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    Clinical Trial Results:
    An Open-Label Study to Assess the Effects of BG00012 on Lymphocyte Subsets in Subjects With Relapsing-Remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2015-001973-42
    Trial protocol
    		 BE   LT   PL   BG   HR  
    Global end of trial date
    23 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2019
    First version publication date
    09 May 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    109MS310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02525874
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of BG00012 on lymphocyte subset counts during the first year of treatment in subjects with relapsing-remitting multiple sclerosis (RRMS).
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Aug 2015
    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
    Bulgaria: 58
    Country: Number of subjects enrolled
    Lithuania: 13
    Country: Number of subjects enrolled
    Kuwait: 2
    Country: Number of subjects enrolled
    Poland: 72
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Belgium: 2
    Worldwide total number of subjects
    218
    EEA total number of subjects
    145
    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)
    217
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted from 11 August 2015 to 23 April 2018 in Belgium, Bulgaria, Lithuania, Kuwait, Poland and United States.

    Pre-assignment
    Screening details
    		 A total of 218 subjects were enrolled in the study of which 158 subjects completed the study

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dimethyl Fumarate (BG00012)
    Arm description
    		 Subjects received 120 mg BID orally for the first 7 days and 240 mg BID thereafter until 96 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dimethyl Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dimethyl Fumarate 120 mg BID for the first 7 days and 240 mg BID thereafter until 96 weeks.

    Number of subjects in period 1
    		Dimethyl Fumarate (BG00012)
    Started
    218
    Completed
    158
    Not completed
    60
         Adverse event, non-fatal
    17
         Other
    6
         Disease relapse
    4
         Non-compliance with study drug
    3
         Investigator Decision
    1
         Lost to follow-up
    5
         Consent withdrawn
    22
         Disease progression, defined by protocol
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dimethyl Fumarate (BG00012)
    Reporting group description
    		 Subjects received 120 mg BID orally for the first 7 days and 240 mg BID thereafter until 96 weeks.

    Reporting group values
    		 Dimethyl Fumarate (BG00012) Total
    Number of subjects
    		 218 218
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.1 ( 10.99 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 151 151
        Male
    		 67 67
    Race
    Units: Subjects
        Race: American Indian or Alaska Native|
    		 1 1
        Race: Black or African American|
    		 9 9
        Race: White|
    		 60 60
        Race: Not Reported|
    		 145 145
        Race: Other|
    		 3 3
    Ethnicity
    Units: Subjects
        Ethnicity: Hispanic or Latino
    		 6 6
        Ethnicity: Not Hispanic or Latino
    		 66 66
        Ethnicity: Not Reported
    		 145 145
        Ethnicity: Unknown
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Dimethyl Fumarate (BG00012)
    Reporting group description
    		 Subjects received 120 mg BID orally for the first 7 days and 240 mg BID thereafter until 96 weeks.

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T Cell, B Cell, Natural Killer Cell (TBNK)

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T Cell, B Cell, Natural Killer Cell (TBNK) [1]
    End point description
    Lymphocyte subsets include T cell, B cell and Natural killer (NK) cells. The Pharmacodynamic (PD) population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here, 'n' signifies number of subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: subset
    arithmetic mean (standard deviation)
        B Cells: Baseline (n= 216)
    235.9 ( 168.88 )
        B Cells: Change at Week 4 (n= 209)
    -18.8 ( 89.71 )
        B Cells: Change at Week 8 (n= 206)
    -48.2 ( 122.20 )
        B Cells: Change at Week 12 (n= 209)
    -65.9 ( 128.53 )
        B Cells: Change at Week 24 (n= 206)
    -76.5 ( 140.33 )
        B Cells: Change at Week 36 (n= 195)
    -70.1 ( 104.80 )
        B Cells: Change at Week 48 (n= 193)
    -60.7 ( 115.26 )
        NK Cells: Baseline (n= 216)
    184.2 ( 107.12 )
        NK Cells: Change at Week 4 (n= 209)
    6.1 ( 84.66 )
        NK Cells: Change at Week 8 (n= 206)
    -9.0 ( 89.55 )
        NK Cells: Change at Week 12 (n= 209)
    -21.7 ( 90.82 )
        NK Cells: Change at Week 24 (n= 206)
    -26.9 ( 88.06 )
        NK Cells: Change at Week 36 (n= 195)
    -41.5 ( 90.37 )
        NK Cells: Change at Week 48 (n= 193)
    -42.0 ( 104.88 )
        T Cells: Baseline (n= 216)
    1318.1 ( 544.00 )
        T Cells: Change at Week 4 (n= 209)
    -44.8 ( 383.55 )
        T Cells: Change at Week 8 (n= 206)
    -167.0 ( 482.86 )
        T Cells: Change at Week 12 (n= 209)
    -284.3 ( 527.58 )
        T Cells: Change at Week 24 (n= 206)
    -446.7 ( 542.06 )
        T Cells: Change at Week 36 (n= 195)
    -545.5 ( 550.87 )
        T Cells: Change at Week 48 (n= 193)
    -580.2 ( 551.52 )
        CD4+ T cells: Baseline (n= 216)
    879.0 ( 400.71 )
        CD4+ T cells: Change at Week 4 (n= 209)
    -27.4 ( 256.21 )
        CD4+ T cells: Change at Week 8 (n= 206)
    -95.4 ( 318.07 )
        CD4+ T cells: Change at Week 12 (n= 209)
    -176.8 ( 353.52 )
        CD4+ T cells: Change at Week 24 (n= 206)
    -269.8 ( 360.92 )
        CD4+ T cells: Change at Week 36 (n= 195)
    -329.7 ( 374.66 )
        CD4+ T cells: Change at Week 48 (n= 193)
    -352.6 ( 380.77 )
        CD8+ T cells: Baseline (n= 216)
    419.5 ( 203.76 )
        CD8+ T cells: Change at Week 4 (n= 209)
    -14.2 ( 147.21 )
        CD8+ T cells: Change at Week 8 (n= 206)
    -65.3 ( 181.65 )
        CD8+ T cells: Change at Week 12 (n= 209)
    -100.4 ( 193.28 )
        CD8+ T cells: Change at Week 24 (n= 206)
    -170.2 ( 201.14 )
        CD8+ T cells: Change at Week 36 (n= 195)
    -201.4 ( 203.10 )
        CD8+ T cells: Change at Week 48 (n= 193)
    -214.9 ( 203.62 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T-Cells Subsets

