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    Clinical Trial Results:
    BENEFIT 11 a long-term, follow-up study (16401) of the BENEFIT (304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to further evaluate the progress of patients with first demyelinating event suggestive of multiple sclerosis

    Summary
    EudraCT number
    2012-005262-35
    Trial protocol
    BE   SE   PT   HU   CZ   NO   AT   FI   DK   GB   ES   IT   SI   PL  
    Global end of trial date
    18 Jun 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Sep 2016
    First version publication date
    26 Jul 2015
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-5046/16401
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01795872
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    18 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were to describe the disease course (in particular conversion to clinically-definite multiple sclerosis [CDMS]), relapse activity, change in disability, cognitive function, resource use, and employment status, in relation to Interferon beta-1b treatment.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Sep 2013
    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
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Slovenia: 4
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Israel: 3
    Worldwide total number of subjects
    278
    EEA total number of subjects
    258
    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)
    278
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 19 countries from 20 September 2013 (first subject first visit) to 11 April 2014 (last subject last visit). Subjects who did not participate in a physical/face-to-face visit, had the option of being assessed via telephone on selected key outcomes, in an attempt to keep the subject's ascertainment as high as possible.

    Pre-assignment
    Screening details
    All subjects who were randomized and treated at least once in the BENEFIT Study NCT00185211 (inclusive of subjects, who prematurely discontinued study participation in that study) and enrolled into the BENEFIT 11 Study 2012-005262-35. Of 468 subjects from original BENEFIT study, a total of 278 subjects were enrolled into the BENEFIT 11 study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)
    Arm description
    Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Beta-1b (IFNB-1b)
    Investigational medicinal product code
    BAY86-5046
    Other name
    Betaserons, Betaferon
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

    Arm title
    Initial Placebo
    Arm description
    Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Started
    167
    111
    Completed
    167
    109
    Not completed
    0
    2
         Death
    -
    1
         Unspecified reason
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)
    Reporting group description
    Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

    Reporting group title
    Initial Placebo
    Reporting group description
    Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

    Reporting group values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo Total
    Number of subjects
    167 111 278
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.2 ± 7.5 30.8 ± 7.2 -
    Gender categorical
    Units: Subjects
        Female
    122 73 195
        Male
    45 38 83

    End points

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    End points reporting groups
    Reporting group title
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046)
    Reporting group description
    Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study; continued in BENEFIT Follow-up (305207 / 91031/ NCT00185211) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

    Reporting group title
    Initial Placebo
    Reporting group description
    Initial placebo treatment administered in original BENEFIT (304747 / 92012 / NCT00185211) study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. Subjects at the time of this current study assessment were on any treatment or had no treatment, upon their choice.

    Subject analysis set title
    BENEFIT 11 set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    BENEFIT 11 set is a subset of the FAS and included all subjects who were enrolled in the BENEFIT 11 study (16401) and treated with IFNB-1b (N=167) and Placebo (N=111).

    Primary: Time to First Relapse by Kaplan-Meier Estimates

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    End point title
    Time to First Relapse by Kaplan-Meier Estimates
    End point description
    Relapses are key features of the clinical presentation of multiple sclerosis. Relapses were assessed retrospectively based on clinical records and subject history. Time to first relapse is the difference from date of first relapse to the date of the BENEFIT baseline visit +1 or time to first relapse is the difference from date of last clinical visit to the date of the BENEFIT baseline visit + 1 (right censored).
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [1]
    111 [2]
    Units: cumulative probability of relapse
        number (not applicable)
    71.9
    77.5
    Notes
    [1] - BENEFIT 11 set
    [2] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1034
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0991
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.792
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.045

    Primary: Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

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    End point title
    Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates
    End point description
    CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1 and a total EDSS of >=2.5. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in multiple sclerosis (MS) in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = the difference from date of CDMS to the date of Day 1 + 1 or time to CDMS = the difference from date of last clinical visit to the Day 1+1 (right censored).
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [3]
    111 [4]
    Units: cumulative probability of CDMS
        number (not applicable)
    68.1
    74.8
    Notes
    [3] - BENEFIT 11 set
    [4] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1307
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1204
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.799
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.601
         upper limit
    1.061

    Primary: Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria

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    End point title
    Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria [5]
    End point description
    MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space (DIS) and dissemination in time (DIT) were established by magnetic resonance imaging (MRI) criteria or a new relapse. Number of subjects with diagnosis of MS within 11 years after CIS according to McDonald 2001 and 2010 criteria were reported. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Primary
    End point timeframe
    Year 11
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    159 [6]
    107 [7]
    Units: Subjects
        McDonald 2010: DIS (n=159,107)
    154
    105
        McDonald 2010: DIT (n=159,107)
    154
    106
        McDonald 2010: McDonald MS (n=159,107)
    150
    104
        McDonald 2001: DIS (n=155,106)
    152
    104
        McDonald 2001: DIT (n=155,106)
    150
    103
        McDonald 2001: McDonald MS (n=155,106)
    148
    102
    Notes
    [6] - BENEFIT 11 set with evaluable subjects
    [7] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Primary: Disease Course as Assessed at the Time of BENEFIT 11

