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    Clinical Trial Results:
    The Benefit of Minocycline on Negative Symptoms in Psychosis: Extent and Mechanisms

    Summary
    EudraCT number
    		 2010-022463-35
    Trial protocol
    		 GB  
    Global end of trial date
    30 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2020
    First version publication date
    20 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1007
    Additional study identifiers
    ISRCTN number
    		 ISRCTN49141214
    US NCT number
    		 NCT02928965
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Former Manchester Mental Health and Social Care Trust
    Sponsor organisation address
    1st floor Harrop House, Bury New Road, Prestwich, Greater Manchester, United Kingdom, M25 3BL
    Public contact
    Prof Bill Deakin, The University of Manchester, bill.deakin@manchester.ac.uk
    Scientific contact
    Prof Bill Deakin, The University of Manchester, bill.deakin@manchester.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
    01 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm that minocycline benefits the negative symptoms of schizophrenia when taken early in the course of the illness and to understand how it does so. To determine whether minocycline acts by protecting brain cells from damage, by lessening inflammation or by improving mental functions (thinking and reasoning).
    Protection of trial subjects
    Protection of trial subjects managed via the IDMC.
    Background therapy
    		 Standard antipsychotic drug treatment from CMHCT
    Evidence for comparator
    		 Placebo, no active comparator
    Actual start date of recruitment
    16 Apr 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: 207
    Worldwide total number of subjects
    207
    EEA total number of subjects
    207
    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)
    7
    Adults (18-64 years)
    200
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment between: 16/04/2013 and 30/06/2016

    Pre-assignment
    Screening details
    		 All details present in the publication: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(18)30345-6/fulltext 229 participants screened, of these 207 were randomised: 10 clinical exclusions 5 patients withdrawn 5 failed to consent 2 unknown reason for withdrawl

    Pre-assignment period milestones
    Number of subjects started
    		 207
    Intermediate milestone: Number of subjects
    Randomised: 207
    Number of subjects completed
    		 207

    Period 1
    Period 1 title
    Assignment and baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Participants were randomly assigned with an automated permuted blocks algorithm and were stratified by pharmacy.openCDMS allocated the patient to a treatment group at randomisation , emailed the local pharmacy to identify the numbered treatment kit of 3 months supply to be dispensed, and recorded when kit was dispensed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline: Minocycline
    Arm description
    		 Participants received capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 Baseline: Placebo
    Arm description
    		 Participants received placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    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
    Participants received placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 1
    		Baseline: Minocycline Baseline: Placebo
    Started
    103
    104
    Completed
    88
    88
    Not completed
    15
    16
         Consent withdrawn by subject
    4
    5
         LTFU
    6
    9
         Skin
    1
    -
         Dysphagia
    2
    -
         Moved
    1
    1
         Abdominal pain
    -
    1
         Malaise
    1
    -
    Period 2
    Period 2 title
    2 month follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 month follow-up: Minocycline
    Arm description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 2 month follow-up: Placebo
    Arm description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 2
    		2 month follow-up: Minocycline 2 month follow-up: Placebo
    Started
    88
    88
    Completed
    77
    74
    Not completed
    11
    14
         Consent withdrawn by subject
    3
    3
         LTFU
    7
    7
         Vomit
    -
    1
         Abdominal pain
    1
    -
         Mole
    -
    1
         Malaise
    -
    2
    Period 3
    Period 3 title
    6 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 6 month follow-up: Minocycline
    Arm description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 6 month follow-up: Placebo
    Arm description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 3
    		6 month follow-up: Minocycline 6 month follow-up: Placebo
    Started
    77
    74
    Completed
    71
    70
    Not completed
    6
    4
         Consent withdrawn by subject
    2
    -
         Relapse
    1
    -
         LTFU
    3
    4
    Period 4
    Period 4 title
    9 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 9 month follow-up: Minocycline
    Arm description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 9 month follow-up: Placebo
    Arm description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 4
    		9 month follow-up: Minocycline 9 month follow-up: Placebo
    Started
    71
    70
    Completed
    64
    65
    Not completed
    7
    5
         Consent withdrawn by subject
    2
    1
         Visual dist
    1
    -
         LTFU
    3
    4
         Epilepsy
    1
    -
    Period 5
    Period 5 title
    12 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 12 month follow-up: Minocycline
    Arm description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 12 month follow-up: Placebo
    Arm description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 5
    		12 month follow-up: Minocycline 12 month follow-up: Placebo
    Started
    64
    65
    Completed
    41
    48
    Not completed
    23
    17
         Consent withdrawn by subject
    5
    2
         LTFU
    18
    15
    Period 6
    Period 6 title
    15 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 15 month follow-up: Minocycline
    Arm description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    ATC code J01AA08 A01
    Other name
    Minocycline hydrochloride
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

