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    Clinical Trial Results:
    A phase II baseline versus treatment study to determine the efficacy of raltegravir (ISENTRESS) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI

    Summary
    EudraCT number
    2012-004847-61
    Trial protocol
    GB  
    Global end of trial date
    10 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jun 2016
    First version publication date
    25 Jun 2016
    Other versions
    Summary report(s)
    INSPIRE end of study report

    Trial information

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    Trial identification
    Sponsor protocol code
    008717QM
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02104661
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E12EF
    Public contact
    Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk
    Scientific contact
    Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E12EF
    Public contact
    Prof Gavin Giovannoni Neuroscience and Trauma Centre Blizard Institute 4 Newark St London E12AT, Queen Mary University of London Blizard Institute 4 Newark St London E12AT, +44 020 7882 8954, g.giovannoni@qmul.ac.uk
    Scientific contact
    Prof Gavin Giovannoni Neuroscience and Trauma Centre Blizard Institute 4 Newark St London E12AT, Queen Mary University of London Blizard Institute 4 Newark St London E12AT, +44 020 7882 8954, g.giovannoni@qmul.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
    12 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess whether treatment with raltegravir in patients with active MS has the effect of reducing the total number or rate of development of new or recurrent Gd-enhanced lesions on brain MRI over the period of treatment, compared to baseline.
    Protection of trial subjects
    All participants provided written informed consent before any study specific assessments were performed. Participants were given ample time for consideration before consenting to take part. Participants were made aware of their right to withdraw from the study at any time for any reason. The investigator also had the right to withdraw participants from the study. The total time on the study for enrolled participants was six months, which was considered to be an ethically acceptable timeframe for patients who are in the early stages of RRMS as this is the time limit before they meet Association of British Neurologists (ABN) criteria for currently licensed disease modifying treatment.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable for this open label single arm study
    Actual start date of recruitment
    01 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All participants were recruited at the Clinical Research Centre of the Royal London Hospital and were drawn prevalently from the catchment area of greater London. Participants were also referred to the site by six Patient Identification Centres (PICs). Recruitment into the study started in May 2013. The last patient was screened in June 2014.

    Pre-assignment
    Screening details
    A total of 31 participants were screened, of these 8 had no evidence of Gd enhancing lesions in their baseline MRI and were screen failed. Of the 23 participants who were recruited into the study 3 were withdrawn prior to starting the treatment phase; one at the request of the participant and the remaining two due to MS relapse.

    Pre-assignment period milestones
    Number of subjects started
    31
    Intermediate milestone: Number of subjects
    Observation period: 23
    Number of subjects completed
    20

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    No gd-enhancing lesions in MRI: 8
    Reason: Number of subjects
    MS relapse: 2
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable for this open label single arm trial.

    Arms
    Arm title
    Treatment
    Arm description
    Single arm open label
    Arm type
    Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Isentress
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg twice a day administrated as the potassium salt in a film coated tablet

    Number of subjects in period 1 [1]
    Treatment
    Started
    20
    Completed
    20
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 31 subjects screened, 20 received treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    -

    Reporting group values
    Treatment period Total
    Number of subjects
    20 20
    Age categorical
    Patients eligible for the study were between 18-55 years of age. PP mean age baseline 41.62yrs (31.15-52.99); ITT mean age baseline 40.73yrs (31.15-52.99).
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
        Adults (18-55 years)
    20 20
    Age continuous
    PP Mean age baseline 41.62yrs (31.15-52.99) ITT Mean age baseline 40.73yrs (31.15-52.99)
    Units: years
        arithmetic mean (standard deviation)
    40.73 ± 6.98 -
    Gender categorical
    PP 12 females (75%), 4 males (25%). ITT 14 females (70%), 6 males (30%).
    Units: Subjects
        Female
    14 14
        Male
    6 6
    Height
    PP mean height 168.91cm (156.0-180.0) ITT mean height 169.04cm (156.0-183.0) There are only reported height values for n=18.
    Units: cm
        arithmetic mean (standard deviation)
    ± -
    Weight
    PP n=14; mean weight 77.9; (51.9-108.3) ITT n=18; mean weight 78.73; (51.9-109.7) Weight was not recorded for 2 subjects.
    Units: Kg
        arithmetic mean (standard deviation)
    ± -
    Baseline EDSS
    PP n=16; mean EDSS 2.25; (0.0-3.5) ITT n=20; mean EDSS 2.4; (0.0-4.0)
    Units: score
        arithmetic mean (standard deviation)
    ± -
    Number of relapses in the past year
    PP n= 16; mean 1.44; sd= 0.63 (1.0-3.0) ITT n= 20; mean 1.50; sd= 0.61 (0.0-4.0)
    Units: number of relapses
        arithmetic mean (standard deviation)
    ± -
    Subject analysis sets

    Subject analysis set title
    Per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    4 subjects were excluded from per protocol (PP) analysis due to concomitant medications (2 has steroids/immunosuppressants at screening and 2 had proton pump inhibitors during the study). PP 12 females (75%), 4 males (25%). Mean age baseline 41.62yrs (31.15-52.99); mean height 168.91cm (156.0-180.0); mean weight 77.9Kg (51.9-108.3); mean EDSS 2.25 (0.0-3.5); mean no. relapses past year 1.44 (1-3)

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All 20 subjects who completed the study were includedin the ITT analysis. ITT 14 females (70%), 6 males (30%). Mean age baseline 40.73yrs (31.15-52.99); mean height 169.04cm (156.0-183.0); mean weight 78.73Kg (51.9-109.7); mean EDSS 2.4 (0.0-4.0); mean no. relapses past year 1.5 (1-3)

    Subject analysis set title
    Flexible per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Flexible PP sample n=18. Two subjects were excluded for all visits, one subject had visits seven and eight excluded, and one subject had just visit eight excluded.

    Subject analysis sets values
    Per protocol ITT Flexible per protocol
    Number of subjects
    16
    20
    18
    Age categorical
    Patients eligible for the study were between 18-55 years of age. PP mean age baseline 41.62yrs (31.15-52.99); ITT mean age baseline 40.73yrs (31.15-52.99).
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
        Adults (18-55 years)
    16
    20
    18
    Age continuous
    PP Mean age baseline 41.62yrs (31.15-52.99) ITT Mean age baseline 40.73yrs (31.15-52.99)
    Units: years
        arithmetic mean (standard deviation)
    41.62 ± 7.49
    40.73 ± 6.98
    ±
    Gender categorical
    PP 12 females (75%), 4 males (25%). ITT 14 females (70%), 6 males (30%).
    Units: Subjects
        Female
    12
    14
        Male
    4
    6
    Height
    PP mean height 168.91cm (156.0-180.0) ITT mean height 169.04cm (156.0-183.0) There are only reported height values for n=18.
    Units: cm
        arithmetic mean (standard deviation)
    168.91 ± 8
    169.04 ± 8.61
    ±
    Weight
    PP n=14; mean weight 77.9; (51.9-108.3) ITT n=18; mean weight 78.73; (51.9-109.7) Weight was not recorded for 2 subjects.
    Units: Kg
        arithmetic mean (standard deviation)
    77.9 ± 18.45
    78.73 ± 19.04
    ±
    Baseline EDSS
    PP n=16; mean EDSS 2.25; (0.0-3.5) ITT n=20; mean EDSS 2.4; (0.0-4.0)
    Units: score
        arithmetic mean (standard deviation)
    2.25 ± 1
    2.4 ± 1.03
    ±
    Number of relapses in the past year
    PP n= 16; mean 1.44; sd= 0.63 (1.0-3.0) ITT n= 20; mean 1.50; sd= 0.61 (0.0-4.0)
    Units: number of relapses
        arithmetic mean (standard deviation)
    1.44 ± 0.63
    1.5 ± 0.61
    ±

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Single arm open label

    Subject analysis set title
    Per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    4 subjects were excluded from per protocol (PP) analysis due to concomitant medications (2 has steroids/immunosuppressants at screening and 2 had proton pump inhibitors during the study). PP 12 females (75%), 4 males (25%). Mean age baseline 41.62yrs (31.15-52.99); mean height 168.91cm (156.0-180.0); mean weight 77.9Kg (51.9-108.3); mean EDSS 2.25 (0.0-3.5); mean no. relapses past year 1.44 (1-3)

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All 20 subjects who completed the study were includedin the ITT analysis. ITT 14 females (70%), 6 males (30%). Mean age baseline 40.73yrs (31.15-52.99); mean height 169.04cm (156.0-183.0); mean weight 78.73Kg (51.9-109.7); mean EDSS 2.4 (0.0-4.0); mean no. relapses past year 1.5 (1-3)

    Subject analysis set title
    Flexible per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Flexible PP sample n=18. Two subjects were excluded for all visits, one subject had visits seven and eight excluded, and one subject had just visit eight excluded.

