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    Clinical Trial Results:
    Dimethyl fumarate treatment of primary progressive multiple sclerosis

    Summary
    EudraCT number
    		 2016-000283-41
    Trial protocol
    		 DK  
    Global end of trial date
    09 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2022
    First version publication date
    20 Mar 2022
    Other versions
    Summary report(s)
    		 Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis A Randomized, Controlled Trial

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    FUMAPMS2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02959658
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Danish Multiple Sclerosis Center
    Sponsor organisation address
    Valdemar Hansens Vej 13, Entrance 5, 7th floor, Glostrup, Denmark, 2600
    Public contact
    Finn Sellebjerg, Copenhagen University Hospital, Rigshospitalet Glostrup Danish Multiple Sclerosis Center , finn.thorup.sellebjerg@regionh.dk
    Scientific contact
    Finn Sellebjerg, Copenhagen University Hospital, Rigshospitalet Glostrup Danish Multiple Sclerosis Center , +45 38633236, finn.thorup.sellebjerg@regionh.dk
    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
    22 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial investigates the use of dimethyl fumarate treatment in patients with primary progressive multiple sclerosis (PPMS).
    Protection of trial subjects
    Local anesthesia before lumbar puncture and sedative in tablet form if requested by the participant before lumbar puncture and or MRI
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    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
    Denmark: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomized-controlled phase inclusion: December 6, 2016 – January 16, 2019 Open-label phase inclusion: January 25, 2018 – December 17, 2019

    Pre-assignment
    Screening details
    		 Inclusion criteria: Age 18 to 65 years, PPMS according to the McDonald (2010) and Lublin (2014) criteria, Disease duration at least one year, EDSS ≤6.5, No other signs of significant disease judged by the investigator, Eligible for randomisation to active treatment or placebo as assessed by CSF NFL levels above 380 ng/L.

    Pre-assignment period milestones
    Number of subjects started
    		 54
    Number of subjects completed
    		 54

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1, DMF
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    Other name
    BG-12
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets, 120 mg each 2 tablets (240 mg), twice daily, eg. 480 mg daily.

    Arm title
    		 Arm 2, placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tbl, 2 tblts twice daily

    Number of subjects in period 1
    		Arm 1, DMF Arm 2, placebo
    Started
    27
    27
    Completed
    27
    27
    Period 2
    Period 2 title
    Phase 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1, DMF
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    Other name
    BG-12
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets, 120 mg each 2 tablets (240 mg), twice daily, e.i. 480 mg daily.

    Arm title
    		 Arm 2, placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tbl, twice daily.

    Number of subjects in period 2
    		Arm 1, DMF Arm 2, placebo
    Started
    27
    27
    Completed
    26
    24
    Not completed
    1
    3
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    1
    -
    Period 3
    Period 3 title
    Phase 2, open label
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1, DMF/DMF
    Arm description
    		 Patients who recevied DMF in Phase 1 and continued DMF treatment in the open-label-phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    Other name
    BG-12
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets, 120 mg each 2 tablets (240 mg), twice daily, eg. 480 mg daily.

    Arm title
    		 Arm 2, UNT/DMF
    Arm description
    		 Patients who received Placebo in Phase 1 and were included in the open-label-phase receiving DMF.
    Arm type
    		 Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    Other name
    BG-12
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets, 120 mg each 2 tablets (240 mg), twice daily, eg. 480 mg daily.

