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    Clinical Trial Results:
    High-field structural and functional MRI to investigate the substrates of fatigue in multiple sclerosis and to monitor the effect of tailored treatments.Pharmacological substudy.

    Summary
    EudraCT number
    		 2010-023678-38
    Trial protocol
    		 IT  
    Global end of trial date
    03 Sep 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jun 2020
    First version publication date
    23 Feb 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    • Changes to summary attachments
    Correction of previous version of results
    Summary report(s)
    		 Summary

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GR-2008-1138784 sottostudio
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IRCCS San Raffaele Scientific Institute
    Sponsor organisation address
    via Olgettina 60, Milan, Italy, 20132
    Public contact
    Prof. Massimo Filippi, IRCCS San Raffaele Scientific Institute, +39 0226433054, filippi.massimo@hsr.it
    Scientific contact
    Prof. Massimo Filippi, IRCCS San Raffaele Scientific Institute, +39 0226433054, filippi.massimo@hsr.it
    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
    03 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this trial was to evaluate the effects on brain activation patterns of drugs that are widely used in clinical practice for the treatment of fatigue in multiple sclerosis
    Protection of trial subjects
    Patients were monitored by a medical doctor during the entire experimental procedure, including MRI assessment. Medical advice was provided to patients about possible pharmacological treatments to solve eventual side effects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    45
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with multiple sclerosis (MS) and the relapsing-remitting (RR) or secondary progressive (SP) disease phenotype were recruited. Patients had to suffer from central fatigue at least from six weeks. Fatigue was assessed using proper evaluation scales, such as the modified fatigue impact scale (MFIS).

    Pre-assignment
    Screening details
    		 Inclusion/exclusion criteria: no relapses/steroid treatment <3 months before study; EDSS score<=4.0; no visual deficits; no right upper limb impairment interfering with fMRI; no other major neurological/psychiatric/mood disorders; no major renal/cardiac/hepatic diseases; no depression; no history of drug/alcohol abuse; no pregnancy/breastfeeding

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Blinding was performed using a computerized procedure

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fampridine
    Arm description
    		 Fampridine treatment group (4-aminopyridine)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fampridine
    Investigational medicinal product code
    Other name
    Ampyra
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg twice daily (8:00 and 20:00 h)

    Arm title
    		 Amantadine
    Arm description
    		 Amantadine treatment group (1-adamantylamine)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amantadine
    Investigational medicinal product code
    Other name
    Mantadan
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg twice daily (8:00 and 20:00 h)

    Arm title
    		 Placebo
    Arm description
    		 Placebo group
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet twice daily (8:00 and 20:00 h)

    Number of subjects in period 1
    		Fampridine Amantadine Placebo
    Started
    15
    15
    15
    Completed
    14
    15
    15
    Not completed
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fampridine
    Reporting group description
    		 Fampridine treatment group (4-aminopyridine)

    Reporting group title
    Amantadine
    Reporting group description
    		 Amantadine treatment group (1-adamantylamine)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Reporting group values
    		 Fampridine Amantadine Placebo Total
    Number of subjects
    		 15 15 15 45
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 15 15 15 45
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.4 ( 13.3 ) 41.2 ( 7.2 ) 41.8 ( 10.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 13 12 31
        Male
    		 9 2 3 14

    End points

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    End points reporting groups
    Reporting group title
    Fampridine
    Reporting group description
    		 Fampridine treatment group (4-aminopyridine)

    Reporting group title
    Amantadine
    Reporting group description
    		 Amantadine treatment group (1-adamantylamine)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Subject analysis set title
    Fampridine baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with fampridine - baseline

    Subject analysis set title
    Fampridine week 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with fampridine - week 4

    Subject analysis set title
    Amantadine baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with amantadine - baseline

    Subject analysis set title
    Amantadine week 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with amantadine - week 4

    Subject analysis set title
    Placebo baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients taking placebo - baseline

    Subject analysis set title
    Placebo week 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients taking placebo - week 4

    Primary: Global MFIS

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    End point title
    		 Global MFIS
    End point description
    modified fatigue impact scale, global score of fatigue
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: unitless
        arithmetic mean (standard deviation)
    45.2 ( 13.1 )
    34.3 ( 12.1 )
    47.5 ( 13.3 )
    39.6 ( 13.5 )
    46.3 ( 16.1 )
    34.4 ( 15.1 )
    Statistical analysis title
    		 within-group change global MFIS fampridine
    Statistical analysis description
    change of global MFIS over time at week 4 vs baseline in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - paired t test
    Statistical analysis title
    		 within-group change global MFIS amantadine
    Statistical analysis description
    change of global MFIS over time at week 4 vs baseline in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - paired t test
    Statistical analysis title
    		 within-group change global MFIS placebo
    Statistical analysis description
    change of global MFIS over time at week 4 vs baseline in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - paired t test