    Primary: Total T1 Gd-enhancing lesions in brain MRI scans

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    End point title
    Total T1 Gd-enhancing lesions in brain MRI scans
    End point description
    Within-patient average no. new Gd-enh lesions observed on serial T1-weighted brain MRI scans. Counts of new or recurrent Gd-enh lesions appearing on brain T1-weighted MRI. These counts are available at each of visits 2 to 8 in the majority of patients. ITT n=20 ‘flexible’ PP n=18. 2 patients were excluded for all visits, 1 patient had just visits 7 and 8 excluded, and 1 had visit 8 excluded. PP n=16, 4 patients had all their visits excluded. There were missing counts for 1patient at visit 3, 1 at visit 5, and missing counts for 2 at visit 6. Lesion outcomes provide no statistical evidence consistent with an effect of raltegravir. This is not because of lack of power: changes were not only non-significant statistically, but also generally clinically small (including both small reductions and small increases). For the most substantial change, a reduction in persisting T1 Gd lesions in the PP sample, the decrease before intervention was greater than that afterwards
    End point type
    Primary
    End point timeframe
    Visit two (enrolment) is excluded from analysis, which covers visits three, four and five "before-", and six, seven and eight "after-" medication was first dispensed.
    End point values
    Treatment Per protocol ITT Flexible per protocol
    Number of subjects analysed
    20
    16
    20
    18
    Units: Number and ratio of lesions
    arithmetic mean (full range (min-max))
        Number of T1 gd-enhancing lesions before
    8.65 (0 to 32)
    7.5 (0 to 32)
    8.65 (0 to 32)
    7.28 (0 to 32)
        Number of T1 Gd-enhancing lesions after
    9.05 (0 to 31)
    7 (0 to 31)
    9.05 (0 to 31)
    6.83 (0 to 31)
        Number of T1 Gd-enh lesions within patient change
    0.12 (-2.67 to 3.33)
    -0.18 (-2.67 to 2.33)
    0.12 (-2.67 to 3.33)
    -0.16 (-2.67 to 2.33)
        Ratio of T1 Gd-Enh lesions within patient change
    0.88 (0.15 to 3.33)
    0.81 (0.15 to 3.33)
    0.88 (0.15 to 3.33)
    0.83 (0.15 to 3.33)
    Statistical analysis title
    Mixed effect Poisson regression model
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.681 [2]
    Method
    Regression, Linear
    Parameter type
    Rate ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.29
    Notes
    [1] - The analyses compare the mean rate after vs before. The potential gradients of change over the three-month before vs after periods were also compared. For all three samples above there was no significant change in the after vs before gradients of monthly lesion accrual: P-values were respectively P=0.659, 0.429 and 0.463 for ITT, flexible PP and PP.
    [2] - Est rate ratio after vs before: 1.04 (95% CI .85, 1.29); represents 4% non-significant incr lesions/month in after period, weighted ITT rate ratio 1.03 Simple non-parametric Wilcoxon sign rank test within-patient changes non-significant, P=0.646
    Statistical analysis title
    Mixed effect Poisson regression model
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value
    Comparison groups
    Treatment v Flexible per protocol
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.714 [3]
    Method
    Regression, Linear
    Parameter type
    rate ratio
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.22
    Notes
    [3] - 5% non-significant decrease in rate. This is in close agreement with the summary weighted rate ratio of 0.92. The p-value from the simple non-parametric Wilcoxon sign rank test of changes is non-significant, P=0.183.
    Statistical analysis title
    Mixed effect Poisson regression model
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value
    Comparison groups
    Treatment v Per protocol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.577 [4]
    Method
    Regression, Linear
    Parameter type
    rate ratio
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.2
    Notes
    [4] - Non-significant 7% decrease. This is similar to the summary weighted rate ratio of 0.92. The p-value from the simple non-parametric Wilcoxon sign rank test of changes is also non-significant, P=0.197.

    Primary: Persisting T1 Gd-enhancing brain MRI lesions

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    End point title
    Persisting T1 Gd-enhancing brain MRI lesions
    End point description
    End point type
    Primary
    End point timeframe
    Visits 3, 4 and 5 (before) and 6, 7 and 8 (after medication was first dispensed).
    End point values
    Treatment Per protocol ITT
    Number of subjects analysed
    20
    16
    20
    Units: Change in gradient of rate ratio
    arithmetic mean (full range (min-max))
        Monthy rate before
    1.46 (0 to 7.67)
    1.53 (0 to 7.67)
    1.46 (0 to 7.67)
        Monthly rate after
    1.35 (0 to 5.67)
    1.19 (0 to 5.67)
    1.35 (0 to 5.67)
        Within patient change in rate
    -0.11 (-2 to 1.67)
    -0.34 (-2 to 0.67)
    -0.11 (-2 to 1.67)
    Statistical analysis title
    Poisson regression
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator.
    Comparison groups
    Treatment v Per protocol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.16 [5]
    Method
    Regression, Linear
    Parameter type
    Slope
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.1
    Notes
    [5] - The rate ratio was estimated as 0.78 (95% CI:0.55, 1.10) P=0.160, a non-significant reduction. There was no significant change in gradient in the PP (0.762). In this PP sample the rate of reduction after was slightly lower than that before.
    Statistical analysis title
    Poisson regression
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.652 [6]
    Method
    Regression, Linear
    Parameter type
    Slope
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.26
    Notes
    [6] - The rate ratio was estimated as 0.93 (95% CI .69, 1.26), P=0.652, a slight and non-significant reduction in persisting lesions.

    Primary: New T1 Gd enhancing brain MRI lesions

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    End point title
    New T1 Gd enhancing brain MRI lesions
    End point description
    Rates in each 3-months period.
    End point type
    Primary
    End point timeframe
    Before (visits 3, 4, 5) vs After (visits 6, 7, 8).
    End point values
    Treatment Per protocol ITT
    Number of subjects analysed
    20
    16
    20
    Units: Monthly rate of new lesions
    arithmetic mean (full range (min-max))
        Monthly rate before
    1.46 (0 to 7.67)
    1.53 (0 to 7.67)
    1.46 (0 to 7.67)
        Monthly rate after
    1.35 (0 to 5.67)
    1.19 (0 to 5.67)
    1.35 (0 to 5.67)
        Within patient change in monthly rate
    -0.11 (-2 to 1.67)
    -0.34 (-2 to 0.67)
    -0.11 (-2 to 1.67)
    Statistical analysis title
    Poisson regression model
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator estimates the rate ratio after vs before as 1.16 (95% CI 0.87, 1.55), P=0.314; this represents a slight and non-significant increase in new lesions per month in the ‘after’ period. The above analyses compare the mean rate after vs before. The gradients of change over the three-month before vs after periods were also compared.
    Comparison groups
    Treatment v Per protocol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.456
    Method
    Regression, Linear
    Confidence interval
    Notes
    [7] - There was no significant change in the after vs before gradients of monthly lesion accrual in the PP (P=0.137).
    Statistical analysis title
    Poisson regression model
    Statistical analysis description
    A mixed effect Poisson regression model with before/after indicator estimates the rate ratio after vs before as 1.16 (95% CI 0.87, 1.55), P=0.314; this represents a slight and non-significant increase in new lesions per month in the ‘after’ period. This analysis compares the mean rate after vs before. The gradients of change over the three-month before vs after periods were also compared.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.314 [8]
    Method
    Regression, Linear
    Parameter type
    Slope
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.55
    Notes
    [8] - There was no significant change in the after vs before gradients of monthly lesion accrual in the ITT (P=0.562) analysis.

