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    Clinical Trial Results:
    The Role of Tetracyclines in the Personalised Management of MMP-9 and Cardiovascular Function in Type 2 Diabetes

    Summary
    EudraCT number
    		 2015-002387-16
    Trial protocol
    		 IE  
    Global end of trial date
    10 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2018
    First version publication date
    26 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SI-C-060
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Solvotrin Innovations Ltd
    Sponsor organisation address
    Hoffman Park, Little Island, Cork, Ireland, T45 YX04
    Public contact
    Fiona Ryan, Solvotrin Innovations Ltd, 353 214510220, Fionaryan@solvotrin.com
    Scientific contact
    Fiona Ryan, Solvotrin Innovations Ltd, 353 214510220, Fionaryan@solvotrin.com
    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
    10 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the impact of one year therapy with minocycline on MMP-9 in patients with with Type 2 diabetes and the MMP-9, 1562 C>T promoter single nucleotide polymorphism
    Protection of trial subjects
    This study was carried out in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Before initiating the study, all relevant documentation including the study protocol and patient information and informed consent form were reviewed and approved by the relevant competent authority and the St Vincent's University Hospital Ethics Committee. Each participant was provided with an information and consent form in clear, simple language and was given ample time to inquire about details of the study and to decide whether of not to participate in the study. Participants anonymity was maintained at all times throughout the study.
    Background therapy
    		 Usual medical care
    Evidence for comparator
    		 The comparator group was usual medical care. There was no placebo.
    Actual start date of recruitment
    13 Jan 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
    Ireland: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    8
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial participants were recruited from the STOP-HF Unit of St Michael's Hospital, Dun Laoghaire, Co Dublin. Male and female patients >18 years of age were eligible to participate once eligibility criteria were met.

    Pre-assignment
    Screening details
    		 The STOP-HF database was screened to identify patients that met the inclusion criteria (age, diabetes, MMP-9 1562 C>T promoter single nucleotide polymorphism). Potentially eligible patients were invited to a 'Screening visit' at which eligibility was further assessed/confirmed.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Unblinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (minocycline)
    Arm description
    		 Usual medical care and additional treatment with minocycline 100mg daily (orally) for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline 100mg capsules
    Investigational medicinal product code
    Other name
    Minosil
    Pharmaceutical forms
    Modified-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Minocycline 100mg once daily (orally) for 12 months

    Arm title
    		 Control
    Arm description
    		 Usual medical care (no minocycline)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intervention (minocycline) Control
    Started
    10
    12
    Completed
    10
    12
    Period 2
    Period 2 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Unblinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (Minocycline)
    Arm description
    		 Usual medical care and additional treatment with minocycline 100mg daily (orally) for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Minocycline
    Investigational medicinal product code
    Other name
    Minosil
    Pharmaceutical forms
    Modified-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Minocycline 100mg once daily (orally) for 12 months

    Arm title
    		 Control
    Arm description
    		 Usual medical care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Intervention (Minocycline) Control
    Started
    10
    12
    Completed
    7
    11
    Not completed
    3
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention (minocycline)
    Reporting group description
    		 Usual medical care and additional treatment with minocycline 100mg daily (orally) for 12 months.

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care (no minocycline)