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    End point title
    Disease Course as Assessed at the Time of BENEFIT 11 [8]
    End point description
    Current diagnosis of MS type were categorized with regard to McDonald 2001 and McDonald 2010 criteria were recorded. CIS and silent disease (no relapse, no sustained EDSS progression and no new MRI lesion), McDonald MS not fulfilling the criteria for CDMS, RRMS (CDMS with relapses without evidence for a secondary disease course), SPMS (CDMS with relapses and evidence for a progressive disease course), Revised diagnosis (other reason than MS found for CIS) and Not assessable. Not assessable means McDonald 2001 and McDonald 2010 criteria could not be judged due to missing MRI scan at BENEFIT 11. Number of subjects with current diagnosis of MS at the time of BENEFIT 11 was assessed.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [8] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [9]
    111 [10]
    Units: subjects
        McDonald2001: CIS and silent disease
    19
    15
        McDonald2001: Not fulfilling the criteria for CDMS
    10
    3
        McDonald2001: RRMS
    127
    87
        McDonald2001: SPMS
    7
    5
        McDonald2001: Revised diagnosis
    1
    0
        McDonald2001: Not assessable
    3
    1
        McDonald2010: CIS and silent disease
    19
    15
        McDonald2010: Not fulfilling the criteria for CDMS
    10
    4
        McDonald2010: RRMS
    127
    87
        McDonald2010: SPMS
    7
    5
        McDonald2010: Revised diagnosis
    1
    0
        McDonald2010: Not assessable
    2
    0
        McDonald2010: CIS not qualifying for McDonald MS
    1
    0
    Notes
    [9] - BENEFIT 11 set
    [10] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS)

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    End point title
    Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS) [11]
    End point description
    SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Percentage of subjects converting to SPMS were stratified by actual treatment group and baseline EDSS. Baseline EDSS defined as lowest of the EDSS scores obtained during BENEFIT screening or baseline (less than or equal to [<=] median or greater than [>] median). In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [11] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [12]
    111 [13]
    Units: percentage of subjects
    number (not applicable)
        Baseline EDSS <= median (N=100,64)
    9
    7.8
        Baseline EDSS > median (N=67,47)
    4.5
    10.6
    Notes
    [12] - BENEFIT 11 set
    [13] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

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    End point title
    Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates
    End point description
    SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Time to SPMS was represented by Kaplan-Meier estimates.
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [14]
    111 [15]
    Units: cumulative probability of SPMS
        number (not applicable)
    4.8
    9
    Notes
    [14] - BENEFIT 11 set
    [15] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.525
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is, IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.504
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.751
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.324
         upper limit
    1.741

    Primary: Expanded Disability Status Scale (EDSS) at Year 11

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    End point title
    Expanded Disability Status Scale (EDSS) at Year 11 [16]
    End point description
    The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [16] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [17]
    111 [18]
    Units: subjects
        EDSS score: 0
    31
    11
        EDSS score: 1
    20
    18
        EDSS score: 1.5
    25
    18
        EDSS score: 2
    23
    20
        EDSS score: 2.5
    19
    9
        EDSS score: 3
    18
    11
        EDSS score: 3.5
    13
    8
        EDSS score: 4
    6
    8
        EDSS score: 4.5
    3
    2
        EDSS score: 5
    4
    0
        EDSS score: 5.5
    0
    0
        EDSS score: 6
    2
    5
        EDSS score: 6.5
    1
    1
        EDSS score: 7
    1
    0
        EDSS score: 7.5
    0
    0
        EDSS score: 8
    1
    0
    Notes
    [17] - BENEFIT 11 set
    [18] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11

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    End point title
    Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11 [19]
    End point description
    The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. EDSS progression was defined as an increase in the EDSS of at least 1.0 point compared to initial EDSS score or an increase in the EDSS of at least 1.5 points compared to initial EDSS score, if this score was = 0 points. Confirmed EDSS progression status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. A confirmed EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies or EDSS progression in BENEFIT 11. A sustained EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies sustained up to and including the BENEFIT 11 visit.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [19] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [20]
    111 [21]
    Units: subjects
        Confirmed 1-point EDSS progression
    75
    52
        Sustained 1-point EDSS progression
    31
    27
    Notes
    [20] - BENEFIT 11 set
    [21] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11

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    End point title
    Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11 [22]
    End point description
    The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale. EDSS progression was defined as an increase in the EDSS of at least 2.5 points compared to initial EDSS score, if this score was <= 3.5 points, or an increase in the EDSS of at least 2.0 points compared to initial EDSS score, if this score was > 3.5 points. Confirmed EDSS increase status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS increase confirmed at scheduled visits after at least 140 days. A confirmed EDSS increase is defined as a confirmed EDSS increase in any of the previous BENEFIT studies or EDSS increase in BENEFIT 11.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [22] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [23]
    111 [24]
    Units: subjects
    19
    14
    Notes
    [23] - BENEFIT 11 set
    [24] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6