    Secondary: New or enlarging T2 weighted lesions on brain MRI

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    End point title
    New or enlarging T2 weighted lesions on brain MRI
    End point description
    For T2 lesions (where the only ‘after’ observation is visit 8, so no comparison is possible for the two ‘flexible PP’ patients), only ITT and PP are given. Within-patient ratios averaged on log scale before back transforming, substituting 0.1 for zero counts. Weighted mean ratios pooled on log scale by weighting for lesion counts.
    End point type
    Secondary
    End point timeframe
    Counts of new or enlarging T2-weighted lesions at visits five (before) and eight (after).
    End point values
    Treatment Per protocol ITT
    Number of subjects analysed
    20
    16
    20
    Units: Number and ratio of lesions
    arithmetic mean (full range (min-max))
        Number of T2 lesions before
    4.45 (0 to 17)
    3.13 (0 to 9)
    4.45 (0 to 17)
        Number of T2 lesions after
    4.65 (0 to 20)
    3.31 (0 to 13)
    4.65 (0 to 20)
        Within patient T2 lesions count change
    0.2 (-4 to 5)
    0.19 (-4 to 5)
    0.2 (-4 to 5)
        Within patient T2 lesions count ratio
    1.47 (0.2 to 10)
    1.64 (0.2 to 10)
    1.47 (0.2 to 10)
    Statistical analysis title
    Wilcoxon sign rank test
    Comparison groups
    Treatment v Per protocol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.462 [9]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Non-significant: Wilcoxon sign rank test of the within-patient changes was P= 0.462 for PP analysis.
    Statistical analysis title
    Wilcoxon sign rank test
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.472 [10]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - Non-significant: Wilcoxon sign rank test of the within-patient changes was P=0.472 for ITT analysis.

    Secondary: Inflammatory markers

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    End point title
    Inflammatory markers
    End point description
    Statistical analysis performed on three inflammatory markers: Interleukin-8 (IL-8), or chemokine (C-X-C motif) ligand 8, CXCL8, is a chemokine produced by macrophages and other cell types. IL-8 secretion is increased by oxidant stress, which thereby cause the recruitment of inflammatory cells and induces a further increase in oxidant stress mediators, making it a key parameter in localized inflammation. Reported in pg/mL Unit. Serum CD163 (a soluble form of the receptor exists in plasma, commonly denoted sCD163. It is generated by ectodomain shedding of the membrane bound receptor. sCD163 is upregulated in a large range of inflammatory diseases). Reported in ng/mL Unit. Human C-reactive protein (HCRP), CRP is used mainly as a marker of inflammation. For HCRP, three measurements above the measureable threshold were assigned values of 10000 ng/ml. The largest measurable HCRP value in the dataset is 9492.25. Reported in ng/mL Unit.
    End point type
    Secondary
    End point timeframe
    Changes in mean at visits 3, 4, and 5 (before) and 6, 7, and 8 (after).
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Changes in mean after - before
    arithmetic mean (standard deviation)
        IL-8
    0.82 ± 2.12
    0.82 ± 2.12
        CD163
    18.67 ± 38.18
    18.67 ± 38.18
        HCRP
    535.82 ± 1244
    535.82 ± 1244
    Statistical analysis title
    IL-8 One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1 [11]
    Method
    One sample t-test
    Confidence interval
    Notes
    [11] - Non significant
    Statistical analysis title
    IL-8 Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.47 [12]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [12] - Non significant
    Statistical analysis title
    IL-8 Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.193 [13]
    Method
    Change in gradient
    Confidence interval
    Notes
    [13] - Non significant
    Statistical analysis title
    CD163 one sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.041 [14]
    Method
    One sample t-test
    Confidence interval
    Notes
    [14] - Significant decline changes to a significant positive gradient. The gradient change is significant in both ITT and PP.
    Statistical analysis title
    CD163 Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.04 [15]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [15] - Significant decline changes to a significant positive gradient. The gradient change is significant in both ITT and PP.
    Statistical analysis title
    CD163 Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.018 [16]
    Method
    Change in gradient
    Confidence interval
    Notes
    [16] - Significant.
    Statistical analysis title
    HCRP one sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.069 [17]
    Method
    One sample t-test
    Confidence interval
    Notes
    [17] - Significant overall increase not credibly attributable to intervention, since the gradient before, though non-significant, is too similar to the gradient after intervention.
    Statistical analysis title
    HCRP Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.04 [18]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [18] - Significant overall increase not credibly attributable to intervention, since the gradient before, though non-significant, is too similar to the gradient after intervention
    Statistical analysis title
    HCRP Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.944 [19]
    Method
    Change in gradient
    Confidence interval
    Notes
    [19] - Non significant

