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    Clinical Trial Results:
    A multicentre, 48 week randomised controlled factorial trial of adding maraviroc and/or metformin for hepatic steatosis in HIV-1-infected adults on combination antiretroviral therapy.

    Summary
    EudraCT number
    		 2016-003575-21
    Trial protocol
    		 GB  
    Global end of trial date
    06 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2021
    First version publication date
    18 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    N/A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03129113
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    90 High Holborn, London, United Kingdom,
    Public contact
    Chief Investigator for MAVMET Trial, University College London, +44 07983806215, mrcctu.mavmet@ucl.ac.uk
    Scientific contact
    Chief Investigator for MAVMET Trial, University College London, +44 07983806215, mrcctu.mavmet@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    MAVMET is trying to find out if maraviroc, metformin or a combination of both results in a change in percentage of liver fat as measured by MR PDFF a type of MRI imaging over 48 weeks.
    Protection of trial subjects
    In consenting to the trial, patients are consenting to trial treatment, trial follow-up and data collection. However, an individual patient may stop treatment early or be stopped early for any of the following reasons:  Unacceptable toxicity or adverse event  Intercurrent illness that prevents further treatment  Any change in the patient’s condition that justifies the discontinuation of treatment in the clinician’s opinion  Inadequate compliance with the protocol treatment in the judgement of the treating physician  Withdrawal of consent for treatment by the patient
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    0
    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)
    86
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment took place in 6 London hospitals between 19/03/2018 and 11/11/2019.

    Pre-assignment
    Screening details
    		 Males or females ≥35 years of age; Chronic HIV-1-infection for ≥5 years; On cART and with virological suppression (<50 copies/mL) for ≥1 year; either i) >1 abnormal (above the upper limit) of LFTS (ALT or AST) in the last 2 years with no other explanation, ii) increased waist circumference, confirmed diagnosis of NAFLD on imaging or biopsy.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maraviroc
    Arm description
    		 Maraviroc p/o BID dosed as follows: 150mg BID in those on ritonavir-boosted PI, cobicistat-boosted PI, or ritonavir-boosted or cobicistat-boosted elvitegravir; 600mg BID in those on efavirenz (EFV)- based regimens, or 300mg BID in those on raltegravir (RAL), dolutegravir (DTG) or nevirapine (NVP)- based regimens.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Maraviroc p/o BID dosed as follows: 150mg BID in those on ritonavir-boosted PI, cobicistat-boosted PI, or ritonavir-boosted or cobicistat-boosted elvitegravir; 600mg BID in those on efavirenz (EFV)- based regimens, or 300mg BID in those on raltegravir (RAL), dolutegravir (DTG) or nevirapine (NVP)- based regimens.

    Arm title
    		 Metformin
    Arm description
    		 Metformin p/o 500mg BID with or after food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin p/o 500mg BID with or after food.

    Arm title
    		 Maraviroc and metformin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Maraviroc p/o BID dosed as follows: 150mg BID in those on ritonavir-boosted PI, cobicistat-boosted PI, or ritonavir-boosted or cobicistat-boosted elvitegravir; 600mg BID in those on efavirenz (EFV)- based regimens, or 300mg BID in those on raltegravir (RAL), dolutegravir (DTG) or nevirapine (NVP)- based regimens.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin p/o 500mg BID with or after food.

    Arm title
    		 No drug
    Arm description
    		 Control arm
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Maraviroc Metformin Maraviroc and metformin No drug
    Started
    23
    21
    22
    24
    Completed
    21
    20
    19
    24
    Not completed
    2
    1
    3
    0
         Consent withdrawn by subject
    2
    1
    2
    -
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 90 90
    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
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 52 (47 to 57) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 84 84
    Ethnicity
    Units: Subjects
        White
    		 73 73
        Hispanic/Latino
    		 3 3
        Black Caribbean/American
    		 1 1
        Black African
    		 9 9
        Mixed ethnic group
    		 2 2
        Other
    		 2 2
    Entry criteria
    Units: Subjects
        Raised LFTs only
    		 1 1
        Increased waist circumference only
    		 20 20
        Scan or biopsy diagnosis only
    		 2 2
        Raised LFTs and large waist circumference
    		 4 4
        Scan or biopsy diagnosis plus 1+ another criteria
    		 63 63
    Baseline ART
    Units: Subjects
        INSTI
    		 43 43
        PI
    		 15 15
        NNRTI
    		 32 32
    BMI
    Units: kg/m^2
        median (inter-quartile range (Q1-Q3))
    		 28 (26 to 33) -
    Waist circumference
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 104 (97 to 112) -
    ALT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 41 (31 to 61) -
    AST
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 32 (27 to 41) -
    ALP
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 83 (66 to 103) -
    GGT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 44 (27 to 70) -
    CD4 count
    Units: cells/mm^3
        median (inter-quartile range (Q1-Q3))
    		 672 (451 to 831) -
    CD4 %
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 34 (29 to 41) -
    CD8 count
    Units: cells/mm^3
        median (inter-quartile range (Q1-Q3))
    		 661 (543 to 834) -
    CD8 %
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 35 (31 to 43) -
    Subject analysis sets

