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    Clinical Trial Results:
    Single Country Study Assessing Cognition in Relapsing Remitting Multiple Sclerosis Patients Treated with BG00012

    Summary
    EudraCT number
    2013-001422-25
    Trial protocol
    IT  
    Global end of trial date
    21 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2018
    First version publication date
    21 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ITA-BGT-12-10389
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02579681
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    109MS410: Biogen
    Sponsors
    Sponsor organisation name
    Biogen Italia S.R.L.
    Sponsor organisation address
    Centro Leoni, Via Spadolini 5, Milan, Italy, 20141
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen 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
    30 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the BG00012 treatment effect on cognition over a 2 year period in subjects with relapsing remitting multiple sclerosis (RRMS). The secondary objectives were to further assess BG00012 treatment effect on cognition, predictors of cognitive impairment, clinical efficacy, and patient reported outcomes (PRO): depression, fatigue, quality of life, and work and social life activity.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 232
    Worldwide total number of subjects
    232
    EEA total number of subjects
    232
    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)
    232
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were recruited from 24 sites in Italy.

    Pre-assignment
    Screening details
    Prior to performing any study-related activities under this protocol, including screening tests and assessments, written informed consent with the approved informed consent form (ICF) was to be obtained from the subject or subject’s legally authorized representative, as applicable, in accordance with local practice and regulations.

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

    Arms
    Arm title
    BG00012
    Arm description
    Subjects with RRMS received 240 milligrams (mg) BG00012 twice daily for 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    Other name
    Tecfidera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg BG00012 twice daily for 24 months.

    Number of subjects in period 1
    BG00012
    Started
    232
    Enrolled (ENR) Set
    232
    Intent to Treat (ITT) Set
    217
    Safety Analysis (SAF) Set
    217
    Completed
    156
    Not completed
    76
         Adverse event
    31
         Patient not treated
    3
         Investigator Decision
    1
         Not specified
    6
         Withdrawal of informed consent
    17
         Eligibility criteria violated
    8
         Clinical worsening
    9
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BG00012
    Reporting group description
    Subjects with RRMS received 240 milligrams (mg) BG00012 twice daily for 24 months.

    Reporting group values
    BG00012 Total
    Number of subjects
    232 232
    Age Categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    232 232
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    37.14 ± 9.75 -
    Gender Categorical
    Units: Subjects
        Female
    172 172
        Male
    60 60

    End points

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    End points reporting groups
    Reporting group title
    BG00012
    Reporting group description
    Subjects with RRMS received 240 milligrams (mg) BG00012 twice daily for 24 months.

    Subject analysis set title
    BG00012 Intent to Treat (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects in the ENR set who received at least 1 dose of study treatment.

    Subject analysis set title
    BG00012 Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects who received at least 1 dose of study treatment.

    Primary: Percentage of Subjects With Worsened Cognitive Impairment (CI) Over Two Years

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    End point title
    Percentage of Subjects With Worsened Cognitive Impairment (CI) Over Two Years [1]
    End point description
    CI was defined as a subject’s failure,at any testing session,on 2 tests that were part of the Rao’s Brief Repeatable Battery of Neuropsychological Tests(BRB-N) or as failure on the 100-item version of the Stroop test.A subject failed any item of the BRB-N and Stroop Test if the normalized score was at least 2 standard deviations (SD) below the Italian normative score.The BRB-N was a measure of CI in subjects with MS that incorporates tests of verbal memory acquisition, visual memory acquisition,delayed recall,attention,concentration and speed of information processing and verbal fluency on semantic stimulus.The Stroop Test was used to measure a person's sustained attention for word reading and color naming with and without interference. Percentages were calculated relative to the total number of subjects in the ITT set with a preexisiting cognitive impairment at baseline assessment and available post baseline values.
    End point type
    Primary
    End point timeframe
    Baseline, End of Study (24 months)
    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 were performed for this single-arm study.
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    34
    Units: percentage of subjects
        number (confidence interval 95%)
    44.1 (28.9 to 60.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Cognitive Impairment Index (CII) Score Over Two Years