    Number of subjects in period 3
    		Arm 1, DMF/DMF Arm 2, UNT/DMF
    Started
    26
    24
    Completed
    17
    16
    Not completed
    9
    8
         Consent withdrawn by subject
    6
    2
         Adverse event, non-fatal
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1, DMF
    Reporting group description
    		 -

    Reporting group title
    Arm 2, placebo
    Reporting group description
    		 -

    Reporting group values
    		 Arm 1, DMF Arm 2, placebo Total
    Number of subjects
    		 27 27 54
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ( 5.5 ) 54.0 ( 6.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 11 21
        Male
    		 17 16 33
    Cell Count
    Subjects with CSF cell count
    Units: Subjects
        >4 cells/uL
    		 8 4 12
        <5 cells/uL
    		 19 23 42
    Oligoclonal bands
    Units: Subjects
        Oligoclonal bands, Yes
    		 25 23 48
        Oligoclonal bands, No
    		 2 4 6
    Gd-enhancing lesions
    Gadolinium-enhancing lesions
    Units: Subjects
        1 Gd enhancing lesions
    		 3 2 5
        0 Gd enhancing lesions
    		 24 23 47
        NA
    		 0 2 2
    Disease duration
    Units: years
        arithmetic mean (standard deviation)
    		 14.3 ( 9.4 ) 13.8 ( 9.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm 1, DMF
    Reporting group description
    		 -

    Reporting group title
    Arm 2, placebo
    Reporting group description
    		 -
    Reporting group title
    Arm 1, DMF
    Reporting group description
    		 -

    Reporting group title
    Arm 2, placebo
    Reporting group description
    		 -
    Reporting group title
    Arm 1, DMF/DMF
    Reporting group description
    		 Patients who recevied DMF in Phase 1 and continued DMF treatment in the open-label-phase.

    Reporting group title
    Arm 2, UNT/DMF
    Reporting group description
    		 Patients who received Placebo in Phase 1 and were included in the open-label-phase receiving DMF.

    Primary: Neurofilament light chain (cerebrospinal fluid)

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    End point title
    		 Neurofilament light chain (cerebrospinal fluid)
    End point description
    End point type
    Primary
    End point timeframe
    Screening, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/L
        arithmetic mean (standard deviation)
    -73 ( 190 )
    35 ( 1002 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.61
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -292
         upper limit
    		 490

    Secondary: Myelin basic protein (cerebrospinal fluid)

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    End point title
    		 Myelin basic protein (cerebrospinal fluid)
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/L
        arithmetic mean (standard deviation)
    -206 ( 461 )
    18 ( 200 )
    Statistical analysis title
    		 generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.01 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -182
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -323
         upper limit
    		 -41
    Notes
    [1] - Conducted with multiple imputation of missing values.

    Secondary: Soluble CD27 (cerebrospinal fluid)

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    End point title
    		 Soluble CD27 (cerebrospinal fluid)
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/L
        arithmetic mean (standard deviation)
    -188 ( 321 )
    -307 ( 481 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -107
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -274
         upper limit
    		 60

    Secondary: Soluble B cell maturation antigen (cerebrospinal fluid)

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    End point title
    		 Soluble B cell maturation antigen (cerebrospinal fluid)
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/L
        arithmetic mean (standard deviation)
    -96 ( 204 )
    -57 ( 146 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.41
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -103
         upper limit
    		 42

    Secondary: Soluble CD14 (cerebrospinal fluid)

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    End point title
    		 Soluble CD14 (cerebrospinal fluid)
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/ml
        arithmetic mean (standard deviation)
    7 ( 24 )
    5 ( 17 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.54
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 15

    Secondary: Soluble chitinase-3-like-1 (cerebrospinal fluid)

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    End point title
    		 Soluble chitinase-3-like-1 (cerebrospinal fluid)
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: ng/ml
        arithmetic mean (standard deviation)
    -17 ( 47 )
    -7 ( 27 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 2, placebo v Arm 1, DMF
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.91
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 20

    Secondary: IgG-index

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    End point title
    		 IgG-index
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: index
        arithmetic mean (standard deviation)
    -0.03 ( 0.08 )
    -0.03 ( 0.12 )
    Statistical analysis title
    		 Generalized linear model
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.82
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.06

    Secondary: Albumin quotient

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    End point title
    		 Albumin quotient
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: index
        arithmetic mean (standard deviation)
    -0.8 ( 1.7 )
    0.1 ( 1.0 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.1