    Subject analysis set title
    Scans as initially planned
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This dataset is limited to those who had their W48 scans within a +/-6 week window around W48. This excludes those who had their treatment lengthened due to the pandemic.

    Subject analysis sets values
    		 Scans as initially planned
    Number of subjects
    62
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    53 (47 to 57)
    Gender categorical
    Units: Subjects
        Female
    57
        Male
    5
    Ethnicity
    Units: Subjects
        White
    51
        Hispanic/Latino
    2
        Black Caribbean/American
    1
        Black African
    5
        Mixed ethnic group
    2
        Other
    1
    Entry criteria
    Units: Subjects
        Raised LFTs only
    1
        Increased waist circumference only
    14
        Scan or biopsy diagnosis only
    2
        Raised LFTs and large waist circumference
    4
        Scan or biopsy diagnosis plus 1+ another criteria
    41
    Baseline ART
    Units: Subjects
        INSTI
    27
        PI
    11
        NNRTI
    24
    BMI
    Units: kg/m^2
        median (inter-quartile range (Q1-Q3))
    28 (26 to 32)
    Waist circumference
    Units: cm
        median (inter-quartile range (Q1-Q3))
    105 (98 to 112)
    ALT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    39 (31 to 57)
    AST
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    31 (27 to 41)
    ALP
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    79 (62 to 102)
    GGT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    42 (25 to 70)
    CD4 count
    Units: cells/mm^3
        median (inter-quartile range (Q1-Q3))
    677 (430 to 801)
    CD4 %
    Units: percent
        median (inter-quartile range (Q1-Q3))
    35 (29 to 41)
    CD8 count
    Units: cells/mm^3
        median (inter-quartile range (Q1-Q3))
    663 (543 to 834)
    CD8 %
    Units: percent
        median (inter-quartile range (Q1-Q3))
    35 (31 to 44)

    End points

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    End points reporting groups
    Reporting group title
    Maraviroc
    Reporting group description
    		 Maraviroc p/o BID dosed as follows: 150mg BID in those on ritonavir-boosted PI, cobicistat-boosted PI, or ritonavir-boosted or cobicistat-boosted elvitegravir; 600mg BID in those on efavirenz (EFV)- based regimens, or 300mg BID in those on raltegravir (RAL), dolutegravir (DTG) or nevirapine (NVP)- based regimens.

    Reporting group title
    Metformin
    Reporting group description
    		 Metformin p/o 500mg BID with or after food.

    Reporting group title
    Maraviroc and metformin
    Reporting group description
    		 -

    Reporting group title
    No drug
    Reporting group description
    		 Control arm

    Subject analysis set title
    Scans as initially planned
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This dataset is limited to those who had their W48 scans within a +/-6 week window around W48. This excludes those who had their treatment lengthened due to the pandemic.

    Primary: Change in % liver fat to 48 weeks (all participants)

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    End point title
    		 Change in % liver fat to 48 weeks (all participants)
    End point description
    End point type
    Primary
    End point timeframe
    48 weeks from randomisation
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    22
    Units: liver fat %
        arithmetic mean (standard deviation)
    2.2 ± 4.6
    1.3 ± 4.1
    0.8 ± 5.7
    1.4 ± 4.0
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.68
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 0.56
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 0.65
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.14
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.14
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.18

    Primary: Change in % liver fat to 48 weeks (scans performed as planned)