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    End point title
    Change From Baseline in the Cognitive Impairment Index (CII) Score Over Two Years
    End point description
    CII was calculated to assess the amount and direction of cognitive changes over time for each subject between year 0 and year 1, and year 0 and year 2. CII was derived from the subject’s performance on the BRB-N and the 100-item Stroop Test. For CII, the mean and SD for each cognitive variable was derived from the matched control normative data obtained from a study by Amato et al (2006) conducted on 200 healthy subjects. For each test, all subjects were graded as Grade 0 if the subject scored at or above the normative data, Grade 1 if below the normative data but within 1 SD of that mean, and Grade 2 if at least 1 but not more than 2 SD below the normative data. The grades were summed across all neuropsychological variables to give one overall score of cognitive dysfunction. Scores on the CII range from 0 (less CI) to 100 (more CI). A negative change from Baseline indicates a decrease in CI. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 4 (12 months), End of Study (24 months or Early Termination [ET])
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=200)
    10.5 ± 6.79
        Change from Baseline at Visit 4 (n=148)
    0.3 ± 4.72
        Change from Baseline at EOS/ET (n=125)
    -2.3 ± 3.96
    No statistical analyses for this end point

    Secondary: Annualized Relapse Rate (ARR) at Year One

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    End point title
    Annualized Relapse Rate (ARR) at Year One
    End point description
    The ARR was calculated as the total number of relapses during year 1 for all subjects, divided by the total number of patient-years followed in year 1. Relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the treating neurologist. New or recurrent neurologic symptoms that occurred less than 30 days following the onset of a protocol-defined relapse were considered part of the same relapse.
    End point type
    Secondary
    End point timeframe
    Visit 4 (12 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: relapses/year
        number (not applicable)
    0.265
    No statistical analyses for this end point

    Secondary: ARR at Year Two

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    End point title
    ARR at Year Two
    End point description
    The ARR was calculated as the total number of relapses during years 1 and 2 for all subjects, divided by the total number of patient-years followed in years 1 and 2. Relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the treating neurologist. New or recurrent neurologic symptoms that occurred less than 30 days following the onset of a protocol-defined relapse were considered part of the same relapse.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: relapses/year
        number (not applicable)
    0.19
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Relapsed Over Two Years

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    End point title
    Percentage of Subjects Who Relapsed Over Two Years
    End point description
    Relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the treating neurologist. New or recurrent neurologic symptoms that occurred less than 30 days following the onset of a protocol-defined relapse were considered part of the same relapse.
    End point type
    Secondary
    End point timeframe
    Visit 4 (12 months) and End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: percentage of subjects
    number (not applicable)
        Year 1
    15.7
        Year 2
    19.4
    No statistical analyses for this end point

    Secondary: Median Time to First Relapse Over Two Years

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    End point title
    Median Time to First Relapse Over Two Years
    End point description
    Time to first relapse was defined as the time from the date of the screening visit to the date when the first relapse occurred during the study period. Subjects without relapse were censored at the date of the last assessment performed. Time to first relapse was estimated by using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    0 [2]
    Units: days
        median (confidence interval 95%)
    ( to )
    Notes
    [2] - The median time to first relapse was not estimable because of the low number of events (< 20%).
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing 6-Month Sustained Progression of Disability as Measured by the Expanded Disability Status Scale (EDSS)

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    End point title
    Percentage of Subjects Experiencing 6-Month Sustained Progression of Disability as Measured by the Expanded Disability Status Scale (EDSS)
    End point description
    Progression of disability was defined as either a ≥ 1.0 point increase on the EDSS from a baseline score ≥1.0 that was sustained for 24 weeks or a ≥ 1.5 point increase on the EDSS from a baseline score = 0 that was sustained for 24 weeks (2 consecutive assessments). EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Total scores range from 0.0 (normal) to 10.0 (death due to MS). Percentages are calculated relative to the total number of subjects in the ITT Set with data.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    188
    Units: percentage of subjects
        number (not applicable)
    5.9
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Two Years in EDSS Total Score

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    End point title
    Change From Baseline Over Two Years in EDSS Total Score
    End point description
    EDSS was based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Total scores range from 0.0 (normal) to 10.0 (death due to MS). A negative change from Baseline indicates a decrease in disability. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 2 (6 months) Visit 4 (12 months), Visit 6 (18 months), End of Study (24 months or ET)
    End point values
    BG00012 Safety
    Number of subjects analysed
    217
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=217)
    1.98 ± 1.17
        Change from Baseline at Visit 2 (n=195)
    -0.01 ± 0.50
        Change from Baseline at Visit 4 (n=184)
    -0.09 ± 0.60
        Change from Baseline at Visit 6 (n=167)
    -0.11 ± 0.63
        Change from Baseline at End of study/ET (n=196)
    -0.04 ± 0.68
    No statistical analyses for this end point

    Secondary: Median Time to 6-Month Sustained Progression of Disability Over Two Years