    Reporting group values
    		 Intervention (minocycline) Control Total
    Number of subjects
    		 10 12 22
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 4 8
        From 65-84 years
    		 6 8 14
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68.2 (60.7 to 73.8) 69 (62.6 to 73.7) -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 6
        Male
    		 8 8 16
    Diabetes
    Units: Subjects
        Diabetes mellitus
    		 10 12 22
        No diabetes mellitus
    		 0 0 0
    Hypertension
    Units: Subjects
        Hypertension
    		 8 11 19
        No hypertension
    		 2 1 3
    Dyslipidemia
    Units: Subjects
        Dyslipidemia
    		 8 11 19
        No dyslipidemia
    		 2 1 3
    Atrial fibrillation
    Units: Subjects
        AF
    		 0 0 0
        No AF
    		 10 12 22
    Coronary artery disease
    Units: Subjects
        CAD
    		 0 1 1
        No CAD
    		 10 11 21
    Smoking history
    Units: Subjects
        Smoker
    		 3 1 4
        Non-smoker
    		 7 11 18
    Medication history. Beta-blocker
    Units: Subjects
        Beta-blocker
    		 3 3 6
        No beta-blocker
    		 7 9 16
    Medication history. Alpha-blocker
    Units: Subjects
        Alpha-blocker
    		 0 1 1
        No alpha-blocker
    		 10 11 21
    Medication history. CCB (calcium channel blocker)
    Units: Subjects
        CCB
    		 6 6 12
        No CCB
    		 4 6 10
    Medication history. AA (aldosterone antagonist)
    Units: Subjects
        AA
    		 0 0 0
        No AA
    		 10 12 22
    Medication history. Statin
    Units: Subjects
        Statin
    		 10 9 19
        No statin
    		 0 3 3
    Medication history. Diuretic
    Units: Subjects
        Diuretic
    		 0 2 2
        No diuretic
    		 10 10 20
    Medication history. Antiplatelet
    Units: Subjects
        Antiplatelet
    		 8 12 20
        No antiplatelet
    		 2 0 2
    Medication history. Metformin
    Units: Subjects
        Metformin
    		 10 8 18
        No metformin
    		 0 4 4
    Medication history (Gliclazide)
    Units: Subjects
        Gliclazide
    		 4 4 8
        No gliclazide
    		 6 8 14
    Medication history (Insulin)
    Units: Subjects
        Insulin
    		 2 0 2
        No insulin
    		 8 12 20
    Family history of CVD
    Units: Subjects
        Family history of CVD
    		 2 3 5
        No family history of CVD
    		 8 9 17
    Medication history. ACEI or ARB
    Units: Subjects
        ACEI or ARB
    		 7 9 16
        No ACEI or ARB
    		 3 3 6
    Medication history. Warfarin
    Units: Subjects
        Warfarin
    		 0 0 0
        No warfarin
    		 10 12 22
    Body mass index (BMI)
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 28.05 (27.1 to 31.1) 29.4 (26.0 to 30.9) -
    Height
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 184 (175 to 186) 168 (168 to 174) -
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    		 90 (81 to 109) 85 (79 to 94) -
    Body surface area
    Units: m2
        median (inter-quartile range (Q1-Q3))
    		 2.12 (1.96 to 2.35) 1.98 (1.90 to 2) -
    Glucose
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 8.2 (6.7 to 8.8) 10.8 (8.8 to 12.5) -
    Total cholesterol
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 3.9 (3.6 to 4.5) 4.1 (3.5 to 4.6) -
    Intraocular pressure
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 15 (12.5 to 16.5) 15 (13 to 17) -
    ABPM. Systolic BP (24h)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 129 (126 to 131) 131 (122 to 136) -
    ABPM. Diastolic BP (24h)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 72 (67 to 75) 73 (66 to 73) -
    ABPM. Heart Rate (24hour)
    Units: bpm
        median (inter-quartile range (Q1-Q3))
    		 80 (75 to 83) 71 (63 to 78) -
    ABPM. Pulse Pressure (24 hour)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 54 (52 to 59) 57 (54 to 64) -
    Echocardiography. Ejection fraction
    Units: %, Teicholtz
        median (inter-quartile range (Q1-Q3))
    		 68 (63 to 73) 65 (63 to 68) -
    Echocardiography. End Diastolic Volume
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    		 97 (69 to 108) 92 (77 to 110) -
    Echocardiography. End Systolic Volume
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    		 31 (23 to 37) 27 (25 to 42) -
    Echocardiography. Left ventricular mass index (LVMI)
    Units: gram(s)/square meter
        median (inter-quartile range (Q1-Q3))
    		 92 (84 to 98) 109 (83 to 119) -
    Echocardiography. E/E' lateral
    Units: Ratio
        median (inter-quartile range (Q1-Q3))
    		 8.75 (7.3 to 11.1) 9.77 (8.9 to 10.6) -
    Echocardiography. Left Atrial Volume Index (LAVI)
    Units: mL/m2
        median (inter-quartile range (Q1-Q3))
    		 22.4 (19.1 to 25) 21.3 (17.8 to 24.2) -
    Brain natriuretic peptide (BNP)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 12.2 (8.0 to 21.5) 24.3 (12.0 to 34.1) -
    Matrix metalloproteinase-2 (MMP-2)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 3.86 (3.66 to 4.12) 3.91 (3.66 to 4.18) -
    Matrix metalloproteinase-9 (MMP-9)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 5.29 (4.56 to 5.53) 5.83 (5.29 to 6.19) -
    Interleukin 6 receptor antagonist (IL6RA)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 11.1 (10.9 to 11.3) 10.9 (10.8 to 11.1) -
    Collagen 1 (Col1a1)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 3.6 (3.3 to 3.9) 3.5 (3.3 to 3.8) -
    Galectin-3 (Gal-3)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 4.9 (4.8 to 5.3) 5.1 (4.8 to 5.5) -
    Tumor necrosis factor 1 receptor 1 (TNFr1)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 5.2 (4.9 to 5.4) 5.3 (5.2 to 5.6) -
    Monocyte chemotactic protein-1 (MCP-1)
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    		 3.4 (2.7 to 3.5) 3.5 (3.0 to 3.7) -
    Triglycerides
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 2.4 (1.9 to 2.9) 1.9 (1.3 to 2.4) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention (minocycline)
    Reporting group description
    		 Usual medical care and additional treatment with minocycline 100mg daily (orally) for 12 months.