    Arm title
    		 15 month follow-up: Placebo
    Arm description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo capsules entirely match minocycline capsules, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Number of subjects in period 6
    		15 month follow-up: Minocycline 15 month follow-up: Placebo
    Started
    41
    48
    Completed
    41
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline: Minocycline
    Reporting group description
    		 Participants received capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    Baseline: Placebo
    Reporting group description
    		 Participants received placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group values
    		 Baseline: Minocycline Baseline: Placebo Total
    Number of subjects
    		 103 104 207
    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
    none
    Units: years
        arithmetic mean (standard deviation)
    		 25.7 ± 5.1 25.5 ± 5.2 -
    Gender categorical
    none
    Units: Subjects
        Female
    		 30 27 57
        Male
    		 73 77 150
    PANSS score: Negative symptoms subscale
    Units: PANSS score
        arithmetic mean (standard deviation)
    		 17.7 ± 5.9 16.8 ± 5.5 -
    PANSS score: Positive symptom subscale
    Units: PANSS score
        arithmetic mean (standard deviation)
    		 16.3 ± 4.1 17.3 ± 5.3 -
    Total PANSS score
    Units: PANSS score
        arithmetic mean (standard deviation)
    		 67.1 ± 13.2 69.3 ± 15.4 -
    CDSS score
    Units: CDSS score
        arithmetic mean (standard deviation)
    		 5.2 ± 4.3 5.5 ± 5.0 -
    GAF score
    Units: GAF score
        arithmetic mean (standard deviation)
    		 55.5 ± 9.1 56.2 ± 11.6 -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 82.6 ± 19.6 86.8 ± 25.3 -
    BMI
    Units: BMI
        arithmetic mean (standard deviation)
    		 27.1 ± 6.2 28.7 ± 7.6 -
    Processing speed
    Units: BIP
        arithmetic mean (standard deviation)
    		 58 ± 16.7 52.8 ± 16.8 -
    Current IQ
    Units: IQ score
        arithmetic mean (standard deviation)
    		 91.2 ± 14 89.2 ± 15.9 -
    Pre-Morbid IQ
    Units: IQ score
        arithmetic mean (standard deviation)
    		 97.7 ± 1.7 95.4 ± 19.8 -
    Medial Prefrontal cortex grey-matter volume: left
    Units: cc
        arithmetic mean (standard deviation)
    		 5.6 ± 0.7 5.7 ± 0.8 -
    Medial Prefrontal cortex grey-matter volume: right
    Units: cc
        arithmetic mean (standard deviation)
    		 4.6 ± 5.8 4.6 ± 0.7 -
    N-Back BOLD activation: 1-back plus 2-back vs 0-back
    Units: % change
        arithmetic mean (standard deviation)
    		 -0.02 ± 1.48 0.12 ± 1.25 -
    N-Back BOLD activation: 2-back vs 1-back
    Units: % change
        arithmetic mean (standard deviation)
    		 -0.04 ± 1.54 0.10 ± 1.23 -
    Cytokine IL-6
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 0.69 ± 0.46 0.84 ± 0.64 -
    hs-CRP
    Units: mg/L
        arithmetic mean (standard deviation)
    		 3.08 ± 3.82 3.83 ± 5.45 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Baseline: Minocycline
    Reporting group description
    		 Participants received capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    Baseline: Placebo
    Reporting group description
    		 Participants received placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Reporting group title
    2 month follow-up: Minocycline
    Reporting group description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    2 month follow-up: Placebo
    Reporting group description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Reporting group title
    6 month follow-up: Minocycline
    Reporting group description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    6 month follow-up: Placebo
    Reporting group description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Reporting group title
    9 month follow-up: Minocycline
    Reporting group description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    9 month follow-up: Placebo
    Reporting group description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Reporting group title
    12 month follow-up: Minocycline
    Reporting group description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    12 month follow-up: Placebo
    Reporting group description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.
    Reporting group title
    15 month follow-up: Minocycline
    Reporting group description
    		 Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Reporting group title
    15 month follow-up: Placebo
    Reporting group description
    		 Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsible medical officer.