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    End point title
    		 Change in % liver fat to 48 weeks (scans performed as planned)
    End point description
    End point type
    Primary
    End point timeframe
    Only scans performed in original W48 window (+/- 6 weeks)
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    14
    16
    15
    17
    Units: liver fat %
        arithmetic mean (standard deviation)
    0.3 ± 2.6
    0.6 ± 4.2
    -0.2 ± 5.8
    1.7 ± 2.2
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.64
         upper limit
    		 0.25
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 -0.38
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.66
         upper limit
    		 -0.63
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.1
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.12
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.09

    Secondary: Change in hepatic steatosis grade

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    End point title
    		 Change in hepatic steatosis grade
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    22
    Units: Change in grade
        -2
    0
    0
    0
    1
        -1
    1
    1
    3
    0
        None
    13
    14
    12
    17
        +1
    6
    4
    4
    4
        +2
    1
    1
    0
    0
    Statistical analysis title
    		 Change in grade: all four arms
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change in grade: maraviroc vs control
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change in grade: metformin vs control
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of life: mobility

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    End point title
    		 Quality of life: mobility
    End point description
    End point type
    Secondary
    End point timeframe
    At 48 weeks
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: EQ-5D
        No change
    20
    15
    15
    17
        Improved
    1
    3
    2
    4
        Worsened
    0
    2
    2
    3
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Metformin v Maraviroc and metformin v No drug v Maraviroc
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of life: Self-care

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    End point title
    		 Quality of life: Self-care
    End point description
    End point type
    Secondary
    End point timeframe
    At W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: EQ-5D level change
        No Change
    21
    15
    16
    23
        Improved
    0
    3
    0
    1
        Worsened
    0
    2
    3
    0
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of life: activities

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    End point title
    		 Quality of life: activities
    End point description
    End point type
    Secondary
    End point timeframe
    At W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: EQ-5D level change
        No change
    21
    19
    15
    14
        Improved
    0
    1
    1
    5
        Worsened
    0
    0
    3
    5
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Metformin v Maraviroc and metformin v Maraviroc v No drug
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of life: pain

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    End point title
    		 Quality of life: pain
    End point description
    End point type
    Secondary
    End point timeframe
    At W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: EQ-5D level change
        No change
    15
    12
    13
    8
        Improved
    4
    4
    2
    4
        Worsened
    2
    4
    4
    12
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of life: anxiety

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    End point title
    		 Quality of life: anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    At W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: EQ-5D level change
        No change
    11
    12
    14
    16
        Improved
    3
    4
    1
    1
        Worsened
    7
    4
    4
    7
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in self-reported health score

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    End point title
    		 Change in self-reported health score
    End point description
    End point type
    Secondary
    End point timeframe
    At W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: health score
        median (inter-quartile range (Q1-Q3))
    0 (-10 to 8)
    5 (-5 to 8)
    -5 (-8 to 10)
    0 (-20 to 5)
    Statistical analysis title
    		 Comparison of all arms
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin v No drug
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Adherence to trial drugs

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    End point title
    		 Adherence to trial drugs [1]
    End point description
    End point type
    Secondary
    End point timeframe
    Over all treatment
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Outcome is adherence to trial drugs so is limited only to the arms that are taking trial drugs.
    End point values
    		 Maraviroc Metformin Maraviroc and metformin
    Number of subjects analysed
    23
    21
    22
    Units: Stopped treatment early
        Yes
    3
    4
    4
        No
    20
    17
    18
    Statistical analysis title
    		 Stopped early
    Comparison groups
    Maraviroc and metformin v Metformin v Maraviroc
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Had at least one dose decrease
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Missed any doses
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Adherence at W4
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Adherence at W12
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Adherence at W24
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Adherence at W36
    Comparison groups
    Maraviroc v Metformin v Maraviroc and metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Adherence at W48
    Comparison groups
    Maraviroc and metformin v Maraviroc v Metformin
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in CD4 count

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    End point title
    		 Change in CD4 count
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    20
    19
    19
    23
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    667 (614 to 720)
    665 (610 to 720)
    737 (683 to 791)
    648 (599 to 698)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61
         upper limit
    		 99
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63
         upper limit
    		 95
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12
         upper limit
    		 166
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.15
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.16
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.25

    Secondary: Change in CD4 %

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    End point title
    		 Change in CD4 %
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    20
    19
    19
    23
    Units: CD4%
        arithmetic mean (confidence interval 95%)
    34 (32 to 35)
    34 (32 to 35)
    34 (33 to 36)
    35 (33 to 36)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.54
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 1.44
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 2.32
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.04
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.02
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.08