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    End point title
    Median Time to 6-Month Sustained Progression of Disability Over Two Years
    End point description
    Time to disability progression was defined as the time from the date of the screening visit to the date of 6-month sustained progression of disability evaluated by the EDSS. EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Total scores range from 0.0 (normal) to 10.0 (death due to MS). Subjects without disability progression were considered censored at the date of the last assessment performed.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    0 [3]
    Units: days
        median (confidence interval 95%)
    ( to )
    Notes
    [3] - The median time to first relapse was not estimable because of the low number of events (< 10%)..
    No statistical analyses for this end point

    Secondary: Correlation Between Age and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between Age and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman Correlation Coefficient (CC) is a non-parametric measure of the correlation between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on Modified Fatigue Impact Scale (MFIS), Montgomery and Asberg Depression Rating Scale (MADRS), Environmental Status Scale (ESS) at baseline, and the EQ-5D Health Survey Visual Analog Scale (VAS) score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: correlation coefficient
    number (not applicable)
        Years of schooling (n=215)
    -0.02391
        Number of relapses preceding enrollment (n=217)
    -0.12023
        Months from MS diagnosis to enrollment (n=217)
    0.44149
        MFIS total score at baseline (n=210)
    0.26667
        MADRS total score at baseline (n=211)
    0.13773
        ESS total score at baseline (n=211)
    0.17740
        EDSS total score at baseline (n=217)
    0.31757
        EQ-5D Health Survey VAS score (n=211)
    -0.22583
    No statistical analyses for this end point

    Secondary: Correlation Between Number of Years of Schooling and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between Number of Years of Schooling and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    215
    Units: correlation coefficient
    number (not applicable)
        Age (n=215)
    -0.02391
        Number of relapses preceding enrollment (n=215)
    0.11535
        Months from MS diagnosis to enrollment (n=215)
    -0.03985
        MFIS total score at baseline (n=209)
    -0.15274
        MADRS total score at baseline (n=210)
    -0.08234
        ESS total score at baseline (n=210)
    -0.10690
        EDSS total score at baseline (n=215)
    -0.18921
        EQ-5D Health Survey VAS score (n=210)
    0.06991
    No statistical analyses for this end point

    Secondary: Correlation Between Number of Relapses in the Year Preceding Study Enrollment and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between Number of Relapses in the Year Preceding Study Enrollment and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: correlation coefficient
    number (not applicable)
        Age (n=217)
    -0.12023
        Years of schooling (n=215)
    0.11535
        Months from MS diagnosis to enrollment (n=217)
    -0.01703
        MFIS total score at baseline (n=210)
    0.07876
        MADRS total score at baseline (n=211)
    -0.04768
        ESS total score at baseline (n=211)
    0.02373
        EDSS total score at baseline (n=217)
    0.10473
        EQ-5D Health Survey VAS score (n=211)
    -0.08656
    No statistical analyses for this end point

    Secondary: Correlation Between Time From MS Diagnosis to Study Enrollment and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between Time From MS Diagnosis to Study Enrollment and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: correlation coefficient
    number (not applicable)
        Age (n=217)
    0.44149
        Years of schooling (n=215)
    -0.03985
        Number of relapses preceding enrollment (n=217)
    -0.01703
        MFIS total score at baseline (n=210)
    0.22082
        MADRS total score at baseline (n=211)
    0.05382
        ESS total score at baseline (n=211)
    0.16246
        EDSS total score at baseline (n=217)
    0.23126
        EQ-5D Health Survey VAS score (n=211)
    -0.28059
    No statistical analyses for this end point

    Secondary: Correlation Between MFIS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between MFIS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    210
    Units: correlation coefficient
    number (not applicable)
        Age (n=210)
    0.26667
        Years of schooling (n=209)
    -0.15274
        Number of relapses preceding enrollment (n=210)
    0.07876
        Months from MS diagnosis to enrollment (n=210)
    0.22082
        MADRS total score at baseline (n=210)
    0.57165
        ESS total score at baseline (n=210)
    0.66357
        EDSS total score at baseline (n=210)
    0.43232
        EQ-5D Health Survey VAS score (n=210)
    -0.56370
    No statistical analyses for this end point

    Secondary: Correlation Between MADRS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between MADRS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    211
    Units: correlation coefficient
    number (not applicable)
        Age (n=211)
    0.13773
        Years of schooling (n=210)
    -0.08234
        Number of relapses preceding enrollment (n=211)
    -0.04768
        Months from MS diagnosis to enrollment (n=211)
    0.05382
        MFIS total score at baseline (n=210)
    0.57165
        ESS total score at baseline (n=211)
    0.46093
        EDSS total score at baseline (n=211)
    0.33939
        EQ-5D Health Survey VAS score (n=211)
    -0.35464
    No statistical analyses for this end point