    Primary: Left grey-matter volume

    		 Close Top of page
    End point title
    		 Left grey-matter volume
    End point description
    Note: measures in mm(squared) for mean and SD
    End point type
    Primary
    End point timeframe
    across follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    94
    88
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    45
    54
    0 [7]
    0 [8]
    Units: Volume (cc)
        arithmetic mean (standard deviation)
    5644 ± 723
    5669 ± 786
    ±
    ±
    ±
    ±
    ±
    ±
    5593 ± 70
    5509 ± 787
    ±
    ±
    Notes
    [1] - Measure not captured at this time point
    [2] - Measure not captured at this time point
    [3] - Measure not captured at this time point
    [4] - Measure not captured at this time point
    [5] - Measure not captured at this time point
    [6] - Measure not captured at this time point
    [7] - Measure not captured at this time point
    [8] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11

    Primary: Right grey-matter volume

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    End point title
    		 Right grey-matter volume
    End point description
    Note: measures in mm(squared) for mean and SD
    End point type
    Primary
    End point timeframe
    across follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    94
    88
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    45
    54
    0 [15]
    0 [16]
    Units: Volume (cc)
        arithmetic mean (standard deviation)
    4574 ± 551
    4581 ± 658
    ±
    ±
    ±
    ±
    ±
    ±
    4543 ± 551
    4425 ± 680
    ±
    ±
    Notes
    [9] - Measure not captured at this time point
    [10] - Measure not captured at this time point
    [11] - Measure not captured at this time point
    [12] - Measure not captured at this time point
    [13] - Measure not captured at this time point
    [14] - Measure not captured at this time point
    [15] - Measure not captured at this time point
    [16] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07

    Primary: Interleukin 6

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    End point title
    		 Interleukin 6
    End point description
    There were no systematic trends in cytokine concentrations over time and no treatment effects
    End point type
    Primary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    101
    100
    0 [17]
    0 [18]
    57
    65
    0 [19]
    0 [20]
    53
    56
    0 [21]
    0 [22]
    Units: concentration (pg/mL)
        arithmetic mean (standard deviation)
    0.690 ± 0.458
    0.840 ± 0.639
    ±
    ±
    0.843 ± 0.926
    0.902 ± 0.753
    ±
    ±
    0.793 ± 0.570
    0.811 ± 0.623
    ±
    ±
    Notes
    [17] - Measure not captured at this time point
    [18] - Measure not captured at this time point
    [19] - Measure not captured at this time point
    [20] - Measure not captured at this time point
    [21] - Measure not captured at this time point
    [22] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41

    Primary: High-sensitivity C-reactive protein

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    End point title
    		 High-sensitivity C-reactive protein
    End point description
    There were no systematic trends in cytokine concentrations over time and no treatment effects
    End point type
    Primary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    101
    100
    0 [23]
    0 [24]
    57
    65
    0 [25]
    0 [26]
    51
    56
    0 [27]
    0 [28]
    Units: find out
        arithmetic mean (standard deviation)
    3.08 ± 3.82
    3.83 ± 5.45
    ±
    ±
    4.56 ± 11.23
    5.33 ± 9.54
    ±
    ±
    6.01 ± 18.91
    4.40 ± 5.30
    ±
    ±
    Notes
    [23] - Measure not captured at this time point
    [24] - Measure not captured at this time point
    [25] - Measure not captured at this time point
    [26] - Measure not captured at this time point
    [27] - Measure not captured at this time point
    [28] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 4.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.6

