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    Clinical Trial Results:
    Mirtazapine added to SSRIs for treatment resistant depression in primary care: a placebo controlled randomised controlled trial

    Summary
    EudraCT number
    2012-000090-23
    Trial protocol
    GB  
    Global end of trial date
    19 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Mar 2019
    First version publication date
    14 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UoB1651
    Additional study identifiers
    ISRCTN number
    ISRCTN06653773
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Bristol
    Sponsor organisation address
    One Cathedral Square, Bristol, United Kingdom, BS1 5DD
    Public contact
    Rachel Davies, University of Bristol, +44 1174284021 , rachel.davies@bristol.ac.uk
    Scientific contact
    Rachel Davies, University of Bristol, +44 1174284021 , rachel.davies@bristol.ac.uk
    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
    02 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effectiveness of the addition of the antidepressant mirtazapine to an SSRI or SNRI in reducing depressive symptoms and improving quality of life at 12 weeks, 24 weeks and 12 months (compared to the addition of a placebo).
    Protection of trial subjects
    usual standard operating procedures in the event of disclosure of ideas of suicide or self harm.
    Background therapy
    not applicable
    Evidence for comparator
    not applicable
    Actual start date of recruitment
    26 Aug 2013
    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
    United Kingdom: 480
    Worldwide total number of subjects
    480
    EEA total number of subjects
    480
    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)
    406
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment took place from August 2013 to October 2015 in four centres, all in the United Kingdom

    Pre-assignment
    Screening details
    751 patients assessed for eligibility 481 eligible, 270 ineligible (Not depressed) 480 randomised

    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, Monitor, Data analyst
    Blinding implementation details
    The treatment allocation schedule was computer generated by a statistician independent of the trial team in a 1:1 ratio, stratified by centre and minimised by baseline depression score, sex and whether the participant was receiving a psychological intervention. Packs contained encapsulated mirtazapine 15mg or identical placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mirtazapine
    Arm description
    participants treated with the active medication
    Arm type
    Active comparator

    Investigational medicinal product name
    Mirtazapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were asked to take one capsule daily for 2 weeks and then increase to 2 capsules daily thereafter

    Arm title
    Placebo
    Arm description
    Patients treated with placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were asked to take one capsule daily for 2 weeks and then increase to 2 capsules daily thereafter

    Number of subjects in period 1
    Mirtazapine Placebo
    Started
    241
    239
    Completed
    214
    217
    Not completed
    27
    22
         Lost to follow-up
    27
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mirtazapine
    Reporting group description
    participants treated with the active medication

    Reporting group title
    Placebo
    Reporting group description
    Patients treated with placebo

    Reporting group values
    Mirtazapine Placebo Total
    Number of subjects
    241 239 480
    Age categorical
    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)
    197 209 406
        From 65-84 years
    44 30 74
        85 years and over
    0 0 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    50.4 ± 13.8 49.9 ± 12.5 -
    Gender categorical
    Units: Subjects
        Female
    168 164 332
        Male
    73 75 148
    Baseline Beck Depression Inventory Score
    Units: Subjects
        14-25
    77 79 156
        26-34
    78 78 156
        >34
    86 82 168
    ICD-10 Diagnosis of Depression
    Units: Subjects
        mild
    38 44 82
        moderate
    138 144 282
        severe
    65 51 116
    Mean BDI score
    Units: scale 0-63
        geometric mean (standard deviation)
    31.5 ± 10.2 30.6 ± 9.6 -
    General Anxiety Disorder (GAD7)
    Units: scale 0-21
        geometric mean (standard deviation)
    11.3 ± 4.8 10.7 ± 4.8 -

    End points

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    End points reporting groups
    Reporting group title
    Mirtazapine
    Reporting group description
    participants treated with the active medication

    Reporting group title
    Placebo
    Reporting group description
    Patients treated with placebo

    Primary: mean BDI score

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    End point title
    mean BDI score
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    Mirtazapine Placebo
    Number of subjects analysed
    214
    217
    Units: scale 0-63
        geometric mean (standard deviation)
    18 ± 12.3
    19.7 ± 12.4
    Statistical analysis title
    Change in mean BDI score analysed as a continuous
    Comparison groups
    Mirtazapine v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.09
    Method
    Regression, Linear
    Parameter type
    Mean difference (net)
    Point estimate
    -1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.92
         upper limit
    0.27

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were reported from the time a signed and dated informed consent form was obtained until completion of the last trial related procedure (collection of follow-up data 12 months after randomisation)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    SMPC and BNF
    Dictionary version
    latest
    Reporting groups
    Reporting group title
    Mirtazapine group
    Reporting group description
    Participants randomised to Mirtazapine

    Reporting group title
    Placebo group
    Reporting group description
    Participants randomised to placebo

    Serious adverse events
    Mirtazapine group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 241 (3.32%)
    3 / 239 (1.26%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Ischaemia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    chest infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Dental care
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Hysterectomy
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    trauma
         subjects affected / exposed
    0 / 241 (0.00%)
    2 / 239 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    infected ulcer
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Mirtazapine group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    180 / 241 (74.69%)
    89 / 239 (37.24%)
    Respiratory, thoracic and mediastinal disorders
    minor respiratory disorders
         subjects affected / exposed
    6 / 241 (2.49%)
    3 / 239 (1.26%)
         occurrences all number
    6
    3
    Nervous system disorders
    psychiatric
    Additional description: This includes drowsiness, headache, TIA, unpleasant dreams, sleep disturbance
         subjects affected / exposed
    70 / 241 (29.05%)
    27 / 239 (11.30%)
         occurrences all number
    70
    27
    General disorders and administration site conditions
    see below
    Additional description: includes anticholinergic effects, allergic reactions, minor endocrine, ENT, Dental, dermatological, ophthalmological, haematological and infective disorders
         subjects affected / exposed
    27 / 241 (11.20%)
    26 / 239 (10.88%)
         occurrences all number
    27
    26
    Gastrointestinal disorders
    Appetite disorder
    Additional description: this includes appetite changes, nausea and weight gain
         subjects affected / exposed
    34 / 241 (14.11%)
    18 / 239 (7.53%)
         occurrences all number
    34
    18
    Reproductive system and breast disorders
    minor disorders
         subjects affected / exposed
    2 / 241 (0.83%)
    1 / 239 (0.42%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    minor injury
         subjects affected / exposed
    15 / 241 (6.22%)
    17 / 239 (7.11%)
         occurrences all number
    15
    17

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30442772
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