    Secondary: Correlation Between ESS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between ESS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    211
    Units: correlation coefficient
    number (not applicable)
        Age (n=211)
    0.17740
        Years of schooling (n=210)
    -0.10690
        Number of relapses preceding enrollment (n=211)
    0.02373
        Months from MS diagnosis to enrollment (n=211)
    0.16246
        MFIS total score at baseline (n=210)
    0.66357
        MADRS total score at baseline (n=211)
    0.46093
        EDSS total score at baseline (n=211)
    0.43068
        EQ-5D Health Survey VAS score (n=211)
    -0.42919
    No statistical analyses for this end point

    Secondary: Correlation Between EDSS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between EDSS Total Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman correlation coefficient (CC) is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, and EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    211
    Units: correlation coefficient
    number (not applicable)
        Age (n=217)
    0.31757
        Years of schooling (n=215)
    -0.18921
        Number of relapses preceding enrollment (n=217)
    0.10473
        Months from MS diagnosis to enrollment (n=217)
    0.23126
        MFIS total score at baseline (n=210)
    0.43232
        MADRS total score at baseline (n=211)
    0.33939
        ESS total score at baseline (n=211)
    0.43068
        EQ-5D Health Survey VAS score (n=211)
    -0.30822
    No statistical analyses for this end point

    Secondary: Correlation Between EQ-5D Health Survey VAS Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years

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    End point title
    Correlation Between EQ-5D Health Survey VAS Score at Baseline and Demographic and Clinical Characteristics (Spearman Rank Order Correlation Coefficient) at Two Years
    End point description
    The Spearman Correlation Coefficient (CC) is a non-parametric measure of the correlation between 2 variables, giving a value between +1 (total positive correlation) and −1 (total negative correlation). CCs were determined for demographic characteristics including age (in years) and the number of years of schooling; clinical characteristics including the number of relapses in the year preceding enrollment in the study, time (in months) from MS diagnosis to study enrollment, EDSS total score at baseline; and patient reported outcomes at the time of initiation of BG00012 including total scores on the MFIS, the MADRS, and the ESS at baseline, and the EQ-5D Health Survey VAS score (in millimeters). Here, ‘n’ signifies those subjects who were evaluable for that characteristic.
    End point type
    Secondary
    End point timeframe
    End of Study (24 months)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    211
    Units: correlation coefficient
    number (not applicable)
        Age (n=211)
    -0.22583
        Years of schooling (n=210)
    0.06991
        Number of relapses preceding enrollment (n=211)
    -0.08656
        Months from MS diagnosis to enrollment (n=211)
    -0.28059
        MFIS total score at baseline (n=210)
    -0.56370
        MADRS total score at baseline (n=211)
    -0.35464
        ESS total score at baseline (n=211)
    -0.42919
        EDSS total score at baseline (n=211)
    -0.30822
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fatigue Over Two Years as Measured by the MFIS

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    End point title
    Change From Baseline in Fatigue Over Two Years as Measured by the MFIS
    End point description
    The MFIS was a modified form of the Fatigue Impact Scale based on items derived from interviews with subjects with MS concerning how fatigue impacts their lives. This instrument provided an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. The full-length MFIS consisted of 21 items scored 0-4 for a total score between 0 (no fatigue) and 84 (severe fatigue). A negative change from Baseline indicates a decrease in fatigue. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 2 (6 months), Visit 4 (12 months), Visit 6 (18 months), End of Study (24 months or ET)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    23.5893 (20.3217 to 26.8570)
        Change from Baseline at Visit 2
    -3.3243 (-4.9106 to -1.7379)
        Change from Baseline at Visit 4
    -3.7791 (-5.3739 to -2.1842)
        Change from Baseline at Visit 6
    -3.6647 (-5.3241 to -2.0053)
        Change from Baseline at End of Study/ET
    -3.3377 (-4.9588 to -1.7167)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Depression Over Two Years as Measured by the Self-rating MADRS

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    End point title
    Change From Baseline in Depression Over Two Years as Measured by the Self-rating MADRS
    End point description
    The self-rating MADRS instrument had nine questions that assessed a subject’s mood, feelings of unease, sleep, appetite, ability to concentrate, initiative, emotional involvement, pessimism, and zest for life. Each question was rated on a 0 to 3 scale, with the total score ranging from 0 points (no depression) to 27 points (severe depression). A negative change from Baseline indicates a decrease in depression. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 2 (6 months), Visit 4 (12 months), Visit 6 (18 months), End of Study (24 months or ET)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    7.8522 (6.5035 to 9.2008)
        Change from Baseline at Visit 2
    0.1298 (-0.6277 to 0.8873)
        Change from Baseline at Visit 4
    -0.9336 (-1.7026 to -0.1646)
        Change from Baseline at Visit 6
    -1.0239 (-1.8236 to -0.2242)
        Change from Baseline at End of Study/ET
    -1.3024 (-2.0807 to -0.5240)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Handicap Over Two Years as Measured by the ESS