    Secondary: PANSS Negative symptoms

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    End point title
    		 PANSS Negative symptoms
    End point description
    Measure = Estimate of treatment effects across all follow up time points.
    End point type
    Secondary
    End point timeframe
    Across all follow up time points.
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    104
    83
    85
    69
    67
    68
    62
    62
    65
    41
    48
    Units: PANSS score
        arithmetic mean (standard deviation)
    17.7 ± 5.9
    16.8 ± 5.5
    16.4 ± 5.9
    15.1 ± 5.8
    15.8 ± 6.5
    15.7 ± 5.8
    15.9 ± 6.3
    14.5 ± 4.9
    16.4 ± 6.2
    14.2 ± 5.2
    15.6 ± 6.6
    14.0 ± 4.9
    Attachments
    		 Main outcome measures for minocycline and placebo
    Statistical analysis title
    		 best estimates of treatment effects
    Statistical analysis description
    Best estimate of treatment effects across all follow-up points
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 2 month follow-up: Minocycline v 2 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 9 month follow-up: Minocycline v 9 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    857
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53

    Secondary: Positive symptoms (PANSS)

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    End point title
    		 Positive symptoms (PANSS)
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    104
    83
    86
    69
    67
    68
    63
    63
    65
    41
    48
    Units: PANSS score
        arithmetic mean (standard error)
    16.3 ± 4.1
    17.3 ± 5.3
    13.8 ± 4.5
    14.5 ± 4.8
    13.4 ± 5.0
    14.4 ± 5.2
    12.8 ± 4.6
    13.6 ± 5.0
    13.4 ± 6.1
    14.0 ± 4.8
    13.2 ± 5.3
    13.8 ± 5.2
    Statistical analysis title
    		 Summary of best estimates of treatment effects
    Statistical analysis description
    Across all follow-up time points
    Comparison groups
    Baseline: Placebo v Baseline: Minocycline v 2 month follow-up: Minocycline v 2 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 9 month follow-up: Minocycline v 9 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 0.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Secondary: Total Symptoms PANSS

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    End point title
    		 Total Symptoms PANSS
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    103
    83
    85
    69
    66
    68
    62
    62
    65
    41
    48
    Units: PANSS score
        arithmetic mean (standard deviation)
    67.1 ± 13.2
    69.3 ± 15.4
    59.6 ± 14.9
    60.1 ± 15.7
    57.5 ± 15.7
    59.4 ± 16.8
    57.0 ± 14.7
    56.8 ± 14.7
    59.0 ± 17.3
    57.1 ± 17.3
    57.7 ± 16.5
    55.8 ± 15.4
    Statistical analysis title
    		 Summary of best estimates of treatment effects
    Statistical analysis description
    Across all follow-up timepoints
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 2 month follow-up: Minocycline v 2 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 9 month follow-up: Minocycline v 9 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    855
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.75
         upper limit
    		 2.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.62

    Secondary: CDSS score

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    End point title
    		 CDSS score
    End point description
    End point type
    Secondary
    End point timeframe
    Across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    102
    100
    84
    85
    68
    67
    68
    63
    62
    63
    41
    48
    Units: CDSS score
        arithmetic mean (standard error)
    5.17 ± 4.27
    5.5 ± 4.96
    3.31 ± 3.85
    3.40 ± 3.99
    2.6 ± 3.59
    3.05 ± 4.17
    3.25 ± 3.78
    2.73 ± 3.77
    3.09 ± 3.98
    3.12 ± 4.28
    2.49 ± 3.53
    2.88 ± 4.43
    Statistical analysis title
    		 Summary of best estimates of treatment effects
    Statistical analysis description
    Across all follow-up timepoints
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 2 month follow-up: Minocycline v 2 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 9 month follow-up: Minocycline v 9 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 0.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: GAF score

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    End point title
    		 GAF score
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    102
    103
    83
    85
    68
    65
    67
    63
    60
    64
    41
    47
    Units: GAF score
        arithmetic mean (standard error)
    55.5 ± 9.1
    56.2 ± 11.6
    58.1 ± 11.6
    59.5 ± 11.4
    60.2 ± 13.2
    59.6 ± 12.1
    58.5 ± 12.7
    60.8 ± 12.0
    56.3 ± 14.1
    60.4 ± 13.4
    56.5 ± 13.6
    61.7 ± 13.0
    Statistical analysis title
    		 Summary of best estimates of treatment effects
    Statistical analysis description
    Across all follow-up timepoints
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 2 month follow-up: Minocycline v 2 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 9 month follow-up: Minocycline v 9 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    848
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 6.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15