    Secondary: Retroviral activity

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    End point title
    Retroviral activity
    End point description
    To date, there has been no definitive evidence to link HERVs as the cause of immune-mediated disease; however, HERV elements have been found in sera of people with a range of diseases such as type 1 diabetes, rheumatoid arthritis and SLE but not in control populations. The evidence suggesting a postulated link between HERVs and MS has been accumulating. evidence is summarized to demonstrate that HERV-H and HERV-W are epidemiologically linked to patients with relapsing remitting MS. Further evidence was recently published by Perron et al. (4) that also links MS to a HERV which Perron calls multiple sclerosis associated retroviral element (MSRV). Raltegravir effect in relation to MS is not known, it may act by inhibiting HERVs, possibly in a similar mode of action that Raltegravir inhibits HIV replication.
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20 [20]
    Units: Changes in mean after - before/ dim-less
    arithmetic mean (standard deviation)
        MSRV_a
    -0.01 ± 0.06
    -0.01 ± 0.06
        MSRV_b
    -0.01 ± 0.08
    -0.01 ± 0.08
        HERV_c
    0 ± 0.09
    0 ± 0.09
        HERV_d
    0 ± 0.07
    0 ± 0.07
        HERV_e
    0.01 ± 0.09
    0.01 ± 0.09
        HERV_f
    0.01 ± 0.04
    0.01 ± 0.04
        HERV_W_a
    -0.05 ± 0.07
    -0.05 ± 0.07
        HERV_H_b
    0.03 ± 0.13
    0.03 ± 0.13
        HERV_H_c
    0.03 ± 0.1
    0.03 ± 0.1
        HERV_H_d
    0.05 ± 0.14
    0.05 ± 0.14
        HERV_W_e
    0 ± 0.09
    0 ± 0.09
        HERV_W_f
    0.02 ± 0.19
    0.02 ± 0.19
        PROP_B_g
    0.46 ± 1.37
    0.46 ± 1.37
        PROP_mon_h
    -1.98 ± 4.31
    -1.98 ± 4.31
        HERV_W_i
    -0.01 ± 0.06
    -0.01 ± 0.06
        HERV_H_j
    0.12 ± 0.05
    0.12 ± 0.05
        HERV_H_k
    0.03 ± 0.09
    0.03 ± 0.09
        HERV_H_l
    0.02 ± 0.14
    0.02 ± 0.14
        HERV_W_m
    -0.03 ± 0.06
    -0.03 ± 0.06
        HERV_W_n
    0.04 ± 0.12
    0.04 ± 0.12
    Notes
    [20] - HERV_W_a; HERV_W_m; HERV_W_n n=18 HERV_H_b; HERV_H_c; HERV_H_k n=17 HERV_W_i n=13 HERV_H_j n=15
    Statistical analysis title
    One sample t-test MSRV_a
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.551 [21]
    Method
    One sample t-test
    Confidence interval
    Notes
    [21] - Non significant.
    Statistical analysis title
    One sample t-test MSRV_b
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.484 [22]
    Method
    One sample t-test
    Confidence interval
    Notes
    [22] - Non significant.
    Statistical analysis title
    One sample t-test HERV_c
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.835 [23]
    Method
    One sample t-test
    Confidence interval
    Notes
    [23] - Non significant.
    Statistical analysis title
    One sample t-test HERV_d
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.928
    Method
    One sample t-test
    Confidence interval
    Statistical analysis title
    One sample t-test HERV_e
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.563 [24]
    Method
    One sample t-test
    Confidence interval
    Notes
    [24] - Non significant.
    Statistical analysis title
    One sample t-test HERV_f
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.408 [25]
    Method
    One sample t-test
    Confidence interval
    Notes
    [25] - Non significant.
    Statistical analysis title
    One sample t-test HERV_W_a
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.012 [26]
    Method
    One sample t-test
    Confidence interval
    Notes
    [26] - There is a significant drop in mean from before to after; however, there is a negative gradient of decline throughout the trial period. Therefore the after vs before drop cannot reasonably be attributed to the intervention.
    Statistical analysis title
    One sample t-test HERV_H_b
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.372 [27]
    Method
    One sample t-test
    Confidence interval
    Notes
    [27] - Non significant.
    Statistical analysis title
    One sample t-test HERV_H_c
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.177 [28]
    Method
    One sample t-test
    Confidence interval
    Notes
    [28] - Non significant.
    Statistical analysis title
    One sample t-test HERV_H_d
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.113 [29]
    Method
    One sample t-test
    Confidence interval
    Notes
    [29] - Non significant.
    Statistical analysis title
    One sample t-test HERV_W_e
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.907 [30]
    Method
    One sample t-test
    Confidence interval
    Notes
    [30] - Non significant.
    Statistical analysis title
    One sample t-test HERV_W_f
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.632 [31]
    Method
    One sample t-test
    Confidence interval
    Notes
    [31] - Non significant.
    Statistical analysis title
    One sample t-test PROP_B_g
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.148 [32]
    Method
    One sample t-test
    Confidence interval
    Notes
    [32] - Non significant.
    Statistical analysis title
    One sample t-test PROP_mon_h
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.053
    Method
    One sample t-test
    Confidence interval
    Statistical analysis title
    One sample t-test HERV_W_i
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.561 [33]
    Method
    One sample t-test
    Confidence interval
    Notes
    [33] - Non significant.
    Statistical analysis title
    One sample t-test HERV_H_j
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.029 [34]
    Method
    One sample t-test
    Confidence interval
    Notes
    [34] - Non significant.
    Statistical analysis title
    One sample t-test HERV_H_k
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.266 [35]
    Method
    One sample t-test
    Confidence interval
    Notes
    [35] - Non significant.
    Statistical analysis title
    One sample t-test HERV_H_l
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.522 [36]
    Method
    One sample t-test
    Confidence interval
    Notes
    [36] - Non significant.
    Statistical analysis title
    One sample t-test HERV_W_m
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.035 [37]
    Method
    One sample t-test
    Confidence interval
    Notes
    [37] - Non significant.
    Statistical analysis title
    One sample t-test HERV_W_n
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.158 [38]
    Method
    One sample t-test
    Confidence interval
    Notes
    [38] - Non significant.
    Statistical analysis title
    Mixed model MSRV_a
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.364 [39]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [39] - Non significant.
    Statistical analysis title
    Mixed model MSRV_b
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.433 [40]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [40] - Non significant.
    Statistical analysis title
    Mixed model HERV_c
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.775 [41]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [41] - Non significant.
    Statistical analysis title
    Mixed model HERV_d
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.609 [42]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [42] - Non significant.
    Statistical analysis title
    Mixed model HERV_e
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.781 [43]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [43] - Non significant.
    Statistical analysis title
    Mixed model HERV_f
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.324 [44]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [44] - Non significant.
    Statistical analysis title
    Mixed model HERV_W_a
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.008
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Mixed model HERV_H_b
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.307 [45]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [45] - Non significant.
    Statistical analysis title
    Mixed model HERV_H_c
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.212 [46]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [46] - Non significant.
    Statistical analysis title
    Mixed model HERV_H_d
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.203 [47]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [47] - Non significant.
    Statistical analysis title
    Mixed model HERV_W_e
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.235 [48]
    Method
    Change in gradient
    Confidence interval
    Notes
    [48] - Non significant.
    Statistical analysis title
    Mixed model HERV_W_f
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.627 [49]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [49] - Non significant.
    Statistical analysis title
    Mixed model PROP_B_g
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.298 [50]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [50] - Non significant.
    Statistical analysis title
    Mixed model PROP_mon_h
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.16 [51]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [51] - Non significant.
    Statistical analysis title
    Mixed model HERV_W_i
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.93 [52]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [52] - Non significant.
    Statistical analysis title
    Mixed model HERV_H_j
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.008
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Mixed model HERV_H_k
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.642
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Mixed model HERV_H_l
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.807
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Mixed model HERV_W_m
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.005
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Mixed model HERV_W_n
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.259 [53]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [53] - Non significant.
    Statistical analysis title
    Change in gradient MSRV_a
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.488 [54]
    Method
    Change in gradient
    Confidence interval
    Notes
    [54] - Non significant.
    Statistical analysis title
    Change in gradient MSRV_b
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.691 [55]
    Method
    Change in gradient
    Confidence interval
    Notes
    [55] - Non significant.
    Statistical analysis title
    Change in gradient HERV_c
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.172 [56]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [56] - Non significant.
    Statistical analysis title
    Change in gradient HERV_d
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.802 [57]
    Method
    Change in gradient
    Confidence interval
    Notes
    [57] - Non significant.
    Statistical analysis title
    Change in gradient HERV_e
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.621 [58]
    Method
    Change in gradient
    Confidence interval
    Notes
    [58] - Non significant.
    Statistical analysis title
    Change in gradient HERV_f
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.533 [59]
    Method
    Change in gradient
    Confidence interval
    Notes
    [59] - Non significant.
    Statistical analysis title
    Change in gradient HERV_W_a
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.438 [60]
    Method
    Change in gradient
    Confidence interval
    Notes
    [60] - Non significant.
    Statistical analysis title
    Change in gradient HERV_H_b
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.012 [61]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [61] - Gradient change significant P=0.012. Gradient before borderline significantly negative. After is significantly positive. Decline in values in period before intervention appears to change significantly after v 5 into an increase in values over time.
    Statistical analysis title
    Change in gradient HERV_H_c
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.197 [62]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [62] - Non significant.
    Statistical analysis title
    Change in gradient HERV_H_d
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [63]
    P-value
    = 0.01 [64]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [63] - The change in gradient is consistent with intervention effect. However, interpretation dependent on biological plausibility because of possibility of Type I error.
    [64] - Borderline significant negative gradient before changes to significant positive after v 5. Decline in values appears to change significantly after intervention into increase in values over time.
    Statistical analysis title
    Change in gradient HERV_W_e
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.008 [65]
    Method
    Change in gradient
    Confidence interval
    Notes
    [65] - Significantly negative decline before visit 5 changes to a non-significant positive gradient after; the change in gradients is significant P=0.008.
    Statistical analysis title
    Change in gradient HERV_W_f
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.195 [66]
    Method
    Change in gradient
    Confidence interval
    Notes
    [66] - Non significant.
    Statistical analysis title
    Change in gradient PROP_B_g
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.405 [67]
    Method
    Change in gradient
    Confidence interval
    Notes
    [67] - Non significant.
    Statistical analysis title
    Change in gradient PROP_mon_h
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.072 [68]
    Method
    Change in gradient
    Confidence interval
    Notes
    [68] - Non-significant positive gradient changes to borderline significant negative gradient; change in gradient borderline significant consistent with intervention effect. Interpretation dependent on biological plausibility due to possibility Type 1 error
    Statistical analysis title
    Change in gradient HERV_W_i
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.552 [69]
    Method
    Change in gradient
    Confidence interval
    Notes
    [69] - Non-significant.
    Statistical analysis title
    Change in gradient HERV_H_i
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.054 [70]
    Method
    Change in gradient
    Confidence interval
    Notes
    [70] - A non-signifiant negative gradient before intervention changes to a significantly positive gradient after; the change is borderline signififcant P=0.054.
    Statistical analysis title
    Change in gradient HERV_H_k
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.802 [71]
    Method
    Change in gradient
    Confidence interval
    Notes
    [71] - Non-significant.
    Statistical analysis title
    Change in gradient HERV_H_l
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.314 [72]
    Method
    Change in gradient
    Confidence interval
    Notes
    [72] - Non-significant.
    Statistical analysis title
    Change in gradient HERV_W_m
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.178 [73]
    Method
    Change in gradient
    Confidence interval
    Notes
    [73] - Non-significant.
    Statistical analysis title
    Change in gradient HERV_W_n
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.047 [74]
    Method
    Change in gradient
    Confidence interval
    Notes
    [74] - Non-significant decline before visit 5 becomes a borderline significant increase after; the change in gradient is significant. Biological plausibility important, both for change displayed and for negative correlation with Gd T1 lesions.