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T-Cells Subsets [2]
    End point description
    T-cells subsets includes Activated CD4+ T-cell [CD38+],ActivatedCD8+T-cell[CD38+HLADR+],Activated CD8+ T-cell,Activated CD8+ T-cell[CD38+],Activated Th(T helper)1 phenotype,Activated Th17 phenotype,Activated Th2-enriched phenotype,Activated CD4+ T-cell[CD38+HLA-DR+],Activated CD4+ T-cell[HLA-DR+],Activated CD8+ T-cell[HLA-DR+],Central Memory (CM) CD4+ T-cell[CD45RA-CCR7+],CM CD4+ T-cell[CD45RA-CCR7+],CM CD8+T-cell[CD45RA-CCR7+],Effector CD4+ T-cell[CD45RA+CCR7-],Effector CD8+ T-cell[CD45RA+CCR7-],Effector Memory (EM) CD4+ T-cell[CD45RA-CCR7-],EM CD8+ T-cell[CD45RA-CCR7-],Effector Regulatory T-cells,Effector CD4+ T-cell[CD45RA+CCR7-],Effector CD8+ T-cell[CD45RA+CCR7-],Naïve CD4+ T-cell[CD45RA+],Naïve CD8+ T-cell[CD45RA+],Naïve CD8+ T-cell [CD45RA+],Naïve Regulatory T-cells,Terminal Effector Regulatory T-cells,Th1 phenotype,Th17 phenotype,Th2-enriched phenotype.Change at week=CW. PD population. n=subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: subset
    arithmetic mean (standard deviation)
        Activated CD4+ T-cell: Baseline (n=140)
    632.6 ( 305.86 )
        Activated CD4+ T-cell: Change at Week 4 (n=136)
    15.2 ( 241.73 )
        Activated CD4+ T-cell: Change at Week 8 (n=133)
    -26.5 ( 241.47 )
        Activated CD4+ T-cell: Change at Week 12 (n=137)
    -53.4 ( 246.22 )
        Activated CD4+ T-cell: Change at Week 24 (n=137)
    -100.4 ( 263.58 )
        Activated CD4+ T-cell: Change at Week 36 (n=129)
    -106.8 ( 308.03 )
        Activated CD4+ T-cell: Change at Week 48 (n=128)
    -125.9 ( 273.26 )
        Activated CD8+T-cell(CD38+HLA-DR+):Baseline(n=216)
    22.9 ( 25.64 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 4 (n=208)
    3.9 ( 21.83 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 8 (n=206)
    -2.2 ( 24.46 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 12 (n=208)
    -3.4 ( 23.53 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 24 (n=206)
    -5.8 ( 24.72 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 36 (n=195)
    -7.9 ( 27.32 )
        ActivatedCD8+T-cell([CD38+HLA-DR+]):CW 48 (n=193)
    -7.7 ( 24.92 )
        Activated CD8+ T-cell [CD38+]: Baseline (n=140)
    275.4 ( 158.04 )
        Activated CD8+ T-cell [CD38+]: CW 4 (n=136)
    18.2 ( 118.67 )
        Activated CD8+ T-cell [CD38+]: CW 8 (n=133)
    -21.7 ( 126.38 )
        Activated CD8+ T-cell [CD38+]: CW 12 (n=137)
    -50.8 ( 132.08 )
        Activated CD8+ T-cell [CD38+]: CW 24 (n=137)
    -91.8 ( 142.99 )
        Activated CD8+ T-cell [CD38+]: CW 36 (n=129)
    -99.3 ( 162.79 )
        Activated CD8+ T-cell [CD38+]: CW 48 (n=128)
    -114.3 ( 152.39 )
        Activated Th1 phenotype: Baseline (n=216)
    10.4 ( 6.52 )
        Activated Th1 phenotype: CW 4 (n=208)
    0.6 ( 6.09 )
        Activated Th1 phenotype: CW 8 (n=206)
    -1.2 ( 6.87 )
        Activated Th1 phenotype: CW 12 (n=209)
    -2.1 ( 6.63 )
        Activated Th1 phenotype: CW 24 (n=206)
    -3.5 ( 6.47 )
        Activated Th1 phenotype: CW 36 (n=195)
    -3.8 ( 6.82 )
        Activated Th1 phenotype: CW 48 (n=193)
    -4.0 ( 6.50 )
        Activated Th17 phenotype: Baseline (n=216)
    1.1 ( 1.33 )
        Activated Th17 phenotype: CW 4 (n=208)
    0.0 ( 1.01 )
        Activated Th17 phenotype: CW 8 (n=206)
    -0.2 ( 1.50 )
        Activated Th17 phenotype: CW 12 (n=209)
    0.0 ( 1.36 )
        Activated Th17 phenotype: CW 24 (n=206)
    -0.4 ( 1.33 )
        Activated Th17 phenotype: CW 36 (n=195)
    -0.4 ( 0.96 )
        Activated Th17 phenotype: CW 48 (n=193)
    -0.3 ( 1.06 )
        Activated Th2-enriched phenotype: Baseline (n=216)
    4.8 ( 4.83 )
        Activated Th2-enriched phenotype: CW 4 (n=208)
    1.2 ( 5.36 )
        Activated Th2-enriched phenotype: CW 8 (n=206)
    0.4 ( 6.13 )
        Activated Th2-enriched phenotype: CW 12 (n=209)
    0.5 ( 6.54 )
        Activated Th2-enriched phenotype: CW 24 (n=206)
    0.6 ( 6.84 )
        Activated Th2-enriched phenotype: CW 36 (n=195)
    0.3 ( 6.57 )
        Activated Th2-enriched phenotype: CW 48 (n=193)
    0.2 ( 5.14 )
        ActivatedCD4+T-cell [CD38+HLA-DR+]:Baseline(n=216)
    17.3 ( 12.77 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 4 (n=208)
    2.5 ( 11.63 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 8 (n=206)
    -0.3 ( 12.81 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 12 (n=209)
    -1.6 ( 12.10 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 24 (n=206)
    -3.2 ( 13.54 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 36 (n=195)
    -4.1 ( 12.07 )
        ActivatedCD4+T-cell[CD38+HLA-DR+]:CW 48 (n=193)
    -4.2 ( 11.62 )
        ActivatedCD4+T-cell [HLA-DR+]: Baseline(n=140)
    64.6 ( 32.45 )
        Activated CD4+T-cell [HLA-DR+]: CW 4 (n=136)
    1.4 ( 27.95 )
        Activated CD4+T-cell [HLA-DR+]: CW 8 (n=133)
    -5.1 ( 38.57 )
        Activated CD4+T-cell [HLA-DR+]: CW 12 (n=137)
    -11.7 ( 31.71 )
        Activated CD4+T-cell [HLA-DR+]: CW 24 (n=137)
    -26.0 ( 30.09 )
        Activated CD4+T-cell [HLA-DR+]: CW 36 (n=129)
    -33.6 ( 36.39 )
        Activated CD4+T-cell [HLA-DR+]: CW 48 (n=128)
    -30.1 ( 38.57 )
        Activated CD8+T-cell [HLA-DR+]: Baseline (n=140)
    81.2 ( 63.34 )
        Activated CD8+T-cell [HLA-DR+]: CW 4 (n=136)
    2.5 ( 46.91 )
        Activated CD8+T-cell [HLA-DR+]: CW 8 (n=133)
    -5.5 ( 67.56 )
        Activated CD8+T-cell [HLA-DR+]: CW 12 (n=137)
    -18.2 ( 59.58 )
        Activated CD8+T-cell [HLA-DR+]: CW 24 (n=137)
    -38.1 ( 57.42 )
        Activated CD8+T-cell [HLA-DR+]: CW 36 (n=129)
    -48.3 ( 63.85 )
        Activated CD8+T-cell [HLA-DR+]: CW 48 (n=128)
    -49.3 ( 59.85 )
        CM CD4+T-cell [CD45RA-CCR7+]:Baseline (n=216)
    433.4 ( 220.05 )
        CM CD4+ T-cell[CD45RA-CCR7+]:CW4(n=208)
    -21.0 ( 185.07 )
        CM CD4+ T-cell[CD45RA-CCR7+]:CW 8 (n=206)
    -68.0 ( 196.02 )
        CM CD4+T-cell[CD45RA-CCR7+]:CW 12 (n=210)
    -105.3 ( 206.11 )
        CM CD4+T-cell[CD45RA-CCR7+]:CW 24 (n=206)
    -204.2 ( 220.61 )
        CM CD4+T-cell[CD45RA-CCR7+]:CW 36 (n=195)
    -235.7 ( 221.44 )
        CM CD4+T-cell[CD45RA-CCR7+]:CW 48 (n=193)
    -231.1 ( 225.25 )
        CM CD8+T-cell [CD45RA-CCR7+]: Baseline (n=216)
    59.9 ( 60.38 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 4 (n=208)
    -9.6 ( 45.92 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 8 (n=206)
    -16.9 ( 41.72 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 12 (n=209)
    -22.0 ( 48.10 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 24 (n=206)
    -39.2 ( 50.00 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 36 (n=195)
    -44.3 ( 55.66 )
        CM CD8+T-cell [CD45RA-CCR7+]:CW 48 (n=193)
    -45.9 ( 53.78 )
        Effector CD4+T-cell [CD45RA+CCR7-]:Baseline(n=216)
    12.0 ( 23.21 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 4 (n=208)
    0.8 ( 12.66 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 8 (n=206)
    -0.1 ( 12.58 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 12 (n=210)
    -1.0 ( 12.43 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 24 (n=206)
    -1.6 ( 17.42 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 36 (n=195)
    -1.9 ( 19.20 )
        Effector CD4+ T-cell [CD45RA+CCR7-]:CW 48 (n=193)
    -4.7 ( 18.75 )
        Effector CD8+T-cell [CD45RA+CCR7-]:Baseline(n=216)
    101.4 ( 91.95 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 4 (n=208)
    1.7 ( 63.49 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 8 (n=206)
    -15.9 ( 67.93 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 12 (n=209)
    -15.2 ( 80.78 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 24 (n=206)
