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    Clinical Trial Results:
    Understanding the molecular basis for the use of adjunctive anti-inflammatory treatment in treatment resistant depression: a stratified, randomised, placebo-controlled, experimental medicine study using minocycline.

    Summary
    EudraCT number
    		 2015-003413-26
    Trial protocol
    		 GB  
    Global end of trial date
    17 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jan 2021
    First version publication date
    30 Jan 2021
    Other versions
    Summary report(s)
    		 Clinical Study report

    Trial information

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    Trial identification
    Sponsor protocol code
    MINDEP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Dr Valeria Mondelli, King's College London, 44 (0)207848 0353, valeria.mondelli@kcl.ac.uk
    Scientific contact
    Dr Valeria Mondelli, King's College London, 44 (0)207848 0353, valeria.mondelli@kcl.ac.uk
    Sponsor organisation name
    South London and Maudsley NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 8AZ
    Public contact
    Dr Valeria Mondelli, South London and Maudsley NHS Foundation Trust, 44 (0)207848 0353, valeria.mondelli@kcl.ac.uk
    Scientific contact
    Dr Valeria Mondelli, South London and Maudsley NHS Foundation Trust, 44 (0)207848 0353, valeria.mondelli@kcl.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
    17 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim is to investigate association between changes in inflammatory biomarkers and improvement in depressive symptoms following adjunctive treatment with minocycline in treatment resistant depressed patients selected for increased inflammation.
    Protection of trial subjects
    Participants will have the right to withdraw from the study at any time for any reason and do not have to provide any explanation. Patients will be informed during the consent seeking process that their withdrawal at any point in the study will not affect their quality of care. The investigator also has the right to withdraw patients from the study drug event of intercurrent illness, AEs, SAE’s, protocol violations, administrative reasons or other reasons.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    44
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were recruited from new referrals to primary (e.g., the Improving Access to Psychological Treatments, IAPT) and secondary care services linked to the South London and Maudsley NHS Foundation Trust (SLAM), in London, from primary care services referring to SLAM and other sources such as public advertisement.

    Pre-assignment
    Screening details
    		 Patients with major depressive disorder who did not respond to the current antidepressant taken at therapeutic doses for at least 6 weeks and who had increased levels of inflammation (CRP levels ≥ 1 mg/L) were recruited

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Minocycline
    Arm description
    		 Minocycline (100 mg x 2) was taken once daily for 4 weeks in adjunct to the current antidepressant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    minocycline
    Investigational medicinal product code
    Other name
    Acnamino MR 100mg capsules
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered minocycline (200 mg) (oral tablets) for the duration of 4 weeks. The dose was taken once daily.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo tablets were taken orally once daily for 4 weeks (56 capsules) in adjunct to their current antidepressant.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    lactose + gelatin capsule were taken orally once daily for 4 weeks (56 capsules) in adjunct to their current antidepressant.

    Number of subjects in period 1
    		Minocycline Placebo
    Started
    22
    22
    Completed
    18
    21
    Not completed
    4
    1
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    2
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Minocycline
    Reporting group description
    		 Minocycline (100 mg x 2) was taken once daily for 4 weeks in adjunct to the current antidepressant.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets were taken orally once daily for 4 weeks (56 capsules) in adjunct to their current antidepressant.

    Reporting group values
    		 Minocycline Placebo Total
    Number of subjects
    		 22 22 44
    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)
    		 22 22 44
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.4 ± 9.9 43.0 ± 10.9 -
    Gender categorical
    Units: Subjects
        Female
    		 14 13 27
        Male
    		 8 9 17
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 33.5 ± 10.1 31.6 ± 6.1 -
    Depression duration from onset
    Units: years
        arithmetic mean (standard deviation)
    		 20.32 ± 10.48 18.05 ± 12.39 -
    HAM-D-17
    Units: score
        arithmetic mean (standard deviation)
    		 19.41 ± 3.66 16.91 ± 3.21 -
    hs-CRP
    Units: score
        arithmetic mean (standard deviation)
    		 3.96 ± 4.14 4.37 ± 5.11 -

    End points

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    End points reporting groups
    Reporting group title
    Minocycline
    Reporting group description
    		 Minocycline (100 mg x 2) was taken once daily for 4 weeks in adjunct to the current antidepressant.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets were taken orally once daily for 4 weeks (56 capsules) in adjunct to their current antidepressant.

    Primary: HAM-D-17

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    End point title
    		 HAM-D-17
    End point description
    Changes from baseline to Week 4 for Hamilton Depression Rating Scale (HAMD) total score (DELTA HAMD), including the percentage of patients who show response, defined as 50% reduction from baseline.
    End point type
    Primary
    End point timeframe
    Changes from baseline to 4 weeks
    End point values
    		 Minocycline Placebo
    Number of subjects analysed
    18
    21
    Units: score
        arithmetic mean (standard deviation)
    5.61 ± 6.36
    2.90 ± 3.88
    Statistical analysis title
    		 Baseline vs Week4 Statistics
    Statistical analysis description
    Both study arms exhibited significant improvement in HAM-D-17 total score (table n 1). We did not find significant differences between the two study arms in the clinical improvement measured in terms of HAM-D-17 change (t=1.57, p=0.13)
    Comparison groups
    Minocycline v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.13
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - At least 50% improvement in HAM-D-17: 3 subjects in the minocycline group and 2 subjects in the placebo group. At least 25% improvement (partial response) in HAM-D-17: 8 subjects in the minocycline group and 9 subjects in the placebo group. Chi square test was not significant. Stratification based on CRP levels: patients with ≥3 mg/L and taking minocycline having the largest HAM-D-17 improvement and the highest proportion of partial responders. See the study report for details.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week 4
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Minocycline
    Reporting group description
    		 Minocycline (100 mg x 2) was taken once daily for 4 weeks in adjunct to the current antidepressant.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets were taken orally once daily for 4 weeks (56 capsules) in adjunct to their current antidepressant.

    Serious adverse events
    		 Minocycline Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 21 (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: 1%
    Non-serious adverse events
    		 Minocycline Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    11 / 21 (52.38%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Headache
         subjects affected / exposed
    4 / 18 (22.22%)
    5 / 21 (23.81%)
         occurrences all number
    5
    8
    General disorders and administration site conditions
    mood flucuations
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Gastrointestinal disorder
    Additional description: Constipation, flatulence, diarrhoea
         subjects affected / exposed
    4 / 18 (22.22%)
    3 / 21 (14.29%)
         occurrences all number
    4
    6
    Dyspepsia
         subjects affected / exposed
    1 / 18 (5.56%)
    5 / 21 (23.81%)
         occurrences all number
    1
    5
    bleeding
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    Decreased appetite
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    sore throat
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    Insomnia
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Pain
    Additional description: General pain/joint pain
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    Infections and infestations
    flu
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2016
    New: Protocol v2.0 22Mar16, PIS v2.0 23Mar16, ICF v2.0 23Mar16, GP letter v2.0 22Mar16 Documents amended following change in CRP level in inclusion criteria and clarification of blood sample amounts.
    06 Dec 2016
    Change in upper age limit in excl criteria from 50 to 60
    25 Jul 2017
    Eligibility updated to: - remove cap on CRP levels - remove restriction on taking other psychotrophic medications
    27 Nov 2019
    Biological outcomes updated within Protocol.

    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
    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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