    Secondary: SFS withdrawal

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    End point title
    		 SFS withdrawal
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    101
    0 [29]
    0 [30]
    65
    65
    0 [31]
    0 [32]
    61
    63
    41
    48
    Units: Find out
        arithmetic mean (standard deviation)
    10.5 ± 3.1
    10.2 ± 2.9
    ±
    ±
    11.0 ± 3.2
    11.0 ± 3.2
    ±
    ±
    10.7 ± 3.7
    10.9 ± 3.4
    10.6 ± 3.2
    11.5 ± 3.5
    Notes
    [29] - Measure not captured at this time point
    [30] - Measure not captured at this time point
    [31] - Measure not captured at this time point
    [32] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo v Baseline: Minocycline
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 6.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15

    Secondary: SFS relations

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    End point title
    		 SFS relations
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    102
    0 [33]
    0 [34]
    65
    65
    0 [35]
    0 [36]
    61
    63
    41
    48
    Units: Find out
        arithmetic mean (standard deviation)
    6.4 ± 8.1
    6.6 ± 1.9
    ±
    ±
    6.8 ± 2.0
    7.2 ± 2.0
    ±
    ±
    6.6 ± 2.2
    7.1 ± 2.0
    6.9 ± 2.1
    7.1 ± 2.0
    Notes
    [33] - Measure not captured at this time point
    [34] - Measure not captured at this time point
    [35] - Measure not captured at this time point
    [36] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27

    Secondary: SFS independence-performance

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    End point title
    		 SFS independence-performance
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    101
    0 [37]
    0 [38]
    65
    65
    0 [39]
    0 [40]
    61
    63
    41
    48
    Units: find out
        arithmetic mean (standard deviation)
    26.3 ± 7.5
    26.1 ± 6.4
    ±
    ±
    26.7 ± 8.2
    27.4 ± 7.2
    ±
    ±
    26.3 ± 6.8
    27.4 ± 7.0
    26.0 ± 7.4
    26.6 ± 6.8
    Notes
    [37] - Measure not captured at this time point
    [38] - Measure not captured at this time point
    [39] - Measure not captured at this time point
    [40] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    547
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 0.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89

    Secondary: SFS Recreation

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    End point title
    		 SFS Recreation
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    102
    0 [41]
    0 [42]
    65
    65
    0 [43]
    0 [44]
    61
    63
    41
    48
    Units: find out
        arithmetic mean (standard deviation)
    18.2 ± 7.8
    17.7 ± 6.02
    ±
    ±
    17.6 ± 7.3
    18.4 ± 7.8
    ±
    ±
    17.4 ± 7.1
    18.4 ± 7.0
    17.4 ± 7.6
    17.1 ± 6.8
    Notes
    [41] - Measure not captured at this time point
    [42] - Measure not captured at this time point
    [43] - Measure not captured at this time point
    [44] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    15 month follow-up: Minocycline v 15 month follow-up: Placebo v Baseline: Minocycline v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 0.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89

    Secondary: SFS Prosocial-activities

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    End point title
    		 SFS Prosocial-activities
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    102
    0 [45]
    0 [46]
    65
    65
    0 [47]
    0 [48]
    61
    63
    41
    48
    Units: find out
        arithmetic mean (standard deviation)
    16.6 ± 10.3
    16.7 ± 10.5
    ±
    ±
    16.3 ± 9.6
    17.3 ± 11.6
    ±
    ±
    16.5 ± 10.1
    17.2 ± 10.8
    15.9 ± 10.0
    18.9 ± 11.5
    Notes
    [45] - Measure not captured at this time point
    [46] - Measure not captured at this time point
    [47] - Measure not captured at this time point
    [48] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v 15 month follow-up: Minocycline v 15 month follow-up: Placebo v Baseline: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.25
         upper limit
    		 2.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24