    -42.8 ( 74.14 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 36 (n=195)
    -55.6 ( 78.88 )
        Effector CD8+ T-cell [CD45RA+CCR7-]:CW 48 (n=193)
    -50.9 ( 82.46 )
        EM CD4+T-cell [CD45RA-CCR7-]: Baseline(n=216)
    179.7 ( 86.21 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 4 (n=208)
    10.9 ( 87.56 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 8 (n=206)
    -33.2 ( 88.53 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 12 (n=210)
    -55.2 ( 90.59 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 24 (n=206)
    -81.7 ( 106.78 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 36 (n=195)
    -98.1 ( 111.77 )
        EM CD4+ T-cell [CD45RA-CCR7-]: CW 48 (n=193)
    -118.5 ( 100.25 )
        EM CD8+ T-cell [CD45RA-CCR7-]: Baseline (n=216)
    129.0 ( 92.24 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 4 (n=208)
    7.6 ( 82.42 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 8 (n=206)
    -22.8 ( 88.05 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 12 (n=209)
    -41.0 ( 85.82 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 24 (n=206)
    -69.9 ( 90.17 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 36 (n=195)
    -80.3 ( 96.19 )
        EM CD8+ T-cell [CD45RA-CCR7-]: CW 48 (n=193)
    -90.3 ( 97.07 )
        Effector Regulatory T-cells: Baseline (n=216)
    56.1 ( 28.88 )
        Effector Regulatory T-cells: CW 4 (n=208)
    0.6 ( 26.13 )
        Effector Regulatory T-cells: CW 8 (n=206)
    -7.1 ( 27.32 )
        Effector Regulatory T-cells: CW 12 (n=210)
    -12.7 ( 25.81 )
        Effector Regulatory T-cells: CW 24 (n=206)
    -20.3 ( 28.31 )
        Effector Regulatory T-cells: CW 36 (n=195)
    -25.8 ( 31.50 )
        Effector Regulatory T-cells: CW 48 (n=193)
    -25.1 ( 29.73 )
        Memory CD4+ T-cell [CD45RA-]: Baseline (n=216)
    617.7 ( 256.07 )
        Memory CD4+ T-cell [CD45RA-]: CW 4 (n=208)
    -6.2 ( 233.54 )
        Memory CD4+ T-cell [CD45RA-]: CW 8 (n=206)
    -100.9 ( 252.99 )
        Memory CD4+ T-cell [CD45RA-]: CW 12 (n=210)
    -157.7 ( 269.36 )
        Memory CD4+ T-cell [CD45RA-]: CW 24 (n=206)
    -287.7 ( 291.97 )
        Memory CD4+ T-cell [CD45RA-]: CW 36 (n=195)
    -335.0 ( 299.23 )
        Memory CD4+ T-cell [CD45RA-]: CW 48 (n=193)
    -349.9 ( 289.24 )
        Memory CD8+ T-cell [CD45RA-]: Baseline (n=216)
    187.5 ( 126.58 )
        Memory CD8+ T-cell [CD45RA-]: CW 4 (n=208)
    -4.7 ( 97.59 )
        Memory CD8+ T-cell [CD45RA-]: CW 8 (n=206)
    -40.9 ( 109.49 )
        Memory CD8+ T-cell [CD45RA-]: CW 12 (n=209)
    -64.0 ( 118.89 )
        Memory CD8+ T-cell [CD45RA-]: CW 24 (n=206)
    -108.6 ( 119.94 )
        Memory CD8+ T-cell [CD45RA-]: CW 36 (n=195)
    -124.9 ( 126.30 )
        Memory CD8+ T-cell [CD45RA-]: CW 48 (n=193)
    -136.3 ( 129.68 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:Baseline (n=216)
    400.9 ( 261.16 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 4 (n=208)
    -10.5 ( 175.86 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 8 (n=206)
    -16.4 ( 169.60 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 12 (n=210)
    -11.8 ( 177.35 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 24 (n=206)
    -31.7 ( 190.17 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 36 (n=195)
    -29.3 ( 204.15 )
        Naïve CD4+ T-cell [CD45RA+CCR7+]:CW 48 (n=193)
    -34.4 ( 197.57 )
        Naïve CD4+ T-cell [CD45RA+]: Baseline (n=216)
    416.7 ( 268.35 )
        Naïve CD4+ T-cell [CD45RA+]:CW 4 (n=208)
    -8.6 ( 177.59 )
        Naïve CD4+ T-cell [CD45RA+]:CW 8 (n=206)
    -15.6 ( 173.25 )
        Naïve CD4+ T-cell [CD45RA+]:CW 12 (n=210)
    -10.2 ( 185.67 )
        Naïve CD4+ T-cell [CD45RA+]:CW 24 (n=206)
    -33.6 ( 193.78 )
        Naïve CD4+ T-cell [CD45RA+]:CW 36 (n=195)
    -30.2 ( 214.46 )
        Naïve CD4+ T-cell [CD45RA+]:CW 48 (n=193)
    -37.0 ( 206.10 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:Baseline (n=216)
    160.1 ( 108.32 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 4 (n=208)
    -11.6 ( 79.05 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 8 (n=206)
    -12.4 ( 75.66 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 12 (n=209)
    -22.0 ( 73.23 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 24 (n=206)
    -41.3 ( 77.22 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 36 (n=195)
    -49.0 ( 88.78 )
        Naïve CD8+ T-cell [CD45RA+CCR7+]:CW 48 (n=193)
    -50.9 ( 80.43 )
        Naïve CD8+ T-cell [CD45RA+]: Baseline (n=216)
    258.0 ( 150.73 )
        Naïve CD8+ T-cell [CD45RA+]: CW 4 (n=208)
    -11.7 ( 118.68 )
        Naïve CD8+ T-cell [CD45RA+]: CW 8 (n=206)
    -28.3 ( 118.33 )
        Naïve CD8+ T-cell [CD45RA+]: CW 12 (n=209)
    -39.7 ( 131.27 )
        Naïve CD8+ T-cell [CD45RA+]: CW 24 (n=206)
    -82.4 ( 134.00 )
        Naïve CD8+ T-cell [CD45RA+]: CW 36 (n=195)
    -106.1 ( 139.47 )
        Naïve CD8+ T-cell [CD45RA+]: CW 48 (n=193)
    -103.4 ( 138.84 )
        Naïve Regulatory T-cells: Baseline (n=216)
    15.8 ( 13.44 )
        Naïve Regulatory T-cells: CW 4 (n=208)
    -0.1 ( 11.90 )
        Naïve Regulatory T-cells: CW 8 (n=206)
    -0.4 ( 12.19 )
        Naïve Regulatory T-cells: CW 12 (n=210)
    -0.7 ( 9.84 )
        Naïve Regulatory T-cells: CW 24 (n=206)
    -0.4 ( 11.87 )
        Naïve Regulatory T-cells: CW 36 (n=195)
    0.1 ( 12.07 )
        Naïve Regulatory T-cells: CW 48 (n=193)
    -0.1 ( 10.25 )
        Regulatory T-cells: Baseline (n=216)
    71.5 ( 36.60 )
        Regulatory T-cells: CW 4 (n=208)
    1.0 ( 34.31 )
        Regulatory T-cells: CW 8 (n=206)
    -7.3 ( 35.01 )
        Regulatory T-cells: CW 12 (n=210)
    -13.3 ( 32.12 )
        Regulatory T-cells: CW 24 (n=206)
    -20.0 ( 36.77 )
        Regulatory T-cells: CW 36 (n=195)
    -25.7 ( 40.18 )
        Regulatory T-cells: CW 48 (n=193)
    -24.4 ( 36.09 )
        Terminal EffectorRegulatoryT-cells:Baseline(n=140)
    327.2 ( 168.48 )
        Terminal Effector Regulatory T-cells:CW 4(n=136)
    16.6 ( 158.45 )
        Terminal Effector Regulatory T-cells:CW 8(n=133)
    -4.4 ( 167.36 )
        Terminal Effector Regulatory T-cells:CW 12(n=137)
    -17.6 ( 167.80 )
        Terminal Effector Regulatory T-cells:CW 24(n=137)
    -58.3 ( 174.97 )
        Terminal Effector Regulatory T-cells:CW 36(n=129)
    -97.2 ( 199.08 )
        Terminal Effector Regulatory T-cells:CW 48(n=128)
    -98.6 ( 186.01 )
        Th1 phenotype: Baseline (n=216)
    329.5 ( 153.17 )
        Th1 phenotype: CW 4 (n=208)
    -14.7 ( 127.21 )
        Th1 phenotype: CW 8 (n=206)
    -65.4 ( 147.25 )
        Th1 phenotype: CW 12 (n=209)
    -102.1 ( 149.63 )
        Th1 phenotype: CW 24 (n=206)
    -159.2 ( 172.24 )
        Th1 phenotype: CW 36 (n=195)
    -183.0 ( 177.40 )
        Th1 phenotype: CW 48 (n=193)
    -187.4 ( 172.19 )
        Th17 phenotype: Baseline (n=216)
    61.9 ( 40.76 )
        Th17 phenotype: CW 4 (n=208)
    -0.5 ( 37.46 )
        Th17 phenotype: CW 8 (n=206)
    -7.3 ( 39.10 )
        Th17 phenotype: CW 12 (n=209)
    -1.1 ( 45.74 )
        Th17 phenotype: CW 24 (n=206)
    -24.6 ( 42.79 )
        Th17 phenotype: CW 36 (n=195)
    -35.1 ( 39.56 )
        Th17 phenotype: CW 48 (n=193)
    -30.1 ( 39.12 )
        Th2-enriched phenotype: Baseline (n=216)
    562.7 ( 289.42 )
        Th2-enriched phenotype: CW 4 (n=208)
    -0.6 ( 211.18 )
        Th2-enriched phenotype: CW 8 (n=206)
    -31.5 ( 227.69 )
        Th2-enriched phenotype: CW 12 (n=209)
    -54.0 ( 210.95 )
        Th2-enriched phenotype: CW 24 (n=206)
    -96.7 ( 241.83 )
        Th2-enriched phenotype: CW 36 (n=195)
    -97.7 ( 267.45 )
        Th2-enriched phenotype: CW 48 (n=193)
    -125.2 ( 242.46 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: B-Cell Subsets