    Primary: Physical MFIS

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    End point title
    		 Physical MFIS
    End point description
    modified fatigue impact scale, score of physical fatigue
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: unitless
        arithmetic mean (standard deviation)
    25.0 ( 6.8 )
    18.8 ( 6.7 )
    21.4 ( 5.2 )
    16.8 ( 5.7 )
    22.8 ( 7.3 )
    16.6 ( 7.2 )
    Statistical analysis title
    		 within-group change physical MFIS fampridine
    Statistical analysis description
    change of physical MFIS over time at week 4 vs baseline in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.003
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - paired t test
    Statistical analysis title
    		 within-group change physical MFIS amantadine
    Statistical analysis description
    change of physical MFIS over time at week 4 vs baseline in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.04
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - paired t test
    Statistical analysis title
    		 within-group change physical MFIS placebo
    Statistical analysis description
    change of physical MFIS over time at week 4 vs baseline in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - paired t test

    Primary: Cognitive MFIS

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    End point title
    		 Cognitive MFIS
    End point description
    modified fatigue impact scale, score of cognitive fatigue
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15 [7]
    Units: unitless
        arithmetic mean (standard deviation)
    16.7 ( 8.7 )
    12.7 ( 7.8 )
    21.5 ( 8.1 )
    19.3 ( 8.2 )
    19.1 ( 9.4 )
    14.6 ( 9.2 )
    Notes
    [7] - 1 miss
    Statistical analysis title
    		 within-group change cognitive MFIS fampridine
    Statistical analysis description
    change of cognitive MFIS over time at week 4 vs baseline in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.014
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [8] - paired t test
    Statistical analysis title
    		 within-group change cognitive MFIS amantadine
    Statistical analysis description
    change of cognitive MFIS over time at week 4 vs baseline in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.32
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [9] - paired t test
    Statistical analysis title
    		 within-group change cognitive MFIS placebo
    Statistical analysis description
    change of cognitive MFIS over time at week 4 vs baseline in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.07
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - paired t test

    Primary: Psycho-social MFIS

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    End point title
    		 Psycho-social MFIS
    End point description
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: unitless
        arithmetic mean (standard deviation)
    3.6 ( 1.4 )
    2.8 ( 1.6 )
    4.5 ( 1.4 )
    3.5 ( 1.3 )
    4.3 ( 1.4 )
    3.1 ( 2.2 )
    Statistical analysis title
    		 within-group change psycho-social MFIS fampridine
    Statistical analysis description
    change of psycho-social MFIS over time at week 4 vs baseline in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.15
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [11] - paired t test
    Statistical analysis title
    		 within-group change psycho-social MFIS amantadine
    Statistical analysis description
    change of psycho-social MFIS over time at week 4 vs baseline in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [12] - paired t test
    Statistical analysis title
    		 within-group change psycho-social MFIS placebo
    Statistical analysis description
    change of psycho-social MFIS over time at week 4 vs baseline in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [13] - paired t test

    Primary: motor fMRI activity

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    End point title
    		 motor fMRI activity
    End point description
    functional MRI activity during a right-hand motor task
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    15
    14
    15
    15
    15
    15
    Statistical analysis title
    		 within-group change motor fMRI activity fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of motor fMRI activity in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [14]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [14] - voxel-wise paired t test using statistical parametric mapping (SPM12) fmri changes localized in: left precentral gyrus (MNI space coordinates: -34 6 42), right superior frontal gyrus (MNI space coordinates: 18 38 48), left supramarginal gyrus (MNI space coordinates: -64 -22 28) and right supramarginal gyrus (MNI space coordinates: 58 10 28)
    Statistical analysis title
    		 within-group change motor fMRI activity placebo
    Statistical analysis description
    change over time at week 4 vs baseline of motor fMRI activity in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [15] - voxel-wise paired t test using statistical parametric mapping (SPM12) fMRI changes localized in the right middle temporal gyrus (MNI space coordinates: 58 10 28)

    Primary: cognitive fMRI activity

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    End point title
    		 cognitive fMRI activity
    End point description
    functional MRI activity during a cognitive task - continuous performance test (CPT)
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15 [16]
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    15
    14
    15
    15
    15
    15
    Notes
    [16] - 15
    Statistical analysis title
    		 within-group change CPT fMRI activity fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of CPT fMRI activity in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [17]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [17] - voxel-wise paired t test using statistical parametric mapping (SPM12) fMRI changes localized in: right cerebellum (MNI space coordinates: 22 -26 -24 and 12 -60 -26), left cerebellum (MNI space coordinates: -24 -58 -30), left MT/V5 (MNI space coordinates: -26 -74 16), right MT/V5 (MNI space coordinates: 34 -64 14) and left inferior parietal lobule (MNI space coordinates: -58 -28 50)
    Statistical analysis title
    		 within-group change CPT fMRI activity placebo
    Statistical analysis description
    change over time at week 4 vs baseline of CPT fMRI activity in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [18]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [18] - voxel-wise paired t test using statistical parametric mapping (SPM12) fMRI changes localized in: left precentral gyrus (MNI space coordinates: -36 6 36), left inferior frontal gyrus (MNI space coordinates: -46 32 10), left superior temporal gyrus (MNI space coordinates: -46 -42 16), right angular gyrus (MNI space coordinates: 42 -58 26), right supramarginal gyrus (MNI space coordinates: 52 -46 34) and left middle temporal gyrus (MNI space coordinates: -46 -24 0)

