criteria were involuntary ECT, previous ECT within the last three months, other neuropsychiatric conditions, alcohol or substance use disorder, or acute suicide risk.

    Period 1
    Period 1 title
    Intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The randomization list was kept in a locked filing cabinet. Preparation of study medication to ensure double-blinding: 1 ml recombinant human EPO (Eprex; 40,000 IU; Janssen-Cilag) or saline (NaCl 0.9%) was injected into a standard 100 ml saline (NaCl 0.9%) infusion bag, which is then given to the study nurse or physician administering the medication. Double-blinding was further ensured by EPO being a colorless liquid undistinguishable from saline.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Erythropoietin
    Arm description
    		 Four intravenous infusions of high-dose recombinant human EPO (Epoetin alpha; Eprex; 40.000 IU/ml) diluted with 100 ml saline (0.9% NaCl) during a 2.5-week add-on treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epoetin alpha; Eprex; 40.000 IU/ml
    Investigational medicinal product code
    B03XA01
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Epoetin alpha; Eprex; 40.000 IU/ml diluted with 100 ml saline (0.9% NaCl) and administered intravenously over 15 minutes.

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Saline (1 ml sodium chloride (NaCl) 0.9%); placebo) diluted with 100 ml saline (0.9% NaCl) and administered intervenously over 15 minutes.

    Arm title
    		 Saline
    Arm description
    		 Saline (1 ml NaCl 0.9%) injected into a saline solution (100 ml NaCl, 0.9%) and administered intravenously over 15 min.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    NaCl 0.9%
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    0.9% NaCl isotonic saline

    Number of subjects in period 1
    		Erythropoietin Saline
    Started
    34
    26
    Completed
    28
    26
    Not completed
    6
    0
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erythropoietin
    Reporting group description
    		 Four intravenous infusions of high-dose recombinant human EPO (Epoetin alpha; Eprex; 40.000 IU/ml) diluted with 100 ml saline (0.9% NaCl) during a 2.5-week add-on treatment period.

    Reporting group title
    Saline
    Reporting group description
    		 Saline (1 ml NaCl 0.9%) injected into a saline solution (100 ml NaCl, 0.9%) and administered intravenously over 15 min.

    Reporting group values
    		 Erythropoietin Saline Total
    Number of subjects
    		 34 26 60
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 34 26 60
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40 ( 14 ) 38 ( 12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 18 42
        Male
    		 10 8 18

    End points

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    End points reporting groups
    Reporting group title
    Erythropoietin
    Reporting group description
    		 Four intravenous infusions of high-dose recombinant human EPO (Epoetin alpha; Eprex; 40.000 IU/ml) diluted with 100 ml saline (0.9% NaCl) during a 2.5-week add-on treatment period.

    Reporting group title
    Saline
    Reporting group description
    		 Saline (1 ml NaCl 0.9%) injected into a saline solution (100 ml NaCl, 0.9%) and administered intravenously over 15 min.

    Primary: Speed of complex cognitive processing composite score

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    End point title
    		 Speed of complex cognitive processing composite score
    End point description
    End point type
    Primary
    End point timeframe
    Baseline (pre-ECT) to after the 8th ECT session (2.5 weeks), corresponding to 4 EPO/saline infusions given over 2.5 weeks
    End point values
    		 Erythropoietin Saline
    Number of subjects analysed
    33 [1]
    26
    Units: z-scores
        arithmetic mean (standard deviation)
    -0.10 ( 1.11 )
    -0.28 ( 1.07 )
    Notes
    [1] - One subject withdrew before the baseline assessment and therefore had no data that could be included
    Statistical analysis title
    		 Linear mixed-effects models
    Comparison groups
    Erythropoietin v Saline
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Autobiographical memory

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    End point title
    		 Autobiographical memory
    End point description
    End point type
    Secondary
    End point timeframe
    Cross-sectional assessment after 8th ECT (2.5 weeks of EPO/saline treatment).
    End point values
    		 Erythropoietin Saline
    Number of subjects analysed
    16 [2]
    12 [3]
    Units: z-scores
        arithmetic mean (standard deviation)
    7 ( 2 )
    10 ( 4 )
    Notes
    [2] - Autobiographical memory was assessed during fMRI, which was conducted for a subgroup of patients
    [3] - Autobiographical memory was assessed during fMRI, which was conducted for a subgroup of patients
    Statistical analysis title
    		 Independent samples t¬test
    Statistical analysis description
    Cross-sectional comparison between EPO and saline groups after 8th ECT.
    Comparison groups
    Erythropoietin v Saline
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.025 [4]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [4] - Given we had 2 secondary outcomes, we conducted Bonferroni correction for multiple comparisons (i.e., p<=0.025).

    Secondary: Verbal memory

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    End point title
    		 Verbal memory
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (pre-ECT) to week 4 (after 8th ECT/ 2.5 weeks of weekly EPO/saline infusions)
    End point values
    		 Erythropoietin Saline
    Number of subjects analysed
    33
    26
    Units: z-scores
        arithmetic mean (standard deviation)
    -0.25 ( 1.09 )
    -0.62 ( 0.97 )
    Statistical analysis title
    		 Linear mixed-effects models
    Comparison groups
    Saline v Erythropoietin
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.025 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [5] - There were two secondary outcomes and the threshold for statistical significance was therefore Bonferroni corrected and set tp P<=0.025.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Active treatment phase, from baseline (pre-ECT) to week 4 (completion of EPO/saline treatment)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Erythropoietin
    Reporting group description
    		 Active treatment arm.

    Reporting group title
    Saline
    Reporting group description
    		 Placebo arm.

    Serious adverse events
    		 Erythropoietin Saline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Deep vein thrombosis
    Additional description: Deep vein thrombosis
         subjects affected / exposed [1]
    1 / 1 (100.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Only one subject experienced a deep vein thrombosis. This was a participant in the EPO arm. None of the patients in the saline arm experienced such a serious adverse event.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Erythropoietin Saline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    Psychiatric disorders
    Symptom deterioration
    Additional description: Symptoms of depression and mania are common in patients with mood disorders.
         subjects affected / exposed [2]
    2 / 2 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    2
    3
    Notes
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: There were 2 participants in the EPO arm and 3 participants in the saline arm who experienced a symptom deterioration during the active treatment period. This is specified in the form.

    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.
    None reported
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