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: B-Cell Subsets [3]
    End point description
    B-cell subsets include CD10+ Transitional B cells, CD138+ Plasma Cells, Ig (Immunoglobulin) D+ Memory B cells [non-class switched], IgD- Memory B cells [class switched], Naïve B cells, Plasma Cells [CD10-], Transitional B-cells and Plasmablasts. Here, Change at week is represented as CW. The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here 'n' signifies number of subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: subset
    arithmetic mean (standard deviation)
        CD10+ Transitional B cells: Baseline (n= 216)
    9.4 ( 9.93 )
        CD10+ Transitional B cells: CW 4 (n= 195)
    -1.2 ( 7.98 )
        CD10+ Transitional B cells: CW 8 (n= 200)
    -0.4 ( 8.73 )
        CD10+ Transitional B cells: CW 12 (n= 210)
    -0.4 ( 9.09 )
        CD10+ Transitional B cells: CW 24 (n= 205)
    3.6 ( 10.16 )
        CD10+ Transitional B cells: CW 36 (n= 195)
    2.8 ( 9.53 )
        CD10+ Transitional B cells:CW 48 (n= 193)
    5.7 ( 13.53 )
        CD138+ Plasma Cells: Baseline (n= 216)
    0.26 ( 0.289 )
        CD138+ Plasma Cells: CW 4 (n= 195)
    -0.02 ( 0.367 )
        CD138+ Plasma Cells: CW 8 (n= 200)
    -0.12 ( 0.291 )
        CD138+ Plasma Cells: CW 12 (n= 210)
    -0.15 ( 0.288 )
        CD138+ Plasma Cells: CW 24 (n= 205)
    -0.21 ( 0.297 )
        CD138+ Plasma Cells: CW 36 (n= 195)
    -0.21 ( 0.327 )
        CD138+ Plasma Cells: CW 48 (n= 193)
    -0.19 ( 0.318 )
        IgD+ MemoryB [non-class switched]:Baseline(n=216)
    37.8 ( 36.96 )
        IgD+ Memory B [non-class switched]:CW 4(n=195)
    -8.9 ( 26.18 )
        IgD+ Memory B [non-class switched]:CW 8(n=200)
    -12.4 ( 29.27 )
        IgD+ Memory B [non-class switched]:CW 12(n=210)
    -12.1 ( 29.13 )
        IgD+ Memory B [non-class switched]:CW 24(n=205)
    -17.6 ( 31.39 )
        IgD+ Memory B [non-class switched]:CW 36(n=195)
    -19.6 ( 31.61 )
        IgD+ Memory B [non-class switched]:CW 48(n=193)
    -13.4 ( 34.89 )
        IgD- Memory B [class switched]: Baseline(n=216)
    50.4 ( 56.97 )
        IgD- Memory B [class switched]:CW 4 (n=195)
    -8.7 ( 32.20 )
        IgD- Memory B [class switched]:CW 8 (n=200)
    -17.7 ( 44.42 )
        IgD- Memory B [class switched]:CW 12 (n=210)
    -23.1 ( 44.76 )
        IgD- Memory B [class switched]:CW 24 (n= 205)
    -29.5 ( 49.95 )
        IgD- Memory B [class switched]:CW 36 (n= 195)
    49.95 ( 32.64 )
        IgD- Memory B [class switched]:CW 48 (n=193)
    -27.4 ( 38.33 )
        Naïve B cells: Baseline (n= 216)
    197.2 ( 140.48 )
        Naïve B cells: CW 4 (n= 195)
    -21.5 ( 82.43 )
        Naïve B cells: CW 8 (n= 200)
    -37.2 ( 95.32 )
        Naïve B cells: CW 12 (n= 210)
    -43.1 ( 99.72 )
        Naïve B cells: CW 24 (n= 205)
    -45.7 ( 114.46 )
        Naïve B cells: CW 36 (n= 195)
    -54.0 ( 94.94 )
        Naïve B cells: CW 48 (n= 193)
    -35.6 ( 107.79 )
        Plasma Cells [CD10-]:Baseline (n= 216)
    0.63 ( 0.668 )
        Plasma Cells [CD10-]: CW 4 (n= 195)
    -0.02 ( 0.816 )
        Plasma Cells [CD10-]: CW 8 (n= 200)
    -0.11 ( 0.643 )
        Plasma Cells [CD10-]:CW 12 (n= 210)
    -0.18 ( 0.647 )
        Plasma Cells [CD10-]:CW 24 (n= 205)
    -0.34 ( 0.649 )
        Plasma Cells [CD10-]: CW 36 (n= 195)
    -0.33 ( 0.786 )
        Plasma Cells [CD10-]:CW 48 (n= 193)
    -0.38 ( 0.633 )
        Transitional B-cells: Baseline (n= 216)
    13.6 ( 13.61 )
        Transitional B-cells: CW 4 (n= 195)
    -1.3 ( 11.44 )
        Transitional B-cells: CW 8 (n= 200)
    0.6 ( 12.97 )
        Transitional B-cells: CW 12 (n= 210)
    0.7 ( 13.41 )
        Transitional B-cells: CW 24 (n= 205)
    5.8 ( 15.60 )
        Transitional B-cells: CW 36 (n= 195)
    4.2 ( 13.20 )
        Transitional B-cells: CW 48 (n= 193)
    7.3 ( 18.56 )
        Plasmablasts: Baseline (n= 216)
    0.91 ( 1.104 )
        Plasmablasts: CW 4 (n= 195)
    -0.04 ( 1.120 )
        Plasmablasts: CW 8 (n= 200)
    -0.21 ( 1.062 )
        Plasmablasts: CW 12 (n= 210)
    -0.31 ( 1.024 )
        Plasmablasts: CW 24 (n= 205)
    -0.46 ( 1.106 )
        Plasmablasts: CW 36 (n= 195)
    -0.46 ( 1.228 )
        Plasmablasts: CW 48 (n= 193)
    -0.50 ( 1.084 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: Myeloid and Natural Killer (NK) Cells