    Secondary: Fractional anisotropy in normal appearing white matter

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    End point title
    		 Fractional anisotropy in normal appearing white matter
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 48, week 96
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: FA
        arithmetic mean (standard deviation)
    0.000 ( 0.01 )
    -0.001 ( 0.014 )
    -0.003 ( 0.009 )
    0.002 ( 0.008 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.89
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.01

    Secondary: T2 lesion volume

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    End point title
    		 T2 lesion volume
    End point description
    End point type
    Secondary
    End point timeframe
    screening visit to week 48, week 48 to week 96
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    0.7 ( 1.1 )
    0.6 ( 1.4 )
    0.3 ( 0.2 )
    0.1 ( 0.6 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.64
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.8
    Variability estimate
    Standard deviation

    Secondary: Magnetization transfer ratio of lesions

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    End point title
    		 Magnetization transfer ratio of lesions
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 48, week 96
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: MTR
        arithmetic mean (standard deviation)
    0.2 ( 1.3 )
    0.4 ( 1.5 )
    0.1 ( 0.5 )
    0.7 ( 0.7 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.6

    Secondary: Expanded disability status scale, change

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    End point title
    		 Expanded disability status scale, change
    End point description
    End point type
    Secondary
    End point timeframe
    Screening visit, week 24, week 48, week 72, week 96
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: EDSS
        arithmetic mean (standard deviation)
    0.2 ( 0.7 )
    0.0 ( 1.0 )
    0.0 ( 0.43 )
    0.22 ( 0.60 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 2, placebo v Arm 1, DMF
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.7

    Secondary: Timed 25-foot walk

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    End point title
    		 Timed 25-foot walk
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, baseline, 24 weeks, 48 weeks, 96 weeks
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: second
        arithmetic mean (standard deviation)
    0.9 ( 2.7 )
    -0.1 ( 1.4 )
    -0.48 ( 3.44 )
    0.43 ( 1.35 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 2, placebo v Arm 1, DMF
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.12
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 2.1

    Secondary: 9-hole peg test

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    End point title
    		 9-hole peg test
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, baseline, 24 weeks, 48 weeks, 96 weeks.
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: second
    arithmetic mean (standard deviation)
        Dominant hand
    1.9 ( 9 )
    -1.4 ( 6 )
    2.1 ( 7.2 )
    1.0 ( 3.9 )
        Nondominant hand
    0 ( 28 )
    5 ( 24 )
    3.4 ( 4.2 )
    2.3 ( 4.5 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.26
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 1.8

    Secondary: Symbol digit modalities test

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    End point title
    		 Symbol digit modalities test
    End point description
    End point type
    Secondary
    End point timeframe
    screening, baseline, week 48, week 96.
    End point values
    		 Arm 1, DMF Arm 2, placebo Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    26
    24
    17
    16
    Units: numbers correct
        arithmetic mean (standard deviation)
    2.5 ( 6.1 )
    3.7 ( 5.3 )
    -1.2 ( 6.3 )
    -1.4 ( 7.3 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.45
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 1.9

    Secondary: Percentage brain volume change

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    End point title
    		 Percentage brain volume change
    End point description
    End point type
    Secondary
    End point timeframe
    Screening to week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: percent volume/volume
        arithmetic mean (standard deviation)
    -0.5 ( 0.8 )
    -0.2 ( 0.8 )
    Statistical analysis title
    		 Generalized linear model
    Statistical analysis description
    ANCOVA adjusted for baseline value.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.1
    Variability estimate
    Standard deviation

    Secondary: New or enlarging lesions

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    End point title
    		 New or enlarging lesions
    End point description
    End point type
    Secondary
    End point timeframe
    Screening to week 48
    End point values
    		 Arm 1, DMF Arm 2, placebo
    Number of subjects analysed
    26
    24
    Units: no.
    3
    3
    Statistical analysis title
    		 New or enlarging lesions
    Statistical analysis description
    negative binomial regression adjusted for number of T2-lesions at screening.
    Comparison groups
    Arm 1, DMF v Arm 2, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.49
    Method
    		 Negative binomial regression
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0