    Primary: resting state functional connectivity default mode network

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    End point title
    		 resting state functional connectivity default mode network
    End point description
    resting state functional connectivity in the default mode network
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    13
    13
    13
    13
    13
    13
    Statistical analysis title
    		 within-group change RS FC fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the default mode network in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [19]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [19] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the left precuneus (MNI space coordinates: -10 -86 32) and right precuneus (MNI space coordinates: 8 -66 52)

    Primary: resting state functional connectivity salience network

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    End point title
    		 resting state functional connectivity salience network
    End point description
    resting state functional connectivity in the salience network
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    13
    13
    13
    13
    13
    13
    Statistical analysis title
    		 within-group change RS FC fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the salience network in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [20]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [20] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the right inferior frontal gyrus (MNI space coordinates: 26 26 -12)

    Primary: resting state functional connectivity fronto-parietal network

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    End point title
    		 resting state functional connectivity fronto-parietal network
    End point description
    resting state functional connectivity in the fronto-parietal network
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    13
    13
    13
    13
    13
    13
    Statistical analysis title
    		 within-group change RS FC fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the fronto-parietal network in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [21]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [21] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes in the right inferior frontal gyrus (MNI space coordinates: 54 12 14)
    Statistical analysis title
    		 within-group change RS FC placebo
    Statistical analysis description
    change over time at week 4 vs baseline in the fronto-parietal network in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [22]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [22] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes in the right superior occipital gyrus (MNI space coordinates: 24 -66 40), right supplementary motor area (MNI space coordinates: 4 12 54), right middle frontal gyrus (MNI space coordinates: 44 32 24)
    Statistical analysis title
    		 within-group change RS FC amantadine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the fronto-parietal network in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [23]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [23] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes in the left angular gyrus (MNI space coordinates: -38 -60 42) and left middle temporal gyrus (MNI space coordinates: -62 -32 6)

    Primary: resting state functional connectivity sensorimotor network

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    End point title
    		 resting state functional connectivity sensorimotor network
    End point description
    resting state functional connectivity in the sensorimotor network
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    13
    13
    13
    13
    13
    13
    Statistical analysis title
    		 within-group change RS FC fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the sensorimotor network in fampridine group
    Comparison groups
    Fampridine baseline v Fampridine week 4
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [24]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [24] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the right cerebellum (MNI space coordinates: 18 -50 -22) and right postcentral gyrus (MNI space coordinates: 30 -30 50)
    Statistical analysis title
    		 within-group change RS FC amantadine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the sensorimotor network in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [25]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [25] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the right postcentral gyrus (MNI space coordinates: 46 -22 40) and right middle cingulate cortex (MNI space coordinates: 10 -36 52)
    Statistical analysis title
    		 within-group change RS FC placebo
    Statistical analysis description
    within-group change of resting state functional connectivity in the sensorimotor network in placebo group
    Comparison groups
    Placebo baseline v Placebo week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [26]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [26] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the right supplementary motor area (MNI space coordinates: 14 -26 52) and left postcentral gyrus (MNI space coordinates: -56 -18 18)

    Primary: resting state functional connectivity basal ganglia network

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    End point title
    		 resting state functional connectivity basal ganglia network
    End point description
    resting state functional connectivity in the basal ganglia network
    End point type
    Primary
    End point timeframe
    baseline and week 4
    End point values
    		 Fampridine baseline Fampridine week 4 Amantadine baseline Amantadine week 4 Placebo baseline Placebo week 4
    Number of subjects analysed
    15
    14
    15
    15
    15
    15
    Units: BOLD signal
        number (not applicable)
    13
    13
    13
    13
    13
    13
    Statistical analysis title
    		 within-group change RS FC fampridine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the basal ganglia network in fampridine group
    Comparison groups
    Fampridine week 4 v Fampridine baseline
    Number of subjects included in analysis
    29
    Analysis specification
    Post-hoc
    Analysis type
    		 other [27]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [27] - voxel-wise paired t test using statistical parametric mapping (SPM12) RS FC changes localized in the left caudate nucleus/putamen (MNI space coordinates: -24 -10 4)
    Statistical analysis title
    		 within-group change RS FC amantadine
    Statistical analysis description
    change over time at week 4 vs baseline of resting state functional connectivity in the basal ganglia network in amantadine group
    Comparison groups
    Amantadine baseline v Amantadine week 4
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 other [28]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [28] - voxel-wise paired t testv using statistical parametric mapping (SPM12) RS FC changes localized in the left thalamus (MNI space coordinates: -10 -4 12)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    July 2011-February 2014
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 45 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 45 (13.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Paresthesia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dysesthesia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    General disorders and administration site conditions
    Insomnia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Gait disturbance
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pyrosis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Sinusitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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