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: Myeloid and Natural Killer (NK) Cells [4]
    End point description
    Myeloid and natural killer cell subsets include CD56Bright NK cells, CD56Dim NK cells, Classical Monocytes, Myeloid dendritic cells, Non-classical Monocytes, Plasmacytoid dendritic cells, Total dendritic cells and Total monocytes [CD14+]. The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here, 'n' signifies number of subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: cells/mm^3
    arithmetic mean (standard deviation)
        CD56Bright NK cells: Baseline (n= 216)
    14.0 ( 8.94 )
        CD56Bright NK cells: CW 4 (n= 209)
    1.8 ( 6.40 )
        CD56Bright NK cells: CW 8 (n= 206)
    1.8 ( 7.07 )
        CD56Bright NK cells: CW 12 (n= 210)
    1.3 ( 7.26 )
        CD56Bright NK cells: CW 24 (n= 206)
    2.1 ( 8.57 )
        CD56Bright NK cells: CW 36 (n= 195)
    2.3 ( 9.73 )
        CD56Bright NK cells: CW 48 (n= 193)
    2.1 ( 8.55 )
        CD56Dim NK cells: Baseline (n= 216)
    192.9 ( 130.45 )
        CD56Dim NK cells: CW 4 (n= 209)
    -2.0 ( 102.59 )
        CD56Dim NK cells: CW 8 (n= 206)
    -17.2 ( 102.92 )
        CD56Dim NK cells: CW 12 (n= 210)
    -31.4 ( 92.14 )
        CD56Dim NK cells: CW 24 (n= 206)
    -50.7 ( 101.34 )
        CD56Dim NK cells: CW 36 (n= 195)
    -61.1 ( 102.96 )
        CD56Dim NK cells: CW 48 (n= 193)
    -68.5 ( 129.83 )
        Classical Monocytes: Baseline (n= 216)
    301.4 ( 153.48 )
        Classical Monocytes: CW 4 (n= 209)
    7.5 ( 182.11 )
        Classical Monocytes: CW 8 (n= 206)
    6.0 ( 165.07 )
        Classical Monocytes: CW 12 (n= 210)
    9.3 ( 197.84 )
        Classical Monocytes: CW 24 (n= 206)
    -8.7 ( 151.23 )
        Classical Monocytes: CW 36 (n= 195)
    -1.5 ( 163.62 )
        Classical Monocytes: CW 48 (n= 193)
    -0.8 ( 153.24 )
        Myeloid dendritic cells: Baseline (n= 216)
    24.96 ( 16.315 )
        Myeloid dendritic cells: CW 4 (n= 209)
    1.46 ( 18.111 )
        Myeloid dendritic cells: CW 8 (n= 206)
    -0.61 ( 17.670 )
        Myeloid dendritic cells: CW 12 (n= 210)
    -0.23 ( 17.932 )
        Myeloid dendritic cells: CW 24 (n= 206)
    3.02 ( 17.882 )
        Myeloid dendritic cells: CW 36 (n= 195)
    3.63 ( 18.779 )
        Myeloid dendritic cells: CW 48 (n= 193)
    -6.20 ( 17.780 )
        Non-classical Monocytes: Baseline (n= 216)
    32.0 ( 22.88 )
        Non-classical Monocytes: CW 4 (n= 209)
    2.2 ( 29.82 )
        Non-classical Monocytes: CW 8 (n= 206)
    -1.9 ( 30.14 )
        Non-classical Monocytes: CW 12 (n= 210)
    -10.8 ( 23.82 )
        Non-classical Monocytes: CW 24 (n= 206)
    -6.9 ( 27.65 )
        Non-classical Monocytes: CW 36 (n= 195)
    -10.6 ( 24.24 )
        Non-classical Monocytes: CW 48 (n= 193)
    -9.2 ( 24.37 )
        Plasmacytoid dendritic cells: Baseline (n= 216)
    6.52 ( 4.617 )
        Plasmacytoid dendritic cells: CW 4 (n= 209)
    0.00 ( 5.168 )
        Plasmacytoid dendritic cells: CW 8 (n= 206)
    0.30 ( 6.427 )
        Plasmacytoid dendritic cells: CW 12 (n= 210)
    -0.86 ( 4.575 )
        Plasmacytoid dendritic cells: CW 24 (n= 206)
    -0.69 ( 4.138 )
        Plasmacytoid dendritic cells: CW 36 (n= 195)
    -0.80 ( 4.086 )
        Plasmacytoid dendritic cells: CW 48 (n= 193)
    -2.22 ( 4.509 )
        Total dendritic cells: Baseline (n= 216)
    35.4 ( 19.92 )
        Total dendritic cells: CW 4 (n= 210)
    2.0 ( 22.35 )
        Total dendritic cells: CW 8 (n= 206)
    -1.3 ( 21.68 )
        Total dendritic cells: CW 12 (n= 210)
    -1.9 ( 21.07 )
        Total dendritic cells: CW 24 (n=206)
    1.6 ( 21.89 )
        Total dendritic cells: CW 36 (n= 195)
    2.5 ( 22.19 )
        Total dendritic cells: CW 48 (n= 193)
    -9.1 ( 22.77 )
        Total monocytes [CD14+]: Baseline (n= 216)
    374.6 ( 179.05 )
        Total monocytes [CD14+]: CW 4 (n= 209)
    26.9 ( 201.63 )
        Total monocytes [CD14+]: CW 8 (n= 206)
    12.6 ( 189.91 )
        Total monocytes [CD14+]: CW 12 (n= 210)
    14.4 ( 211.67 )
        Total monocytes [CD14+]: CW 24 (n= 206)
    -19.3 ( 174.82 )
        Total monocytes [CD14+]: CW 36 (n= 195)
    -21.7 ( 186.41 )
        Total monocytes [CD14+]: CW 48 (n= 193)
    -19.2 ( 175.10 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T-Cell Cytokines