    Secondary: Change in CD8 count

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    End point title
    		 Change in CD8 count
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    20
    19
    19
    23
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    752 (664 to 840)
    767 (676 to 858)
    817 (727 to 908)
    689 (606 to 770)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51
         upper limit
    		 175
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    80
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58
         upper limit
    		 217
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 236
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.25
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.25
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.33

    Secondary: Change in CD8 %

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    End point title
    		 Change in CD8 %
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    17
    17
    18
    22
    Units: CD8 %
        arithmetic mean (confidence interval 95%)
    37 (34 to 41)
    38 (35 to 41)
    37 (34 to 41)
    40 (36 to 42)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.58
         upper limit
    		 3.32
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.11
         upper limit
    		 3.45
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.96
         upper limit
    		 3.16
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.13
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.09
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.12

    Secondary: Change in ALT over time

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    End point title
    		 Change in ALT over time
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    18
    24
    Units: U/L
        arithmetic mean (confidence interval 95%)
    47 (35 to 59)
    46 (33 to 58)
    44 (31 to 57)
    52 (40 to 63)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23
         upper limit
    		 14
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23
         upper limit
    		 11
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 11
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.32
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.2
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.2

    Secondary: Change in AST

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    End point title
    		 Change in AST
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    20
    19
    19
    22
    Units: U/L
        arithmetic mean (confidence interval 95%)
    35 (29 to 40)
    33 (27 to 39)
    35 (29 to 41)
    39 (34 to 44)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 5
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 2
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 5
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.12
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.06
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.16

    Secondary: Change in ALP

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    End point title
    		 Change in ALP
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    21
    20
    19
    24
    Units: U/L
        arithmetic mean (confidence interval 95%)
    80 (74 to 85)
    77 (71 to 83)
    70 (64 to 76)
    84 (78 to 89)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 4
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 2
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21
         upper limit
    		 -5
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.05
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.03
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 -0.07

    Secondary: Change in GGT

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    End point title
    		 Change in GGT
    End point description
    End point type
    Secondary
    End point timeframe
    Up to W48
    End point values
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Number of subjects analysed
    20
    18
    19
    24
    Units: U/L
        arithmetic mean (confidence interval 95%)
    61 (47 to 74)
    51 (37 to 65)
    62 (48 to 76)
    53 (40 to 65)
    Statistical analysis title
    		 Absolute change: maraviroc
    Comparison groups
    Maraviroc v No drug
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 26
    Statistical analysis title
    		 Absolute change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 9
    Statistical analysis title
    		 Absolute change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 30
    Statistical analysis title
    		 Relative change: maraviroc
    Comparison groups
    No drug v Maraviroc
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.43
    Statistical analysis title
    		 Relative change: metformin
    Comparison groups
    No drug v Metformin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.2
    Statistical analysis title
    		 Relative change: maraviroc and metformin
    Comparison groups
    No drug v Maraviroc and metformin
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.49

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Across the entire trial - up to W48 visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Maraviroc
    Reporting group description
    		 Maraviroc p/o BID dosed as follows: 150mg BID in those on ritonavir-boosted PI, cobicistat-boosted PI, or ritonavir-boosted or cobicistat-boosted elvitegravir; 600mg BID in those on efavirenz (EFV)- based regimens, or 300mg BID in those on raltegravir (RAL), dolutegravir (DTG) or nevirapine (NVP)- based regimens.

    Reporting group title
    Metformin
    Reporting group description
    		 Metformin p/o 500mg BID with or after food.

    Reporting group title
    Maraviroc and metformin
    Reporting group description
    		 -

    Reporting group title
    No drug
    Reporting group description
    		 Control arm

    Serious adverse events
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac ischemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Right retinal 'u' tear
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Maraviroc Metformin Maraviroc and metformin No drug
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 23 (13.04%)
    7 / 21 (33.33%)
    7 / 22 (31.82%)
    1 / 24 (4.17%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma of skin
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Labyrinthitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 21 (23.81%)
    3 / 22 (13.64%)
    0 / 24 (0.00%)
         occurrences all number
    0
    7
    4
    0
    Flatulance
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    GI upset
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stomach discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Grief reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Knee cramp
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Surgical site infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    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 Apr 2020
    Due to the Covid-19 pandemic, participants were not able to attend their final visit as planned. The protocol was changed to allow those participants to continue on their randomised treatments until it was safe for them to visit clinics again.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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