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care (no minocycline)
    Reporting group title
    Intervention (Minocycline)
    Reporting group description
    		 Usual medical care and additional treatment with minocycline 100mg daily (orally) for 12 months.

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care

    Primary: Baseline to 1 year change in matrix metalloproteinase-9 (MMP-9)

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    End point title
    		 Baseline to 1 year change in matrix metalloproteinase-9 (MMP-9)
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    0.66 (-0.02 to 1.32)
    0.04 (-0.88 to 0.59)
    Statistical analysis title
    		 Wilcoxon (Mann Whitney)
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.22
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Baseline to 1 year change in matrix metalloproteinase-2 (MMP-2)

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    End point title
    		 Baseline to 1 year change in matrix metalloproteinase-2 (MMP-2)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        median (inter-quartile range (Q1-Q3))
    0.16 (0.02 to 0.33)
    0.09 (-0.06 to 0.17)
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in interleukin 6 receptor antagonist (IL6RA)

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    End point title
    		 Baseline to 1 year change in interleukin 6 receptor antagonist (IL6RA)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        arithmetic mean (standard deviation)
    0.1 ( 0.23 )
    0.01 ( 0.26 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.31
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in collagen 1 (Col1a1)

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    End point title
    		 Baseline to 1 year change in collagen 1 (Col1a1)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        arithmetic mean (standard deviation)
    -0.03 ( 0.41 )
    0.15 ( 0.19 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.39
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in galectin-3 (Gal-3)

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    End point title
    		 Baseline to 1 year change in galectin-3 (Gal-3)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        arithmetic mean (standard deviation)
    0.03 ( 0.33 )
    0.03 ( 0.49 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.91
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in tumor necrosis factor 1 receptor 1 (TNFa R1)

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    End point title
    		 Baseline to 1 year change in tumor necrosis factor 1 receptor 1 (TNFa R1)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        arithmetic mean (standard deviation)
    0.12 ( 0.45 )
    0.05 ( 0.36 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.66
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in monocyte chemotactic protein 1 (MCP-1)

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    End point title
    		 Baseline to 1 year change in monocyte chemotactic protein 1 (MCP-1)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    10
    11
    Units: Normalised protein expression units (NPX
        arithmetic mean (standard deviation)
    0.27 ( 0.47 )
    0.29 ( 0.71 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.85
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in ejection fraction (echo)