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: T-Cell Cytokines [5]
    End point description
    T-cell cytokine subsets include IFN (interferon) g+ (% of CD4+ T cells), IFNg+ (% of CD8+ T cells), IFNg+ (% of memory CD4+ T cells), IFNg+ (% of memory CD8+ T cells), IL- (interleukin) 17A+/IFNg- (% of CD4+ T cells), IL-17A+/IFNg- (% of CD8+ T cells), IL-17A+/IFNg- (% of memory CD4+ T cells), IL-17A+/IFNg- (% of memory CD8+ T cells), IL-2+ (% of CD4+ T cells), IL-2+ (% of CD8+ T cells), IL-2+ (% of memory CD4+ T cells), IL-2+ (% of memory CD8+ T cells), IL-4+ (% of CD4+ T cells), IL-4+ (% of CD8+ T cells), IL-4+ (% of memory CD4+ T cells) and IL-4+ (% of memory CD8+ T cells). Here, Change at week is represented as CW. The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here, 'n' signifies number of subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: subset
    arithmetic mean (standard deviation)
        IFNg+ (% of CD4+ T cells): Baseline (n=210)
    3.340 ( 2.7365 )
        IFNg+ (% of CD4+ T cells):CW 4(n=193)
    0.090 ( 2.2350 )
        IFNg+ (% of CD4+ T cells):CW 8(n=187)
    -0.356 ( 1.9676 )
        IFNg+ (% of CD4+ T cells):CW 12(n=195)
    -0.729 ( 2.1570 )
        IFNg+ (% of CD4+ T cells):CW 24(n=193)
    -1.134 ( 2.4239 )
        IFNg+ (% of CD4+ T cells):CW 36(n=180)
    -1.511 ( 2.5109 )
        IFNg+ (% of CD4+ T cells):CW 48(n=182)
    -1.222 ( 2.3513 )
        IFNg+ (% of CD8+ T cells):Baseline(n=125)
    6.166 ( 4.6199 )
        IFNg+ (% of CD8+ T cells):CW 4(n=118)
    0.493 ( 2.8636 )
        IFNg+ (% of CD8+ T cells):CW 8(n=113)
    -0.264 ( 3.0735 )
        IFNg+ (% of CD8+ T cells):CW 12(n=117)
    -1.345 ( 3.3647 )
        IFNg+ (% of CD8+ T cells):CW 24(n=118)
    -1.650 ( 2.7202 )
        IFNg+ (% of CD8+ T cells):CW 36(n=109)
    -1.922 ( 4.1425 )
        IFNg+ (% of CD8+ T cells):CW 48(n=111)
    -1.306 ( 4.3931 )
        IFNg+ (% of memory CD4+ T cells):Baseline(n=210)
    4.518 ( 3.0417 )
        IFNg+ (% of memory CD4+ T cells):CW 4(n=193)
    0.050 ( 2.5996 )
        IFNg+ (% of memory CD4+ T cells):CW 8(n=187)
    -0.295 ( 2.6287 )
        IFNg+ (% of memory CD4+ T cells):CW 12(n=195)
    -0.851 ( 2.8590 )
        IFNg+ (% of memory CD4+ T cells):CW 24(n=193)
    -1.019 ( 2.8120 )
        IFNg+ (% of memory CD4+ T cells):CW 36(n=180)
    -1.804 ( 2.6448 )
        IFNg+ (% of memory CD4+ T cells):CW 48(n=182)
    -1.369 ( 3.0958 )
        IFNg+ (% of memory CD8+ T cells):Baseline(n=125)
    8.795 ( 5.9060 )
        IFNg+ (% of memory CD8+ T cells):CW 4(n=118)
    0.360 ( 3.6006 )
        IFNg+ (% of memory CD8+ T cells):CW 8(n=113)
    -0.285 ( 4.2645 )
        IFNg+ (% of memory CD8+ T cells):CW 12(n=117)
    -1.543 ( 3.7393 )
        IFNg+ (% of memory CD8+ T cells):CW 24(n=118)
    -0.964 ( 3.6799 )
        IFNg+ (% of memory CD8+ T cells):CW 36(n=109)
    -2.035 ( 5.3349 )
        IFNg+ (% of memory CD8+ T cells):CW 48(n=111)
    -0.497 ( 5.3126 )
        IL-17A+/IFNg- (% of CD4+ T cells)Baseline(n=210)
    1.244 ( 1.5863 )
        IL-17A+/IFNg- (% of CD4+ T cells):CW 4(n=193)
    0.115 ( 1.9918 )
        IL-17A+/IFNg- (% of CD4+ T cells):CW 8(n=187)
    0.131 ( 1.9097 )
        IL-17A+/IFNg- (% of CD4+ T cells)CW 12(n=195)
    0.470 ( 2.3445 )
        IL-17A+/IFNg- (% of CD4+ T cells)CW 24(n=193)
    0.165 ( 2.0104 )
        IL-17A+/IFNg- (% of CD4+ T cells)CW 36(n=180)
    0.419 ( 2.5007 )
        IL-17A+/IFNg- (% of CD4+ T cells)CW 48(n=182)
    1.693 ( 4.2412 )
        IL-17A+/IFNg- (% of CD8+ T cells)Baseline(n=125)
    0.455 ( 0.5309 )
        IL-17A+/IFNg- (% of CD8+ T cells):CW 4 (n=118)
    0.239 ( 1.3557 )
        IL-17A+/IFNg- (% of CD8+ T cells):CW 8 (n=113)
    0.032 ( 0.6448 )
        IL-17A+/IFNg- (% of CD8+ T cells)CW 12 (n=117)
    0.301 ( 0.8912 )
        IL-17A+/IFNg- (% of CD8+ T cells)CW 24(n=118)
    0.289 ( 0.8526 )
        IL-17A+/IFNg- (% of CD8+ T cells)CW 36(n=109)
    0.911 ( 1.3499 )
        IL-17A+/IFNg- (% of CD8+ T cells)CW 48(n=111)
    1.457 ( 2.1499 )
        IL-17A+/IFNg-(%of memoryCD4+Tcells)Baseline(n=210)
    1.075 ( 1.1770 )
        IL-17A+/IFNg-(% of memory CD4+T cells):CW4(n=193)
    0.000 ( 1.3599 )
        IL-17A+/IFNg-(% of memory CD4+T cells):CW8(n=187)
    0.040 ( 1.3593 )
        IL-17A+/IFNg-(% of memory CD4+T cells)CW12(n=195)
    0.373 ( 1.7166 )
        IL-17A+/IFNg-(% of memory CD4+T cells)CW24(n=193)
    0.228 ( 1.4980 )
        IL-17A+/IFNg-(% of memory CD4+T cells)CW36(n=180)
    0.333 ( 1.8786 )
        IL-17A+/IFNg-(% of memory CD4+T cells)CW48(n=182)
    1.255 ( 2.9557 )
        IL-17A+/IFNg-(%of memoryCD8+Tcells)Baseline(n=125)
    0.155 ( 0.2356 )
        IL-17A+/IFNg-(% of memory CD8+T cells):CW4(n=118)
    0.113 ( 0.6972 )
        IL-17A+/IFNg-(% of memory CD8+T cells):CW8(n=113)
    0.027 ( 0.3641 )
        IL-17A+/IFNg-(% of memory CD8+T cells)CW 12(n=117)
    0.064 ( 0.3641 )
        IL-17A+/IFNg-(% of memory CD8+T cells)CW 24(n=118)
    0.254 ( 0.8682 )
        IL-17A+/IFNg-(% of memory CD8+T cells)CW 36(n=109)
    0.270 ( 0.6113 )
        IL-17A+/IFNg-(% of memory CD8+T cells)CW 48(n=111)
    0.680 ( 1.2842 )
        IL-2+ (% of CD4+ T cells):Baseline (n=210)
    5.177 ( 4.5225 )
        IL-2+ (% of CD4+ T cells): CW 4 (n=193)
    0.062 ( 3.4662 )
        IL-2+ (% of CD4+ T cells): CW 8 (n=187)
    0.149 ( 4.0713 )
        IL-2+ (% of CD4+ T cells): CW 12 (n=195)
    -0.069 ( 4.0822 )
        IL-2+ (% of CD4+ T cells): CW 24 (n=193)
    -0.448 ( 3.6280 )
        IL-2+ (% of CD4+ T cells): CW 36 (n=180)
    -1.837 ( 3.8603 )
        IL-2+ (% of CD4+ T cells): CW 48 (n=182)
    -1.840 ( 5.0951 )
        IL-2+ (% of CD8+ T cells): Baseline (n=125)
    1.180 ( 1.4533 )
        IL-2+ (% of CD8+ T cells): CW 4 (n=118)
    -0.081 ( 1.2797 )
        IL-2+ (% of CD8+ T cells): CW 8 (n=113)
    -0.227 ( 1.1579 )
        IL-2+ (% of CD8+ T cells): CW 12 (n=117)
    -0.2622 ( 1.2601 )
        IL-2+ (% of CD8+ T cells): CW 24 (n=118)
    -0.525 ( 1.0201 )
        IL-2+ (% of CD8+ T cells): CW 36 (n=109)
    -0.547 ( 1.2886 )
        IL-2+ (% of CD8+ T cells): CW 48 (n=111)
    -0.248 ( 1.1860 )
        IL-2+ (% of memory CD4+ T cells): Baseline (n=210)
    7.053 ( 5.6653 )
        IL-2+ (% of memory CD4+ T cells): CW 4 (n=193)
    -0.105 ( 4.4131 )
        IL-2+ (% of memory CD4+ T cells): CW 8 (n=187)
    0.056 ( 4.6541 )
        IL-2+ (% of memory CD4+ T cells): CW 12 (n=195)
    0.012 ( 4.9241 )
        IL-2+ (% of memory CD4+ T cells): CW 24 (n=193)
    0.015 ( 4.6456 )
        IL-2+ (% of memory CD4+ T cells): CW 36 (n=180)
    -2.140 ( 4.7723 )
        IL-2+ (% of memory CD4+ T cells): CW 48 (n=182)
    -1.946 ( 5.6985 )
        IL-2+ (% of memory CD8+ T cells): Baseline (n=125)
    1.879 ( 1.7964 )
        IL-2+ (% of memory CD8+ T cells): CW 4 (n=118)
    -0.218 ( 1.6838 )
        IL-2+ (% of memory CD8+ T cells): CW 8 (n=113)
    -0.318 ( 1.7272 )
        IL-2+ (% of memory CD8+ T cells): CW 12 (n=117)
    -0.115 ( 1.7354 )
        IL-2+ (% of memory CD8+ T cells): CW 24 (n=118)
    -0.461 ( 1.4512 )
        IL-2+ (% of memory CD8+ T cells): CW 36 (n=109)
    -0.803 ( 1.8525 )
        IL-2+ (% of memory CD8+ T cells): CW 48 (n=111)
    -0.315 ( 2.0510 )
        IL-4+ (% of CD4+ T cells: Baseline (n=210)
    1.261 ( 1.1190 )
        IL-4+ (% of CD4+ T cells): CW 4 (n=193)
    -0.150 ( 1.0429 )
        IL-4+ (% of CD4+ T cells): CW 8 (n=187)
    -0.113 ( 1.2168 )
        IL-4+ (% of CD4+ T cells): CW 12 (n=195)
    -0.370 ( 1.0594 )
        IL-4+ (% of CD4+ T cells): CW 24 (n=193)
    -0.170 ( 1.1551 )
        IL-4+ (% of CD4+ T cells): CW 36 (n=180)
    -0.376 ( 1.0920 )
        IL-4+ (% of CD4+ T cells): CW 48 (n=182)
    0.281 ( 4.7206 )
        IL-4+ (% of CD8+ T cells): Baseline (n=125)
    1.107 ( 1.2924 )
        IL-4+ (% of CD8+ T cells): CW 4 (n=118)
    -0.222 ( 1.2163 )
        IL-4+ (% of CD8+ T cells): CW 8 (n=113)
    -0.189 ( 1.3377 )
        IL-4+ (% of CD8+ T cells): CW 12 (n=117)
    -0.553 ( 1.3754 )
        IL-4+ (% of CD8+ T cells): CW 24 (n=118)
    -0.032 ( 1.3170 )
        IL-4+ (% of CD8+ T cells): CW 36 (n=109)
    -0.195 ( 1.3334 )
        IL-4+ (% of CD8+ T cells): CW 48 (n=111)
    0.786 ( 1.3454 )
        IL-4+ (% of memory CD4+ T cells): Baseline (n=210)
    1.406 ( 1.2437 )
        IL-4+ (% of memory CD4+ T cells): CW 4 (n=193)
    -0.128 ( 1.2649 )
        IL-4+ (% of memory CD4+ T cells): CW 8 (n=187)
    -0.141 ( 1.4642 )
        IL-4+ (% of memory CD4+ T cells): CW 12 (n=195)
    -0.412 ( 1.3656 )
        IL-4+ (% of memory CD4+ T cells): CW 24 (n=193)
    -0.136 ( 1.3059 )
        IL-4+ (% of memory CD4+ T cells): CW 36 (n=180)
    -0.266 ( 1.4005 )
        IL-4+ (% of memory CD4+ T cells): CW 48 (n=182)
    0.325 ( 1.7918 )
        IL-4+ (% of memory CD8+ T cells): Baseline (n=125)
    1.376 ( 1.8963 )
        IL-4+ (% of memory CD8+ T cells): CW 4 (n=118)
    -0.180 ( 2.0821 )
        IL-4+ (% of memory CD8+ T cells): CW 8 (n=113)
    -0.269 ( 1.9840 )
        IL-4+ (% of memory CD8+ T cells): CW 12 (n=117)
    -0.795 ( 2.2486 )
        IL-4+ (% of memory CD8+ T cells): CW 24 (n=118)
    0.416 ( 2.3613 )
        IL-4+ (% of memory CD8+ T cells): CW 36 (n=109)
    -0.284 ( 2.4433 )
        IL-4+ (% of memory CD8+ T cells): CW 48 (n=111)
    1.836 ( 2.7709 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: Very Late Antigen-4 (VLA-4/Lymphocyte Function-Associated Antigen-1 (LFA-1) Antigen