    Secondary: EDSS Clinical responses (disability data)

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    End point title
    EDSS Clinical responses (disability data)
    End point description
    Expanded Disability Status Scale score at screening between 0-6.0 inclusive for trial eligibility. Disability measures summaries at baseline, before and after.
    End point type
    Secondary
    End point timeframe
    EDSS performed at visits 1, 2, 4, 6 and 8. Summaries of disability measured at baseline, before and after.
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Within patient change in means
    arithmetic mean (standard deviation)
        EDSS
    0.14 ± 0.45
    0.14 ± 0.45
    Statistical analysis title
    One-sample t-test
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [75]
    P-value
    = 0.179
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [75] - One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Statistical analysis title
    Mixed model
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other [76]
    P-value
    = 0.13
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [76] - Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

    Secondary: MSFC Clinical responses (disability data)

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    End point title
    MSFC Clinical responses (disability data)
    End point description
    MSFC (the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores); higher scores indicate less disability
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before (treatment)
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Changes in mean after - before
    arithmetic mean (standard deviation)
        MSFC
    0.23 ± 0.28
    0.23 ± 0.28
    Statistical analysis title
    One-sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [77]
    Method
    One sample t-test
    Confidence interval
    Notes
    [77] - Both change and change in gradient significant.
    Statistical analysis title
    Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [78]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [78] - Both change and change in gradient significant.

    Secondary: 9HPT speed Clinical responses (disability data)

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    End point title
    9HPT speed Clinical responses (disability data)
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Changes in mean after - before
    arithmetic mean (standard deviation)
        9HPT
    0.003 ± 0.003
    0.003 ± 0.003
    Statistical analysis title
    One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [79]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [79] - Highly significant improvement. There are statistically significant improvements in the 9HPT, but the rate of improvement slowed after intervention. This is not consistent with an effect of intervention.
    Statistical analysis title
    Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [80]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [80] - There are statistically significant improvements in the 9HPT, but the rate of improvement slowed after intervention. This is not consistent with an effect of intervention.
    Statistical analysis title
    Change in gradient
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.217 [81]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [81] - No significant gradient change. Rate of improvement substantially greater before than after intervention

    Secondary: 25 foot walk speed Clinical responses (disability data)

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    End point title
    25 foot walk speed Clinical responses (disability data)
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Changes in mean after - before
    arithmetic mean (standard deviation)
        25' walk speed
    -0.04 ± 0.47
    -0.04 ± 0.47
    Statistical analysis title
    One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.738 [82]
    Method
    One sample t-test
    Confidence interval
    Notes
    [82] - Non significant.
    Statistical analysis title
    Mixed model analysis
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.669 [83]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [83] - Non significant.
    Statistical analysis title
    Change in gradient
    Statistical analysis description
    Change in gradient’: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.908 [84]
    Method
    change in gradient
    Confidence interval
    Notes
    [84] - Non significant

    Secondary: PASAT Clinical responses (disability data)

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    End point title
    PASAT Clinical responses (disability data)
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Changes in mean after - before
    arithmetic mean (standard deviation)
        PASAT
    4.66 ± 5.21
    4.66 ± 5.21
    Statistical analysis title
    One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [85]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [85] - Highly significant improvement, but rate of improvement substantially greater before than after intervention
    Statistical analysis title
    Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [86]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [86] - Highly significant improvement, but rate of improvement substantially greater before than after intervention.
    Statistical analysis title
    Change in gradient
    Statistical analysis description
    Change in gradient’: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [87]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [87] - There is a significant gradient change, but rate of improvement substantially greater before than after intervention

    Secondary: Quality of life measures

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    End point title
    Quality of life measures
    End point description
    Quality of life measures: patient reported outcomes (PROs) including 3 questionnaires: Health Status Questionnaire (SF-36), Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Walking Scale (MSWS-12) and 2 Visual Analogue Scales (VAS): Patient Fatigue Assessment (PFA) and Patient Pain Assessment (PPA). The SF-36 generates 8 subscale scores for Physical Functional Scale (PF), Role-Physical Scale (RP), Bodily Pain Scale (BP), General Health scale (GH), Vitality Scale (VT), Social Functioning Scale (SF), Role Emotional Scale (RE) and Mental Health Scale (MH). Higher scores indicate better health/quality of life on all eight SF-36 measures, and worse health/quality of life on the last four measures.
    End point type
    Secondary
    End point timeframe
    Quality of life measures baseline, before and after summeries. Patient reported outcomes completed at visits 2 (baseline), 3, 4 and 5 (before) and 6, 7 and 8 (after).
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: Change after - before
    arithmetic mean (standard deviation)
        SF36 PF Before
    72.63 ± 23.37
    72.63 ± 23.37
        Sf36 PF After
    71.71 ± 26.04
    71.71 ± 26.04
        SF36 RP Before
    59.06 ± 39.66
    59.06 ± 39.66
        Sf36 RP After
    49.58 ± 38.47
    49.58 ± 38.47
        Sf36 BP Before
    72.22 ± 19.59
    72.22 ± 19.59
        SF36 BP After
    66.8 ± 22.63
    66.8 ± 22.63
        SF36 GH Before
    50.86 ± 15.02
    50.86 ± 15.02
        SF36 GH After
    46.18 ± 16.86
    46.18 ± 16.86
        SF36 VT Before
    42.98 ± 21.53
    42.98 ± 21.53
        SF36 VT After
    48.04 ± 22.21
    48.04 ± 22.21
        SF36 Sf After
    77.92 ± 16.06
    77.92 ± 16.06
        SF36 RE Before
    71.92 ± 33.39
    71.92 ± 33.39
        SF36 RE After
    63.3 ± 38.35
    63.3 ± 38.35
        SF36 MH Before
    65.85 ± 12.77
    65.85 ± 12.77
        SF36 MH After
    71.57 ± 11.05
    71.57 ± 11.05
        PFA Before
    40.02 ± 24.36
    40.02 ± 24.36
        PFA After
    38.51 ± 26.35
    38.51 ± 26.35
        PPA Before
    22.8 ± 19.46
    22.8 ± 19.46
        PPA After
    27.96 ± 21.46
    27.96 ± 21.46
        MSIS Before
    52.16 ± 17.4
    52.16 ± 17.4
        MSIS After
    50.06 ± 13.95
    50.06 ± 13.95
        MSWS-12 Before
    20.87 ± 9.61
    20.87 ± 9.61
        MSWS-12 After
    20.52 ± 9.76
    20.52 ± 9.76
    Statistical analysis title
    SF36 PF One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.713 [88]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [88] - Non significant
    Statistical analysis title
    SF36 PF Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.685 [89]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [89] - Non significant
    Statistical analysis title
    SF36 PF Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [90]
    P-value
    = 0.063 [91]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [90] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [91] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 RP One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.198 [92]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [92] - Non significant.
    Statistical analysis title
    SF36 RP Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [93]
    P-value
    = 0.034 [94]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [93] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [94] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 RP Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.873 [95]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [95] - Non significant.
    Statistical analysis title
    SF36 BP One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.14 [96]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [96] - Non significant
    Statistical analysis title
    SF36 BP Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [97]
    P-value
    = 0.024 [98]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [97] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [98] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 BP Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [99]
    P-value
    = 0.026 [100]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [99] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [100] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 GH One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [101]
    P-value
    = 0.019 [102]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [101] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
    [102] - Significant improvements in well-being/slowing of deterioration after compared to before intervention. Although consistent with effect of raltegravir, this is most credibly attributable to placebo effect of patients receiving unblinded intervention.
    Statistical analysis title
    SF36 GH Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [103]
    P-value
    = 0.001 [104]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [103] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
    [104] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 GH Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [105]
    P-value
    = 0.022 [106]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [105] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [106] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 VT One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.14 [107]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [107] - Non significant.
    Statistical analysis title
    SF36 VT Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [108]
    P-value
    = 0.011 [109]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [108] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
    [109] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 VT Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [110]
    P-value
    = 0.004 [111]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [110] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [111] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 SF One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.567 [112]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [112] - Non significant.
    Statistical analysis title
    SF36 SF Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.414 [113]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [113] - Non significant.
    Statistical analysis title
    SF36 SF Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [114]
    P-value
    = 0.039 [115]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [114] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [115] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    SF36 RE One sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.252 [116]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [116] - Non significant.
    Statistical analysis title
    SF36 RE Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.096 [117]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [117] - Non significant.
    Statistical analysis title
    SF36 RE Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.768 [118]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [118] - Non significant.
    Statistical analysis title
    PFA One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.665 [119]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [119] - Non significant.
    Statistical analysis title
    PFA Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.683 [120]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [120] - Non significant.
    Statistical analysis title
    PFA Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [121]
    P-value
    = 0.057 [122]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [121] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [122] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    PPA One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.17 [123]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [123] - Non significant.
    Statistical analysis title
    PPA Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.144 [124]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [124] - Non significant.
    Statistical analysis title
    PPA Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [125]
    P-value
    = 0.01 [126]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [125] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
    [126] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.
    Statistical analysis title
    MSIS One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.477 [127]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [127] - Non significant.
    Statistical analysis title
    MSIS Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.22 [128]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [128] - Non significant.
    Statistical analysis title
    MSIS Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.196 [129]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [129] - Non significant.
    Statistical analysis title
    MSWS One sample t-test
    Statistical analysis description
    One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.817 [130]
    Method
    One sample t-test
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [130] - Non significant.
    Statistical analysis title
    MSWS Mixed model
    Statistical analysis description
    Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.772 [131]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Confidence interval
    Notes
    [131] - Non significant.
    Statistical analysis title
    MSWS Change in gradient
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.12 [132]
    Method
    Change in gradient
    Parameter type
    Slope
    Confidence interval
    Notes
    [132] - Non significant.