    Secondary: SFS independence-competence

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    End point title
    		 SFS independence-competence
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    102
    0 [49]
    0 [50]
    65
    65
    0 [51]
    0 [52]
    61
    63
    41
    48
    Units: find out
        arithmetic mean (standard deviation)
    34.8 ± 4.9
    34.0 ± 6.2
    ±
    ±
    34.7 ± 5.4
    35.0 ± 4.8
    ±
    ±
    34.0 ± 5.1
    34.8 ± 5.0
    34.0 ± 7.1
    35.5 ± 3.9
    Notes
    [49] - Measure not captured at this time point
    [50] - Measure not captured at this time point
    [51] - Measure not captured at this time point
    [52] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.79
         upper limit
    		 0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.67

    Secondary: SFS employment

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    End point title
    		 SFS employment
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    103
    102
    0 [53]
    0 [54]
    64
    65
    0 [55]
    0 [56]
    61
    63
    41
    47
    Units: find out
        arithmetic mean (standard deviation)
    4.7 ± 3.1
    4.9 ± 3.0
    ±
    ±
    4.9 ± 3.3
    5.6 ± 3.4
    ±
    ±
    5.3 ± 3.3
    5.9 ± 3.1
    5.4 ± 3.7
    5.3 ± 3.3
    Notes
    [53] - Measure not captured at this time point
    [54] - Measure not captured at this time point
    [55] - Measure not captured at this time point
    [56] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo v 6 month follow-up: Minocycline v 6 month follow-up: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    546
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43

    Secondary: Processing speed

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    End point title
    		 Processing speed
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    95
    91
    0 [57]
    0 [58]
    0 [59]
    0 [60]
    0 [61]
    0 [62]
    58
    59
    36
    47
    Units: find out
        arithmetic mean (standard deviation)
    58.0 ± 16.7
    52.8 ± 16.8
    ±
    ±
    ±
    ±
    ±
    ±
    56.1 ± 16.2
    58.2 ± 15.8
    62.6 ± 16.2
    61.2 ± 15.9
    Notes
    [57] - Measure not captured at this time point
    [58] - Measure not captured at this time point
    [59] - Measure not captured at this time point
    [60] - Measure not captured at this time point
    [61] - Measure not captured at this time point
    [62] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    386
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.63
         upper limit
    		 2.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26

    Secondary: Weight

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    End point title
    		 Weight
    End point description
    End point type
    Secondary
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    97
    101
    0 [63]
    0 [64]
    0 [65]
    0 [66]
    0 [67]
    0 [68]
    53
    58
    0 [69]
    0 [70]
    Units: Kg
        arithmetic mean (standard deviation)
    82.6 ± 19.6
    86.8 ± 25.3
    ±
    ±
    ±
    ±
    ±
    ±
    88 ± 18.2
    91.8 ± 28.5
    ±
    ±
    Notes
    [63] - Measure not captured at this time point
    [64] - Measure not captured at this time point
    [65] - Measure not captured at this time point
    [66] - Measure not captured at this time point
    [67] - Measure not captured at this time point
    [68] - Measure not captured at this time point
    [69] - Measure not captured at this time point
    [70] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 6.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15

    Other pre-specified: Current IQ

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    End point title
    		 Current IQ
    End point description
    End point type
    Other pre-specified
    End point timeframe
    across all follow-up timepoints
    End point values
    		 Baseline: Minocycline Baseline: Placebo 2 month follow-up: Minocycline 2 month follow-up: Placebo 6 month follow-up: Minocycline 6 month follow-up: Placebo 9 month follow-up: Minocycline 9 month follow-up: Placebo 12 month follow-up: Minocycline 12 month follow-up: Placebo 15 month follow-up: Minocycline 15 month follow-up: Placebo
    Number of subjects analysed
    101
    100
    0 [71]
    0 [72]
    0 [73]
    0 [74]
    0 [75]
    0 [76]
    59
    61
    38
    48
    Units: Score
        arithmetic mean (standard deviation)
    91.2 ± 14.0
    89.2 ± 15.9
    ±
    ±
    ±
    ±
    ±
    ±
    93.7 ± 14.2
    94.6 ± 16.6
    98.2 ± 16.1
    97.0 ± 17.5
    Notes
    [71] - Measure not captured at this time point
    [72] - Measure not captured at this time point
    [73] - Measure not captured at this time point
    [74] - Measure not captured at this time point
    [75] - Measure not captured at this time point
    [76] - Measure not captured at this time point
    Statistical analysis title
    		 best estimates of treatment effects
    Comparison groups
    Baseline: Minocycline v Baseline: Placebo v 12 month follow-up: Minocycline v 12 month follow-up: Placebo v 15 month follow-up: Minocycline v 15 month follow-up: Placebo
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.59
         upper limit
    		 2.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.53