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    End point title
    		 Change From Baseline in Lymphocyte Subsets Counts up to 48 Weeks: Very Late Antigen-4 (VLA-4/Lymphocyte Function-Associated Antigen-1 (LFA-1) Antigen [6]
    End point description
    VLA-4/LFA-1 antigen subsets include CD11a+ (% of B cells), CD11a+ (% of T cells), CD11a+ (% of MNC), CD11a+ (% of dendritic cells [CD11c++]), CD11a+ (% of lymphocytes), CD11a+ (% of monocytes), CD11a+ (% of neutrophils), CD49d+ (% of B cells), CD49d+ (% of T cells), CD49d+ (% of MNC), CD49d+ (% of dendritic [D] cells [CD11c++]), CD49d+ (% of lymphocytes), CD49d+ (% of monocytes) and CD49d+ (% of neutrophils). The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here, 'n' signifies number of subjects analyzed at specified timepoint for each subset.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: subset
    arithmetic mean (standard deviation)
        CD11a+ (% of B cells): Baseline (n= 205)
    99.33 ( 2.106 )
        CD11a+ (% of B cells): CW 4 (n= 197)
    0.34 ( 2.497 )
        CD11a+ (% of B cells): CW 8 (n= 196)
    0.44 ( 2.203 )
        CD11a+ (% of B cells): CW 12 (n= 200)
    0.17 ( 2.534 )
        CD11a+ (% of B cells): CW 24 (n= 195)
    0.19 ( 2.549 )
        CD11a+ (% of B cells): CW 36 (n= 185)
    -1.43 ( 11.406 )
        CD11a+ (% of B cells): CW 48 (n= 183)
    -0.14 ( 7.751 )
        CD11a+ (% of T cells): Baseline (n= 205)
    99.90 ( 0.312 )
        CD11a+ (% of T cells): CW 4 (n= 197)
    0.05 ( 0.319 )
        CD11a+ (% of T cells): CW 8 (n= 196)
    0.07 ( 0.327 )
        CD11a+ (% of T cells): CW 12 (n= 200)
    0.06 ( 0.321 )
        CD11a+ (% of T cells): CW 24 (n= 195)
    0.02 ( 0.633 )
        CD11a+ (% of T cells): CW 36 (n= 185)
    -1.29 ( 9.760 )
        CD11a+ (% of T cells): CW 48 (n= 183)
    -0.53 ( 7.410 )
        CD11a+ (% of MNC): Baseline (n= 205)
    96.85 ( 3.089 )
        CD11a+ (% of MNC): CW 4 (n= 197)
    0.47 ( 3.630 )
        CD11a+ (% of MNC): CW 8 (n= 196)
    0.59 ( 3.532 )
        CD11a+ (% of MNC): CW 12 (n= 200)
    0.59 ( 3.710 )
        CD11a+ (% of MNC): CW 24 (n= 195)
    -0.38 ( 3.963 )
        CD11a+ (% of MNC): CW 36 (n= 185)
    -1.55 ( 10.918 )
        CD11a+ (% of MNC): CW 48 (n= 183)
    -2.31 ( 8.402 )
        CD11a+ (% of D cells [CD11c++]): Baseline (n= 205)
    99.81 ( 0.933 )
        CD11a+ (% of D cells [CD11c++]): CW 4 (n= 197)
    0.04 ( 0.867 )
        CD11a+ (% of D cells [CD11c++]): CW 8 (n= 196)
    0.02 ( 1.573 )
        CD11a+ (% of D cells [CD11c++]): CW 12 (n= 200)
    0.10 ( 1.250 )
        CD11a+ (% of D cells [CD11c++]): CW 24 (n= 195)
    0.01 ( 1.477 )
        CD11a+ (% of D cells [CD11c++]): CW 36 (n= 185)
    -1.27 ( 10.857 )
        CD11a+ (% of D cells [CD11c++]): CW 48 (n= 183)
    -0.84 ( 7.813 )
        CD11a+ (% of lymphocytes): Baseline (n= 205)
    98.24 ( 1.870 )
        CD11a+ (% of lymphocytes): CW 4 (n= 197)
    0.04 ( 2.227 )
        CD11a+ (% of lymphocytes): CW 8 (n= 196)
    0.07 ( 2.649 )
        CD11a+ (% of lymphocytes): CW 12 (n= 200)
    0.26 ( 2.604 )
        CD11a+ (% of lymphocytes): CW 24 (n= 195)
    -0.35 ( 2.519 )
        CD11a+ (% of lymphocytes): CW 36 (n= 185)
    -1.99 ( 10.532 )
        CD11a+ (% of lymphocytes): CW 48 (n= 183)
    -2.56 ( 8.696 )
        CD11a+ (% of monocytes): Baseline (n= 205)
    98.00 ( 2.303 )
        CD11a+ (% of monocytes): CW 4 (n= 197)
    0.29 ( 3.241 )
        CD11a+ (% of monocytes): CW 8 (n= 196)
    0.92 ( 2.416 )
        CD11a+ (% of monocytes): CW 12 (n= 200)
    0.77 ( 2.539 )
        CD11a+ (% of monocytes): CW 24 (n= 195)
    -0.40 ( 3.046 )
        CD11a+ (% of monocytes): CW 36 (n= 185)
    -0.36 ( 7.843 )
        CD11a+ (% of monocytes): CW 48 (n= 183)
    -1.52 ( 7.711 )
        CD11a+ (% of neutrophils): Baseline (n= 205)
    97.80 ( 5.352 )
        CD11a+ (% of neutrophils): CW 4 (n= 197)
    0.83 ( 6.672 )
        CD11a+ (% of neutrophils): CW 8 (n= 196)
    1.23 ( 5.675 )
        CD11a+ (% of neutrophils): CW 12 (n= 200)
    0.55 ( 6.113 )
        CD11a+ (% of neutrophils): CW 24 (n= 195)
    0.35 ( 9.220 )
        CD11a+ (% of neutrophils): CW 36 (n= 185)
    -2.88 ( 18.513 )
        CD11a+ (% of neutrophils): CW 48 (n= 183)
    0.42 ( 10.736 )
        CD49d+ (% of B cells): Baseline (n= 205)
    99.87 ( 0.679 )
        CD49d+ (% of B cells): CW 4 (n= 197)
    -0.50 ( 7.105 )
        CD49d+ (% of B cells): CW 8 (n= 196)
    0.00 ( 0.642 )
        CD49d+ (% of B cells): CW 12 (n= 200)
    0.01 ( 0.486 )
        CD49d+ (% of B cells): CW 24 (n= 194)
    -0.01 ( 0.663 )
        CD49d+ (% of B cells): CW 36 (n= 185)
    -0.07 ( 0.744 )
        CD49d+ (% of B cells): CW 48 (n= 183)
    -0.04 ( 0.964 )
        CD49d+ (% of T cells): Baseline (n= 205
    91.23 ( 4.427 )
        CD49d+ (% of T cells): CW 4 (n= 197)
    -0.45 ( 6.909 )
        CD49d+ (% of T cells): CW 8 (n= 196)
    -0.11 ( 2.055 )
        CD49d+ (% of T cells): CW 12 (n= 200)
    -0.06 ( 1.930 )
        CD49d+ (% of T cells): CW 24 (n= 194)
    -0.12 ( 2.209 )
        CD49d+ (% of T cells): CW 36 (n= 185)
    -1.32 ( 4.256 )
        CD49d+ (% of T cells): CW 48 (n= 183)
    -0.02 ( 2.935 )
        CD49d+ (% of MNC): Baseline (n= 205)
    86.79 ( 5.369 )
        CD49d+ (% of MNC): CW 4 (n= 197)
    0.23 ( 8.274 )
        CD49d+ (% of MNC): CW 8 (n= 196)
    0.38 ( 5.600 )
        CD49d+ (% of MNC): CW 12 (n= 200)
    0.85 ( 5.900 )
        CD49d+ (% of MNC): CW 24 (n= 194)
    -0.07 ( 6.051 )
        CD49d+ (% of MNC): CW 36 (n= 185)
    -0.46 ( 8.264 )
        CD49d+ (% of MNC): CW 48 (n= 183)
    -1.25 ( 6.561 )
        CD49d+ (% of D cells [CD11c++]):Baseline (n= 205)
    99.77 ( 0.771 )
        CD49d+ (% of D cells [CD11c++]): CW 4 (n= 197)
    -0.42 ( 7.185 )
        CD49d+ (% of D cells [CD11c++]): CW 8 (n= 196)
    0.12 ( 0.874 )
        CD49d+ (% of D cells [CD11c++]): CW 12 (n= 200)
    0.03 ( 1.252 )
        CD49d+ (% of D cells [CD11c++]): CW 24 (n= 194)
    0.00 ( 1.162 )
        CD49d+ (% of D cells [CD11c++]): CW 36 (n= 185)
    -0.06 ( 1.532 )
        CD49d+ (% of D cells [CD11c++]): CW 48 (n= 183)
    -0.23 ( 1.530 )
        CD49d+ (% of lymphocytes): Baseline (n= 205)
    91.29 ( 4.715 )
        CD49d+ (% of lymphocytes): CW 4 (n= 197)
    -0.31 ( 7.260 )
        CD49d+ (% of lymphocytes): CW 8 (n= 196)
    0.03 ( 5.899 )
        CD49d+ (% of lymphocytes): CW 12 (n= 200)
    0.44 ( 2.989 )
        CD49d+ (% of lymphocytes): CW 24 (n= 194)
    0.01 ( 3.237 )
        CD49d+ (% of lymphocytes): CW 36 (n= 185)
    -0.75 ( 5.045 )
        CD49d+ (% of lymphocytes): CW 48 (n= 183)
    -1.10 ( 5.739 )
        CD49d+ (% of monocytes): Baseline (n=205)
    88.77 ( 8.126 )
        CD49d+ (% of monocytes): CW 4 (n= 197)
    0.82 ( 10.895 )
        CD49d+ (% of monocytes): CW 8 (n= 196)
    0.96 ( 10.161 )
        CD49d+ (% of monocytes): CW 12 (n= 200)
    0.82 ( 10.350 )
        CD49d+ (% of monocytes): CW 24 (n= 197)
    0.98 ( 9.793 )
        CD49d+ (% of monocytes): CW 36 (n= 195)
    3.87 ( 9.683 )
        CD49d+ (% of monocytes): CW 48 (n= 183)
    0.69 ( 10.594 )
        CD49d+ (% of neutrophils): Baseline (n= 205)
    5.61 ( 7.277 )
        CD49d+ (% of neutrophils): CW 4 (n= 197)
    4.43 ( 9.345 )
        CD49d+ (% of neutrophils): CW 8 (n= 196)
    1.17 ( 4.892 )
        CD49d+ (% of neutrophils): CW 12 (n= 200)
    0.27 ( 4.137 )
        CD49d+ (% of neutrophils): CW 24 (n= 194)
    -0.67 ( 10.365 )
        CD49d+ (% of neutrophils): CW 36 (n= 185)
    -0.29 ( 12.678 )
        CD49d+ (% of neutrophils): CW 48 (n= 183)
    0.92 ( 10.291 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin A (IgA) up to 48 Weeks