    Post-hoc: New lesions

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    End point title
    		 New lesions
    End point description
    No statistics performed
    End point type
    Post-hoc
    End point timeframe
    Week 48 - week 96
    End point values
    		 Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    17
    16
    Units: no.
    2
    3
    No statistical analyses for this end point

    Post-hoc: Enlarging lesions

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    End point title
    		 Enlarging lesions
    End point description
    No statistics performed
    End point type
    Post-hoc
    End point timeframe
    Week 48 - week 96
    End point values
    		 Arm 1, DMF/DMF Arm 2, UNT/DMF
    Number of subjects analysed
    17
    16
    Units: no.
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening to week 48 and Week 48 to week 96 (open label phase)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Treatment group - phase 1
    Reporting group description
    		 -

    Reporting group title
    Placebo group - phase 1
    Reporting group description
    		 -

    Reporting group title
    Open label phase
    Reporting group description
    		 From week 48 to week 96

    Serious adverse events
    		 Treatment group - phase 1 Placebo group - phase 1 Open label phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 27 (11.11%)
    5 / 42 (11.90%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Testicular seminoma (pure)
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder disorder
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Basal cell carcinoma
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment group - phase 1 Placebo group - phase 1 Open label phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 27 (77.78%)
    13 / 27 (48.15%)
    37 / 42 (88.10%)
    Vascular disorders
    Lymphedema
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    2
    0
    6
    Creatinine renal clearance abnormal
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    1
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Lymphocyte count decreased
         subjects affected / exposed
    13 / 27 (48.15%)
    1 / 27 (3.70%)
    14 / 42 (33.33%)
         occurrences all number
    13
    1
    14
    Reproductive system and breast disorders
    Epididymitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Spermatic cord hemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Uterine polyp
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    Ovarian cyst
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Lung cyst
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 27 (18.52%)
    4 / 27 (14.81%)
    5 / 42 (11.90%)
         occurrences all number
    5
    4
    5
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    Psychiatric disorders
    NIghtmares
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    1
    Depression
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    2
    0
    3
    Fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Ankle distortion
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Syncope
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    0 / 42 (0.00%)
         occurrences all number
    0
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Paresthesia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Vertigo positional
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 27 (3.70%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    1
    Dysaesthesia pharynx
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Epistaxis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Gastrointestinal pain
         subjects affected / exposed
    6 / 27 (22.22%)
    0 / 27 (0.00%)
    7 / 42 (16.67%)
         occurrences all number
    6
    0
    7
    Nausea
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 27 (11.11%)
    4 / 42 (9.52%)
         occurrences all number
    3
    3
    4
    Diarrhoea
         subjects affected / exposed
    4 / 27 (14.81%)
    5 / 27 (18.52%)
    6 / 42 (14.29%)
         occurrences all number
    4
    5
    6
    Vomiting
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    2
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    1
    0
    2
    Constipation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Gastric ulcer
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    1
    Anal haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Flushing
         subjects affected / exposed
    16 / 27 (59.26%)
    1 / 27 (3.70%)
    15 / 42 (35.71%)
         occurrences all number
    16
    1
    15
    Eczema
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    1
    Dry skin
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 27 (7.41%)
    5 / 42 (11.90%)
         occurrences all number
    3
    2
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    3
    Arthralgia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    2 / 42 (4.76%)
         occurrences all number
    0
    1
    2
    Radicular pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Flu like symptoms
         subjects affected / exposed
    5 / 27 (18.52%)
    2 / 27 (7.41%)
    1 / 42 (2.38%)
         occurrences all number
    5
    2
    1
    Fever
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
    2 / 42 (4.76%)
         occurrences all number
    2
    1
    2
    Tooth infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    0
    2
    gum infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Borrelia infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2017
    Age criterion increased from 60 to 65 years of age.
    24 Sep 2018
    New principal investigator and extension of study phase
    18 Feb 2020
    Removal of secondary endpoint (LCVA) and changes in statistical analysis plan

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

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