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    End point title
    Change From Baseline in Handicap Over Two Years as Measured by the ESS
    End point description
    The ESS is used to quickly evaluate a subject for handicap. It was derived from a measure of socio-economic status. It consists of seven parameters: (1) actual work status, (2) financial and economic status, (3) personal residence or home, (4) personal assistance required, (5) transportation, (6) community services, (7) social activity. Each parameter has a single score from minimum 0 to maximum 5. The ESS total score is the sum of the points for all 7 parameters: minimum score: 0 (no handicap); maximum score: 35 (maximum handicap). A negative change from Baseline indicates a decrease in handicap. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 2 (6 months), Visit 4 (12 months), Visit 6 (18 months), End of Study (24 months or ET)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    2.2908 (1.6278 to 2.9538)
        Change from Baseline at Visit 2
    -0.2500 (-0.5892 to 0.08910)
        Change from Baseline at Visit 4
    -0.4500 (-0.7937 to -0.1063)
        Change from Baseline at Visit 6
    -0.4065 (-0.7677 to -0.04535)
        Change from Baseline at End of Study/ET
    -0.5736 (-0.9242 to -0.2231)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life (QoL) Over Two Years as Measured by the EQ-5D Health Survey

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    End point title
    Change From Baseline in Quality of Life (QoL) Over Two Years as Measured by the EQ-5D Health Survey
    End point description
    The EQ-5D is a widely-used survey instrument for measuring economic preferences for health states and quality of life. It is a self-administered questionnaire consisting of questions pertaining to 5 specific health states (mobility, self-care, pain, usual activities, anxiety). The subject is asked to indicate his/her health state at one of three levels: no problems, some problems, or extreme problems. Health state values are used to generate an index score, with a minimum score of 0 (death) and a maximum score of 1 (full health). A positive change from Baseline indicates an increase in QoL. Here, ‘n’ signifies those subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 2 (6 months), Visit 4 (12 months), Visit 6 (18 months), End of Study (24 months or ET)
    End point values
    BG00012 Intent to Treat (ITT)
    Number of subjects analysed
    217
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Baseline
    0.7550 (0.7207 to 0.7892)
        Change from Baseline at Visit 2
    0.04517 (0.02264 to 0.06770)
        Change from Baseline at Visit 4
    0.04903 (0.02621 to 0.07185)
        Change from Baseline at Visit 6
    0.05276 (0.02903 to 0.07649)
        Change from Baseline at End of Study/ET
    0.04516 (0.02206 to 0.06827)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months ± 5 days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    BG00012
    Reporting group description
    Subjects with RRMS received 240 milligrams (mg) BG00012 twice daily for 24 months.

    Serious adverse events
    BG00012
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 217 (5.07%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic Adenoma
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intraductal Papilloma Of Breast
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small Intestinal Perforation
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 217 (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
    BG00012
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 217 (58.06%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    91 / 217 (41.94%)
         occurrences all number
    119
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    12 / 217 (5.53%)
         occurrences all number
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 217 (5.07%)
         occurrences all number
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 217 (6.91%)
         occurrences all number
    15
    Gastrointestinal disorders
    Gastrointestinal Disorder
         subjects affected / exposed
    11 / 217 (5.07%)
         occurrences all number
    12
    Diarrhoea
         subjects affected / exposed
    17 / 217 (7.83%)
         occurrences all number
    17
    Abdominal Pain
         subjects affected / exposed
    18 / 217 (8.29%)
         occurrences all number
    21
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    19 / 217 (8.76%)
         occurrences all number
    22
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    12 / 217 (5.53%)
         occurrences all number
    14
    Influenza
         subjects affected / exposed
    20 / 217 (9.22%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2016
    The primary reasons for this amendment to Protocol ITA-BGT-12-10389 are: * The schedule of hematology parameters has been aligned with the monitoring (i.e. every three months) recommended in the SmPC of the investigational product. * The number of subjects to be enrolled in the study has been better specified (changed from 220 to 221). * A new section with subparagraphs has been added to define the procedures for modification of dose and of treatment schedule for abnormal laboratory values and for abnormal lymphocyte count. * The section on Withdrawal of Subjects from Study Treatment and/or the Study has been updated to better reflect the procedures for modification of dose and of treatment schedule for abnormal laboratory values and for abnormal lymphocyte count.

    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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