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    End point title
    		 Change From Baseline in Immunoglobulin A (IgA) up to 48 Weeks
    End point description
    The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here 'n' signifies number of subjects analyzed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: microgram per litre (mg/L)
    arithmetic mean (standard deviation)
        Baseline (n= 216)
    2116.5 ( 910.47 )
        Change at Week 4 (n= 211)
    -120.0 ( 231.16 )
        Change at Week 8 (n= 209)
    -112.8 ( 243.28 )
        Change at Week 12 (n= 210)
    -93.6 ( 291.76 )
        Change at Week 24 (n= 205)
    -101.5 ( 324.27 )
        Change at Week 36 (n= 193)
    -65.1 ( 279.53 )
        Change at Week 48 (n= 193)
    -94.9 ( 291.25 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin M (IgM) up to 48 Weeks

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    End point title
    		 Change From Baseline in Immunoglobulin M (IgM) up to 48 Weeks
    End point description
    The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here 'n' signifies number of subjects analyzed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: mg/L
    arithmetic mean (standard deviation)
        Baseline (n= 216)
    1330.1 ( 705.92 )
        Change at Week 4 (n= 211)
    -68.9 ( 214.07 )
        Change at Week 8 (n= 209)
    -23.2 ( 208.48 )
        Change at Week 12 (n= 210)
    -18.8 ( 270.82 )
        Change at Week 24 (n= 205)
    -36.9 ( 293.14 )
        Change at Week 36 (n=193)
    -19.4 ( 406.86 )
        Change at Week 48 (n=193)
    -96.8 ( 236.48 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin G (IgG) up to 48 Weeks

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    End point title
    		 Change From Baseline in Immunoglobulin G (IgG) up to 48 Weeks
    End point description
    The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here 'n' signifies number of subjects analyzed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline (n= 216)
    10.51 ( 2.328 )
        Change at Week 4 (n= 211)
    -0.77 ( 1.039 )
        Change at Week 8 (n= 209)
    -0.64 ( 1.077 )
        Change at Week 12 (n= 210)
    -0.44 ( 1.187 )
        Change at Week 24 (n= 205)
    -0.62 ( 1.324 )
        Change at Week 36 (n= 193)
    -0.36 ( 1.025 )
        Change at Week 48 (n= 193)
    -0.53 ( 1.142 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin G (IgG) Subclasses up to 48 Weeks

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    End point title
    		 Change From Baseline in Immunoglobulin G (IgG) Subclasses up to 48 Weeks
    End point description
    The PD population was defined as all subjects who received at least 1 dose of study treatment and had at least 1 pharmacodynamic measurement after baseline. Here 'n' signifies number of subjects analyzed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Dimethyl Fumarate (BG00012)
    Number of subjects analysed
    218
    Units: milligram per deciliter
    arithmetic mean (standard deviation)
        IgG Subclass 1: Baseline (n= 189)
    542.9 ( 152.87 )
        IgG Subclass 1: CW 4 (n= 169)
    -29.2 ( 68.22 )
        IgG Subclass 1: CW 8 (n= 170)
    -28.5 ( 71.46 )
        IgG Subclass 1: CW 12 (n= 182)
    -14.8 ( 79.07 )
        IgG Subclass 1: CW 24 (n= 170)
    -3.0 ( 78.80 )
        IgG Subclass 1: CW 36 (n= 163)
    -23.1 ( 61.73 )
        IgG Subclass 1: CW 48 (n= 166)
    -0.5 ( 102.41 )
        IgG Subclass 2: Baseline (n= 189)
    350.7 ( 116.43 )
        IgG Subclass 2: CW 4 (n= 169)
    -22.7 ( 47.42 )
        IgG Subclass 2: CW 8 (n= 170)
    -26.5 ( 48.98 )
        IgG Subclass 2: CW 12 (n= 182)
    -18.9 ( 44.11 )
        IgG Subclass 2: CW 24 (n= 170)
    -5.5 ( 54.39 )
        IgG Subclass 2: CW 36 (n= 163)
    -22.4 ( 45.49 )
        IgG Subclass 2: CW 48 (n= 166)
    -21.5 ( 50.98 )
        IgG Subclass 3: Baseline (n= 189)
    56.93 ( 26.860 )
        IgG Subclass 3: CW 4 (n= 169)
    -2.1 ( 8.56 )
        IgG Subclass 3: CW 8 (n= 170)
    -0.7 ( 12.36 )
        IgG Subclass 3: CW 12 (n= 182)
    -1.0 ( 15.48 )
        IgG Subclass 3: CW 24 (n= 170)
    -0.4 ( 11.31 )
        IgG Subclass 3: CW 36 (n= 163)
    4.6 ( 19.09 )
        IgG Subclass 3: CW 48 (n= 166)
    1.5 ( 12.55 )
        IgG Subclass 4: Baseline (n= 189)
    30.35 ( 29.681 )
        IgG Subclass 4: CW 4 (n= 169)
    1.24 ( 9.242 )
        IgG Subclass 4: CW 8 (n= 170)
    -0.38 ( 10.995 )
        IgG Subclass 4: CW 12 (n= 182)
    -0.12 ( 11.711 )
        IgG Subclass 4: CW 24 (n= 170)
    1.08 ( 15.253 )
        IgG Subclass 4: CW 36 (n= 163)
    1.28 ( 12.236 )
        IgG Subclass 4: CW 48 (n= 166)
    3.26 ( 10.962 )
        IgG Subclasses 1-4 Quant: Baseline (n= 189)
    1029.9 ( 232.33 )
        IgG Subclasses 1-4 Quant: CW 4 (n= 169)
    -54.6 ( 101.48 )
        IgG Subclasses 1-4 Quant: CW 8 (n= 170)
    -41.9 ( 100.16 )
        IgG Subclasses 1-4 Quant: CW 12 (n= 181)
    -28.5 ( 114.30 )
        IgG Subclasses 1-4 Quant: CW 24 (n= 170)
    -55.7 ( 116.69 )
        IgG Subclasses 1-4 Quant: CW 36 (n= 164)
    -70.3 ( 103.59 )
        IgG Subclasses 1-4 Quant: CW 48 (n= 167)
    -65.1 ( 130.94 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 33 months
    Adverse event reporting additional description
    The safety population was defined as all subjects who received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Dimethyl Fumarate (BG00012)
    Reporting group description
    		 Subjects received 120 mg BID orally for the first 7 days and 240 mg BID thereafter until 96 weeks.

    Serious adverse events
    		 Dimethyl Fumarate (BG00012)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 218 (11.93%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer stage I
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Anembryonic gestation
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    16 / 218 (7.34%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dimethyl Fumarate (BG00012)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    160 / 218 (73.39%)
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    25
    Vascular disorders
    Flushing
         subjects affected / exposed
    100 / 218 (45.87%)
         occurrences all number
    122
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 218 (7.34%)
         occurrences all number
    25
    Multiple sclerosis relapse
         subjects affected / exposed
    41 / 218 (18.81%)
         occurrences all number
    58
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    27 / 218 (12.39%)
         occurrences all number
    31
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences all number
    13
    Abdominal pain
         subjects affected / exposed
    22 / 218 (10.09%)
         occurrences all number
    29
    Abdominal pain upper
         subjects affected / exposed
    22 / 218 (10.09%)
         occurrences all number
    31
    Diarrhoea
         subjects affected / exposed
    28 / 218 (12.84%)
         occurrences all number
    30
    Nausea
         subjects affected / exposed
    22 / 218 (10.09%)
         occurrences all number
    26
    Vomiting
         subjects affected / exposed
    14 / 218 (6.42%)
         occurrences all number
    20
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences all number
    15
    Pruritus
         subjects affected / exposed
    17 / 218 (7.80%)
         occurrences all number
    19
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 218 (5.96%)
         occurrences all number
    15
    Depression
         subjects affected / exposed
    12 / 218 (5.50%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 218 (6.88%)
         occurrences all number
    16
    Pain in extremity
         subjects affected / exposed
    14 / 218 (6.42%)
         occurrences all number
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    33 / 218 (15.14%)
         occurrences all number
    50
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 218 (12.84%)
         occurrences all number
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2016
    1. The protocol was amended to extend the duration of lymphocyte testing during the study in subjects with lymphopenia upon discontinuation of treatment with BG00012 from 24 weeks to 48 weeks. 2. A magnetic resonance imaging examination was added prior to the start of BG00012 therapy if not already available within the previous 3 months and where required per local guidelines. 3. Schedule of activities was updated. 4. A statement was added about progressive multifocal leukoencephalopathy to include additional information as it relates to lymphopenia in the postmarketing setting. 5. The option of treating relapses with oral corticosteroids was added to provide the Neurologist with the option of treating relapses with oral corticosteroids and not just intravenous methylprednisolone (IVMP). 6. A condition for exclusion of subjects due to a positive test result for human immunodeficiency virus (HIV) at Screening was added to clarify the outcome of HIV testing in study sites where testing is required by local authorities. HIV testing is not required for all subjects. 7. The timing of dose reduction was revised to provide some flexibility in the event that the subject does not need to take the study treatment beyond 4 weeks.

    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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