    Secondary: EBV copy number in saliva

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    End point title
    EBV copy number in saliva
    End point description
    Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), infection is associated with with a higher risk of certain autoimmune diseases, such as Multiple Sclerosis. In particular, people who have had glandular fever, the symptomatic EBV infection , have a higher risk to develop MS. EBV may be found in the saliva of someone who has had glandular fever for several months after their symptoms pass, and most people may continue to have the virus in their saliva on and off for years. Studies of dynamics of virus shedding in healthy carriers demonstrate that EBV shedding into saliva is constant.
    End point type
    Secondary
    End point timeframe
    Changes in mean after - before.
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    13
    Units: Copies/microlitre
    arithmetic mean (standard deviation)
        EBV
    -16.3 ± 46.02
    -16.3 ± 46.02
    Statistical analysis title
    EBV one sample t-test
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.226 [133]
    Method
    One sample t-test
    Confidence interval
    Notes
    [133] - Non significant.
    Statistical analysis title
    EBV Mixed model
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.616 [134]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [134] - Non significant.
    Statistical analysis title
    EBV change in gradient
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    [135]
    P-value
    = 0.219 [136]
    Method
    Change in gradient
    Confidence interval
    Notes
    [135] - Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    [136] - Non significant.

    Secondary: Laboratory safety data

    Close Top of page
    End point title
    Laboratory safety data
    End point description
    Laboratory safety outcomes. Assessments collected at screening were used to determe study eligibility only. Safety assessments were collected at all visits. Severity of abnormal results was evaluated by the investigator as mild, moderate or severe. Lab findings which the investigator felt were clinically significant based on the Laboratory Guidelines were recorded as adverse events. The relationship of the adverse event to the administration of the study drug was also determined by the investigator.
    End point type
    Secondary
    End point timeframe
    Changes in after - before (treatment).
    End point values
    Treatment ITT
    Number of subjects analysed
    20
    20
    Units: After - before changes in mean
    arithmetic mean (standard deviation)
        Adjusted calcium serum
    0.02 ± 0.05
    0.02 ± 0.05
        ALT
    1.12 ± 8.75
    1.12 ± 8.75
        AST
    1.24 ± 4.83
    1.24 ± 4.83
        Basophil count
    0 ± 0.02
    0 ± 0.02
        Chloride serum
    -0.75 ± 1.65
    -0.75 ± 1.65
        Cholesterol HDL ratio serum
    0.04 ± 0.21
    0.04 ± 0.21
        Cholesterol serum
    0.28 ± 0.38
    0.28 ± 0.38
        Creatinine serum
    2.08 ± 5.91
    2.08 ± 5.91
        Eosinophil count
    0 ± 0.06
    0 ± 0.06
        Estimated GFR
    -3 ± 9.77
    -3 ± 9.77
        GGT
    -0.5 ± 8.18
    -0.5 ± 8.18
        Glucose plasma
    -0.18 ± 0.47
    -0.18 ± 0.47
        Haemoglobin
    -0.13 ± 0.56
    -0.13 ± 0.56
        HDL cholesterol serum
    0.05 ± 0.16
    0.05 ± 0.16
        LDL Cholesterol serum
    0.17 ± 0.32
    0.17 ± 0.32
        Lymphocyte count
    0.05 ± 0.31
    0.05 ± 0.31
        Monocyte count
    0 ± 0.11
    0 ± 0.11
        Neutrophil count
    0.15 ± 0.61
    0.15 ± 0.61
        Platelet count
    6.86 ± 13.92
    6.86 ± 13.92
        Potassium serum
    0.05 ± 0.15
    0.05 ± 0.15
        Sodium serum
    0.14 ± 1.57
    0.14 ± 1.57
        Total bilirubin serum
    0.18 ± 1.5
    0.18 ± 1.5
        Triglicerides serum
    0.08 ± 0.29
    0.08 ± 0.29
        Urea serum
    0.24 ± 0.78
    0.24 ± 0.78
        White blood count
    0.22 ± 0.71
    0.22 ± 0.71
    Statistical analysis title
    One sample t-test Adjusted Calcium serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.025 [137]
    Method
    One sample t-test
    Confidence interval
    Notes
    [137] - There was a significant increase after vs before, 0.02 (P=0.025). However, there was no significant change in gradient P=0.406
    Statistical analysis title
    One sample t-test ALT
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.575 [138]
    Method
    One sample t-test
    Confidence interval
    Notes
    [138] - Non significant.
    Statistical analysis title
    One sample t-test AST
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.266 [139]
    Method
    One sample t-test
    Confidence interval
    Notes
    [139] - Non significant.
    Statistical analysis title
    One sample t-test basophil count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.883 [140]
    Method
    One sample t-test
    Confidence interval
    Notes
    [140] - Non significant.
    Statistical analysis title
    One sample t-test chloride serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.055 [141]
    Method
    One sample t-test
    Confidence interval
    Notes
    [141] - Borderline significant drop, -0.75 (P=0.055). However, there was no significant change in gradient, P=0.194.
    Statistical analysis title
    One sample t-test Cholesterol HDL ratio serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.369 [142]
    Method
    One sample t-test
    Confidence interval
    Notes
    [142] - Non significant.
    Statistical analysis title
    One sample t-test Cholesterol serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.004 [143]
    Method
    One sample t-test
    Confidence interval
    Notes
    [143] - There was a significant increase P=0.004. However, there was no significant change in gradient P=0.437. Faster increase before than after.
    Statistical analysis title
    One sample t-test Creatinine serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.132 [144]
    Method
    One sample t-test
    Confidence interval
    Notes
    [144] - Non significant.
    Statistical analysis title
    One sample t-test Eosinophil count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.855 [145]
    Method
    One sample t-test
    Confidence interval
    Notes
    [145] - Non significant.
    Statistical analysis title
    One sample t-test Estimated GFR
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.186 [146]
    Method
    One sample t-test
    Confidence interval
    Notes
    [146] - Non significant.
    Statistical analysis title
    One sample t-test GGT
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.789 [147]
    Method
    One sample t-test
    Confidence interval
    Notes
    [147] - Non significant.
    Statistical analysis title
    One sample t-test Glucose plasma
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.108 [148]
    Method
    One sample t-test
    Confidence interval
    Notes
    [148] - Non significant.
    Statistical analysis title
    One sample t-test Haemoglobin
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.308 [149]
    Method
    One sample t-test
    Confidence interval
    Notes
    [149] - Non significant.
    Statistical analysis title
    One sample t-test HDL Cholesterol serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.174 [150]
    Method
    One sample t-test
    Confidence interval
    Notes
    [150] - Non significant.
    Statistical analysis title
    One sample t-test LDL Cholesterol serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.027 [151]
    Method
    One sample t-test
    Confidence interval
    Notes
    [151] - There was a significant increase, but no significant change in gradient P=0.432.
    Statistical analysis title
    One sample t-test Lymphocyte count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.465 [152]
    Method
    One sample t-test
    Confidence interval
    Notes
    [152] - Non significant.
    Statistical analysis title
    One sample t-test Monocyte count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.958 [153]
    Method
    One sample t-test
    Confidence interval
    Notes
    [153] - Non significant.
    Statistical analysis title
    One sample t-test Neutrophil count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.291 [154]
    Method
    One sample t-test
    Confidence interval
    Notes
    [154] - Non significant.
    Statistical analysis title
    One sample t-test Platelet count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.04 [155]
    Method
    One sample t-test
    Confidence interval
    Notes
    [155] - There was asignificant increase P=0.040. However, there was no significant change in gradient P=0.352.
    Statistical analysis title
    One sample t-test Potassium serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.161 [156]
    Method
    One sample t-test
    Confidence interval
    Notes
    [156] - There was asignificant increase P=0.040. However, there was no significant change in gradient P=0.352.
    Statistical analysis title
    One sample t-test Sodium serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.692 [157]
    Method
    One sample t-test
    Confidence interval
    Notes
    [157] - Non significant.
    Statistical analysis title
    One sample t-test Total bilirubin serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.591 [158]
    Method
    One sample t-test
    Confidence interval
    Notes
    [158] - Non significant.
    Statistical analysis title
    One sample t-test Triglicerides serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.225 [159]
    Method
    One sample t-test
    Confidence interval
    Notes
    [159] - Non significant.
    Statistical analysis title
    One sample t-test Urea serum
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.183 [160]
    Method
    One sample t-test
    Confidence interval
    Notes
    [160] - Non significant.
    Statistical analysis title
    One sample t-test White blood count
    Statistical analysis description
    One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.184 [161]
    Method
    One sample t-test
    Confidence interval
    Notes
    [161] - Non significant.
    Statistical analysis title
    Mixed model Adjusted calcium serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.027 [162]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [162] - There was a significant increase after vs before. However, there was no significant change in gradient.
    Statistical analysis title
    Mixed model ALT
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.643 [163]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [163] - Non significant.
    Statistical analysis title
    Mixed model AST
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.265 [164]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [164] - Non significant.
    Statistical analysis title
    Mixed model Basophil count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.954 [165]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [165] - Non significant.
    Statistical analysis title
    Mixed model Chloride serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.032 [166]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [166] - Borderline significant drop. However, there was no significant change in gradient
    Statistical analysis title