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    End point title
    		 Baseline to 1 year change in ejection fraction (echo)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    9
    10
    Units: percentage
        arithmetic mean (standard deviation)
    2.8 ( 7.1 )
    3.46 ( 10.1 )
    Statistical analysis title
    		 T test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.81
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in left atrial volume index (LAVI) (echo)

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    End point title
    		 Baseline to 1 year change in left atrial volume index (LAVI) (echo)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    9
    11
    Units: ml/m2
        arithmetic mean (standard deviation)
    0.39 ( 4.1 )
    1.19 ( 5.4 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.56
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in left ventricular mass index (LVMI) (echo)

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    End point title
    		 Baseline to 1 year change in left ventricular mass index (LVMI) (echo)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    8
    10
    Units: g/m2
        arithmetic mean (standard deviation)
    13.4 ( 24.7 )
    1.6 ( 18.7 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.73
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in systolic BP (24 hour)

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    End point title
    		 Baseline to 1 year change in systolic BP (24 hour)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    8
    11
    Units: mmHg
        arithmetic mean (standard deviation)
    -3.6 ( 7.4 )
    0 ( 11.3 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.61
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in diastolic BP (24 hour)

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    End point title
    		 Baseline to 1 year change in diastolic BP (24 hour)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    8
    11
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.5 ( 3.8 )
    -0.4 ( 5.6 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.66
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in pulse pressure (24 hour)

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    End point title
    		 Baseline to 1 year change in pulse pressure (24 hour)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    8
    11
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.9 ( 4.6 )
    0.6 ( 5.4 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.67
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.67
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in intraocular pressure

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    End point title
    		 Baseline to 1 year change in intraocular pressure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    4
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.8 ( 0.5 )
    -2.0 ( 1.6 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.73
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Baseline to 1 year change in E/E' (echo)

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    End point title
    		 Baseline to 1 year change in E/E' (echo)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention (Minocycline) Control
    Number of subjects analysed
    6
    9
    Units: ratio
        arithmetic mean (standard deviation)
    -0.22 ( 1.47 )
    0.01 ( 1.54 )
    Statistical analysis title
    		 T-test
    Comparison groups
    Intervention (Minocycline) v Control
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.94
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization
    Adverse event reporting additional description
    Safety information was provided spontaneously by the participant and/or through questioning by the investigator. If any changes to medication suggested a new illness or worsening of a pre-existing condition, the participant was questioned further. Abnormal laboratory/test results, if deemed medically significant, were considered adverse events
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Intervention (Minocycline)
    Reporting group description
    		 Minocycline 100mg daily orally in addition to usual medical care.

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care

    Serious adverse events
    		 Intervention (Minocycline) Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Phrenic nerve paralysis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (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
    Atelectasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention (Minocycline) Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    9 / 12 (75.00%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Knee operation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin cyst excision
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    2
    Sinusitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Blood glucose increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (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
    22 Mar 2016
    Screening and baseline visits can be combined. Update to eligibility criteria. Subjects with a contraindication to cardiac MRI can be randomized into the study; however, they will not undergo MRI. Update to exclusion criteria. Subjects with a soya or peanut allergy can be randomized into the study as the study drug does not contain these ingredients. Follow up visits at month 2, 4, 8 and 10 deleted so that subjects are followed up at 6 and 12 months only. Schedule of assessments: Measurement of natriuretic peptide (NT-proBNP) added at baseline, 6 and 12 months (previously captured under 'biomarkers' but separated out for clarity). Schedule of assessments: Pulse wave velocity. A more comprehensive analysis of arterial stiffness will be done on a sub-set of subjects that are willing to travel to another site (Tallaght Hospital). Schedule of assessments: Some changes to the retinopathy assessment were made (measurement of IOP using non-contact tonometry instead of applanation tonometry and Schnellan chart instead of Log Mar visual acuity chart ). Cardiac MRI: The site for performing cMRI was changed and the need for gadolinium contrast media was removed as this is not necessary. Alk Phos measurement not required during screening visit. Glucose monitoring was removed from the protocol. Randomisation: A method of sealed envelopes at the investigator site was implemented and replaced the need to contact the study monitor during this process.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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