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Recorded from the randomisation visit to the month 3 non interventional post trial follow up visit.
    Adverse event reporting additional description
    Standard variables collected: verbatim, start and end time/date, seriousness, causality, action regarding IMP, outocome.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Minocycline
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Minocycline Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 103 (11.65%)
    7 / 104 (6.73%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    DVT
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 103 (1.94%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hospitalisation
    Additional description: Psychiatric hospitalisations- admissions due to worsening of psychiatric illness, with a combination of intensification of psychosis, dysphoria, suicidal ideation and intent. Other factors contributing: poor meds adherance & substance/alcohol misuse.
         subjects affected / exposed
    10 / 103 (9.71%)
    6 / 104 (5.77%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Minocycline Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 103 (58.25%)
    67 / 104 (64.42%)
    Immune system disorders
    Immune system disorder
    Additional description: Immune system disorder
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders
    Additional description: Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 104 (0.96%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Psychiatric disorders
    Additional description: Psychiatric disorders
         subjects affected / exposed
    8 / 103 (7.77%)
    16 / 104 (15.38%)
         occurrences all number
    8
    16
    Congenital, familial and genetic disorders
    Congenital, familial and genetic disorder
    Additional description: Congenital, familial and genetic disorder
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiac disorders
    Additional description: Cardiac disorders
         subjects affected / exposed
    1 / 103 (0.97%)
    5 / 104 (4.81%)
         occurrences all number
    1
    5
    Nervous system disorders
    Nervous system disorders
    Additional description: Nervous system disorders
         subjects affected / exposed
    12 / 103 (11.65%)
    8 / 104 (7.69%)
         occurrences all number
    12
    8
    Ear and labyrinth disorders
    Ear disorder
    Additional description: Ear and labyrinth disorders
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: Gastrointestinal disorders including GI upset
         subjects affected / exposed
    19 / 103 (18.45%)
    12 / 104 (11.54%)
         occurrences all number
    19
    12
    Skin and subcutaneous tissue disorders
    Skin disorder
    Additional description: Skin and subcutaneous tissue disorder including rash.
         subjects affected / exposed
    8 / 103 (7.77%)
    10 / 104 (9.62%)
         occurrences all number
    8
    10
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: Renal and urinary disorders
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 104 (0.96%)
         occurrences all number
    1
    1
    Endocrine disorders
    Endocrine disorder
    Additional description: Endocrine disorder
         subjects affected / exposed
    2 / 103 (1.94%)
    1 / 104 (0.96%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
    Additional description: Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    3 / 103 (2.91%)
    3 / 104 (2.88%)
         occurrences all number
    3
    3
    Infections and infestations
    Infections and infestations
    Additional description: Infections and infestations
         subjects affected / exposed
    2 / 103 (1.94%)
    9 / 104 (8.65%)
         occurrences all number
    2
    9
    Metabolism and nutrition disorders
    Metabolism and nutrition dsorders
    Additional description: Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (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
    19 Jun 2012
    Included a Data Monitoring Committee, added the Mini International Neuropsychiatric Interview to screening procedures, added the Auditory Verbal Learning Task to the cognitive tasks.
    25 Mar 2013
    Removal of ANF- anitnuclear anitbody ANA- from the screening as test was deemed obsolete.
    03 Jun 2013
    Inclusion of hallucinations to the PANNS criteria for inclusion into the study.
    26 Sep 2013
    Changed inclusion criterion 6 'within 3 years of onset of symptoms' to 'within 5 years of onset of symptoms.

    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.
    High drop out rate but does not differ between the 2 treatment arms. Full information available at https://doi.org/10.3310/eme06070

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30322824
    http://www.ncbi.nlm.nih.gov/pubmed/31465163
    For support, Contact us.
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