    Mixed model Cholesterol HDL ratio serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.441 [167]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [167] - Borderline significant drop.
    Statistical analysis title
    Mixed model Cholesterol serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0 [168]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [168] - There was a significant increase. However, there was no significant change in gradient.
    Statistical analysis title
    Mixed model Creatinine serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.097 [169]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [169] - Non significant.
    Statistical analysis title
    Mixed model Eosinophil count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.711 [170]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [170] - Non significant.
    Statistical analysis title
    Mixed model Estimated GFR
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.153 [171]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [171] - Non significant.
    Statistical analysis title
    Mixed model GGT
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.794 [172]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [172] - Non significant.
    Statistical analysis title
    Mixed model Glucose Plasma
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.196 [173]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [173] - Non significant.
    Statistical analysis title
    Mixed model Haemoglobin
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.168 [174]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [174] - Non significant.
    Statistical analysis title
    Mixed model HDL cholesterol serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.101 [175]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [175] - Non significant.
    Statistical analysis title
    Mixed model LDL cholesterol serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.018 [176]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [176] - There was a significant increase. However, there was no significant change in gradient.
    Statistical analysis title
    Mixed model Lymphocyte count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.304 [177]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [177] - Non significant.
    Statistical analysis title
    Mixed model Monocyte count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.789 [178]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [178] - Non significant.
    Statistical analysis title
    Mixed model Neutrophil count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.244 [179]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [179] - Non significant.
    Statistical analysis title
    Mixed model Platelet count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.013 [180]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [180] - There was a significant increase. However, there was no significant change in gradient.
    Statistical analysis title
    Mixed model Potassium serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.143 [181]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [181] - Non significant.
    Statistical analysis title
    Mixed model Sodium serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.732 [182]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [182] - Non significant.
    Statistical analysis title
    Mixed model Total bilirubin serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.57 [183]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [183] - Non significant.
    Statistical analysis title
    Mixed model Triglicerides serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.133 [184]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [184] - Non significant.
    Statistical analysis title
    Mixed model Urea serum
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.107 [185]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [185] - Non significant.
    Statistical analysis title
    Mixed model White blood count
    Statistical analysis description
    Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.154 [186]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [186] - Non significant.
    Statistical analysis title
    Change in gradient Adjusted calcium serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [187]
    P-value
    = 0.406 [188]
    Method
    Change in gradient
    Confidence interval
    Notes
    [187] - Gradients reported are estimated rates of change in test units per month.
    [188] - No significant chnge gradient SE z P-value 95% Conf. Int before -.0000267 .005385 -0.00 0.996 -.0105811 .0105277 after .0077586 .0053828 1.44 0.149 -.0027916 .0183087
    Statistical analysis title
    Change in gradient ALT
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [189]
    P-value
    = 0.179 [190]
    Method
    Change in gradient
    Confidence interval
    Notes
    [189] - Gradients reported are estimated rates of change in test units per month
    [190] - No signif change gradient SE z P-value 95% Conf. Int before -.0000267 .005385 -0.00 0.996 -.0105811 .0105277 after .0077586 .0053828 1.44 0.149 -.0027916 0183087
    Statistical analysis title
    Change in gradient AST
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.385 [191]
    Method
    Change in gradient
    Confidence interval
    Notes
    [191] - Non significant.
    Statistical analysis title
    Change in gradient Basophil count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.779 [192]
    Method
    Change in gradient
    Confidence interval
    Notes
    [192] - Non significant.
    Statistical analysis title
    Change in gradient Chloride serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.194 [193]
    Method
    Change in gradient
    Confidence interval
    Notes
    [193] - No signif change gradient SE z P-value 95% Conf. Int before .1363255 .2036459 0.67 0.503 -.2628131 .5354641 after -.3119152 .1915487 -1.63 0.103 -.6873437 .0635134
    Statistical analysis title
    Change in gradient Chlolesterol HDL ratio serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.928 [194]
    Method
    Change in gradient
    Confidence interval
    Notes
    [194] - Non significant.
    Statistical analysis title
    Change in gradient Chlolesterol serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [195]
    P-value
    = 0.437 [196]
    Method
    Change in gradient
    Confidence interval
    Notes
    [195] - Gradients reported are estimated rates of change in test units per month.
    [196] - No signif change gradient SE z P-value 95% Conf. Int before .0826927 .043773 1.89 0.059 -.0031008 .1684862 after .0258226 .040227 0.64 0.521 -.0530208 .1046661
    Statistical analysis title
    Change in gradient Creatinine serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [197]
    P-value
    = 0.769 [198]
    Method
    Change in gradient
    Confidence interval
    Notes
    [197] - Gradients reported are estimated rates of change in test units per month.
    [198] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Eosinophil count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.768 [199]
    Method
    Change in gradient
    Confidence interval
    Notes
    [199] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Estimated GFR
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.874 [200]
    Method
    Change in gradient
    Confidence interval
    Notes
    [200] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Estimated GGT
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.345 [201]
    Method
    Change in gradient
    Confidence interval
    Notes
    [201] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Estimated Glucose plasma
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.072 [202]
    Method
    Change in gradient
    Confidence interval
    Notes
    [202] - There was a borderline significant gradient change P=0.072, from a non-significant increase before to a significant decline after.
    Statistical analysis title
    Change in gradient Haemoglobin
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.558 [203]
    Method
    Change in gradient
    Confidence interval
    Notes
    [203] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient HDL Cholesterol serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.843 [204]
    Method
    Change in gradient
    Confidence interval
    Notes
    [204] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient LDL Cholesterol serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.432 [205]
    Method
    Change in gradient
    Confidence interval
    Notes
    [205] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Lymphocyte count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.775 [206]
    Method
    Change in gradient
    Confidence interval
    Notes
    [206] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Monocyte count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.089 [207]
    Method
    Change in gradient
    Confidence interval
    Notes
    [207] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Neutrophil count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.899 [208]
    Method
    Change in gradient
    Confidence interval
    Notes
    [208] - There was no significant change in gradient.
    Statistical analysis title
    Change in gradient Platelet count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    [209]
    P-value
    = 0.352 [210]
    Method
    Change in gradient
    Confidence interval
    Notes
    [209] - Gradients reported are estimated rates of change in test units per month.
    [210] - No signif change gradient SE z P-value 95% Conf. Int before -.274596 1.820794 -0.15 0.880 -3.843288 3.294096 after 2.592704 1.709353 1.52 0.129 -.7575659 5.942974
    Statistical analysis title
    Change in gradient Potassium serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.221 [211]
    Method
    Change in gradient
    Confidence interval
    Notes
    [211] - There was no significant change in gradient
    Statistical analysis title
    Change in gradient Sodium serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.445 [212]
    Method
    Change in gradient
    Confidence interval
    Notes
    [212] - There was no significant change in gradient
    Statistical analysis title
    Change in gradient total bilirubin serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.123 [213]
    Method
    Change in gradient
    Confidence interval
    Notes
    [213] - There was no significant change in gradient
    Statistical analysis title
    Change in gradient Triglicerides serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.767 [214]
    Method
    Change in gradient
    Confidence interval
    Notes
    [214] - There was no significant change in gradient
    Statistical analysis title
    Change in gradient Urea serum
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.197 [215]
    Method
    Change in gradient
    Confidence interval
    Notes
    [215] - There was no significant change in gradient
    Statistical analysis title
    Change in gradient White blood count
    Statistical analysis description
    Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
    Comparison groups
    Treatment v ITT
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.674 [216]
    Method
    Change in gradient
    Confidence interval
    Notes
    [216] - There was no significant change in gradient

    Secondary: Adverse events

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    End point title
    Adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    After - before (treatment) changes
    End point values
    Treatment Per protocol ITT
    Number of subjects analysed
    20
    16
    20
    Units: Number of visits with adverse events
    arithmetic mean (standard deviation)
        Number of visits with AEs before intervention
    2.35 ± 0.75
    2.31 ± 0.79
    2.35 ± 0.75
        Number of visits with AEs after intervention
    2.3 ± 0.73
    2.31 ± 0.79
    2.3 ± 0.73
        Adverse events
    -0.05 ± 1.28
    0 ± 1.37
    -0.05 ± 1.28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reporting of adverse events from screening
    Adverse event reporting additional description
    Adverse events were recorded for all subjects screened (n=31) and include events for patients who did not receive IMP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Non-serious adverse events
    Reporting group description
    Adverse events were recorded from screening (n=31) and include subjects who did not receive IMP.

    Serious adverse events
    Non-serious adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    MS relapse
    Additional description: MS relapse which required hospitalisation for administration of IV methylprednisolone. Normal practise would not have been to admit to hospital. However the patient had no care at home and could not care for self at home.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Non-serious adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Immune system disorders
    Adenopathies
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Itchy eyes
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Allergic skin rash worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hayfever congestion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hayfever worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    10 / 20 (50.00%)
         occurrences all number
    12
    Liver function test abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Liver function test increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Fall
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    poor sleep
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Swelling in left arm
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Stomach pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Loss of libido
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Problems concentrating
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Stiff neck
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fainting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vivid dreams
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tiredness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Weight loss diet
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Lack of motivation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Low blood pressure asymptomatic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Choking on liquids
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Flushing to face
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Strange sensation when swallowing
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Swelling in fingers
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Swelling feeling in fingers
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Depression worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Low mood
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Panic attack increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Emotional instability
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Menopause onset
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pelvic mass
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Haematoma
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Bruised knee (due to fall)
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Broken toenail
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cut knee
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Twisted knee
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hurt wrist
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    7
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Hypertension worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Arrhythmia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Wheeze
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Dyslipidemia
         subjects affected / exposed
    10 / 20 (50.00%)
         occurrences all number
    17
    Mycrocytic Anemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Normocytic anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Multiple sclerosis relapse
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    9
    Multiple sclerosis sensory relapse
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Sensory disturbance
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Fatigue increased
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Migraine
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Dysaesthesia worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nystagmus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neuropathic pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Tremor in hands
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Numbness - loss of sensation
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Tremor in arm worsened
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Subjective worsening of leg weakness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neurological signs worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Back pain (burning sensation)
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye disorders
    Visual fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Decreased vision
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Stye
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Defective gastro-ileal valve
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Bloated abdomen (during antibiotics)
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Bladder dysfunction
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Dysuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Bladder problems worsening
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Eczema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Fungal infection worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Petechial purpura
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Naevus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Scar from mole removal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash on face
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mole on toe
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Allergic rash worsening
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain
         subjects affected / exposed
    14 / 20 (70.00%)
         occurrences all number
    17
    Pain worsening
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cramps in legs
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Common cold
         subjects affected / exposed
    14 / 20 (70.00%)
         occurrences all number
    21
    Urinary tract infection
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    Sore throat
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Cough
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Tooth infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Chest infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2013
    Approved documents: • Protocol Version 5.0 • PIS/ICF Version 6.0 • Questionnaires Version 2.0 • Website Advertising Text Version 1.0 • Additional IMP Label 1. Updates to Patient Questionnaires The following questionnaires remain in the study and patients will be asked to complete these at visits 2-8. 1. Health Status Questionnaire (SF-36) 2. Multiple Sclerosis Impact Scale (MSIS-29) 3. Multiple Sclerosis Walking Scale (MSWS-12v2) The following assessments replace patient assessments of pain and fatigue. 1. Patient Fatigue Assessment – Visual Analogue Scale 2. Patient Pain Assessment – Visual Analogue Scale 2. Reduction of EDSS Frequency Frequency of EDSS assessments was reduced (every 2 months)as it was deemed unnecessary by the Chief Investigator to have this number of EDSS in the study. 3. Use of an Additional Pharmacy Label Additional IMP label to be attached to the study IMP. 4. Pregnancy Tests before MRI Clarification on pregnancy tests to be performed prior to MRI scans (standard of care but this information was not clearly outlined in the Protocol and Patient Information Sheet). 5. Advertising Materials In order to advertise the study on the websites of patient support groups such as the MS Society and Shift MS to aid recruitment.
    11 Nov 2014
    Approved document: Protocol Version 6.0 Summary of changes made to the protocol: 1. End of Trial Definition The end of study definition was revised from ‘Last Patient Last Visit’ to ‘Last Patient Last Visit plus six months’. 2. Criteria for Premature Withdrawal Both protocol sections 3.4 and sections 5.8 of the protocol indicated the reasons for premature withdrawal from this study. However, section 3.4 did not include all reasons as given in protocol section 5.8. Section 3.4 was updated with the reason, which was previously present in protocol section 5.8 but missing in protocol section 3.4 : Severe or disabling MS relapse needing IVMP and admission to hospital during the 3 months on treatment phase of the study.
    13 Apr 2015
    Clarifications were made to the following sections of the protocol post last patient last visit: 1. Inclusion/Exclusion criteria section 3.3 2. Criteria for Premature Withdrawal section 3.4 3. Prior and concomitant therapies section 4.8 The amendment was approved by the MHRA but rejected by the ethics committee. Therefore it was felt appropriate to withdraw the amendment. MHRA were notified of this on 08/06/15.

    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
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