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    End point title
    Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6 [25]
    End point description
    The DSS 3, and DSS 6 are important milestones in the course of disability progression and were documented if reached by the subject.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [25] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [26]
    111 [27]
    Units: percentage of subjects
    number (not applicable)
        DSS 3 reached
    27.5
    28.8
        DSS 6 reached
    3
    4.5
    Notes
    [26] - BENEFIT 11 set
    [27] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

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    End point title
    Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates
    End point description
    The DSS 3 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 3 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 3 at Year 11 were estimated by Kaplan-Meier.
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [28]
    111 [29]
    Units: cumulative probability of DSS 3
        number (not applicable)
    19.1
    27.6
    Notes
    [28] - BENEFIT 11 set
    [29] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5609
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 4, 5 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4768
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.525
         upper limit
    1.351

    Primary: Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

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    End point title
    Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates
    End point description
    The DSS 6 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 6 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 6 at Year 11 were estimated by Kaplan-Meier.
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [30]
    111 [31]
    Units: cumulative probability of DSS 6
        number (not applicable)
    3
    3.7
    Notes
    [30] - BENEFIT 11 set
    [31] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5011
    Method
    Logrank
    Confidence interval

    Primary: Multiple Sclerosis Functional Composite (MSFC) at Year 11

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    End point title
    Multiple Sclerosis Functional Composite (MSFC) at Year 11 [32]
    End point description
    The MSFC score consists of three subtests (Timed 25 Foot Walk, 9 Hole Peg Test, 3" Paced Auditory Serial Addition Test [PASAT]) whose Z-standardized results (based on baseline values on Day 1 in Study 304747) were combined into a composite score including upper and lower extremities function, and cognitive function. Standardized results (Z-scores) of the subtests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [32] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    127 [33]
    87 [34]
    Units: Z-scores
        median (inter-quartile range (Q1-Q3))
    -0.137 (-0.765 to 0.307)
    0.014 (-0.548 to 0.269)
    Notes
    [33] - BENEFIT 11 set with evaluable subjects
    [34] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Primary: Multiple Sclerosis Severity Score (MSSS) at Year 11

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    End point title
    Multiple Sclerosis Severity Score (MSSS) at Year 11 [35]
    End point description
    The MSSS added the element of disease duration to the EDSS and was designed to provide a measure of disease severity. It was derived from the EDSS during the data evaluation. The MSSS corrects the EDSS for the duration of disease by using an arithmetical method to compare an individual’s disability with the distribution of scores in case of having equivalent disease duration.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [35] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [36]
    111 [37]
    Units: scores on a scale
        median (inter-quartile range (Q1-Q3))
    1.978 (0.641 to 3.246)
    1.978 (0.641 to 3.246)
    Notes
    [36] - BENEFIT 11 set
    [37] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

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    End point title
    Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11
    End point description
    The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability.
    End point type
    Primary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    133 [38]
    90 [39]
    Units: PASAT-3 total scores
        median (inter-quartile range (Q1-Q3))
    56 (50 to 59)
    56 (49 to 59)
    Notes
    [38] - BENEFIT 11 set with evaluable subjects
    [39] - BENEFIT 11 set with evaluable subjects
    Statistical analysis title
    Statistical analysis 1: PASAT-3 score at baseline
    Statistical analysis description
    Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Linear
    Parameter type
    longitudinal linear mixed model
    Point estimate
    0.7415
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6829
         upper limit
    0.8001
    Statistical analysis title
    Statistical analysis 2: Treatment (IFNB-1b)
    Statistical analysis description
    Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0083
    Method
    Regression, Linear
    Parameter type
    longitudinal linear mixed model
    Point estimate
    1.3346
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3461
         upper limit
    2.323
    Statistical analysis title
    Statistical analysis 3: Time
    Statistical analysis description
    Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.016
    Method
    Regression, Linear
    Parameter type
    longitudinal linear mixed model
    Point estimate
    -0.0138
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0251
         upper limit
    -0.0026
    Statistical analysis title
    Statistical analysis 4: Time*Treatment (IFNB-1b)
    Statistical analysis description
    Parametric longitudinal linear mixed model, including PASAT-3 score at baseline in addition to time and initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8947
    Method
    Regression, Linear
    Parameter type
    longitudinal linear mixed model
    Point estimate
    -0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0155
         upper limit
    0.0136
    Statistical analysis title
    Statistical analysis 5: PASAT-3 at baseline-ANCOVA
    Statistical analysis description
    Parametric analysis of covariance including PASAT-3 score at baseline in addition to initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical analysis 6: Treatment - ANCOVA
    Statistical analysis description
    Parametric analysis of covariance including PASAT-3 score at baseline in addition to initial treatment. An inferential statistical analysis included subjects with baseline and post-baseline values, hence number of subjects analysed for this analysis were 222. EudraCT database does auto-addition of number of subjects while reporting an explorative analysis of two treatment groups. Due to this format constraint, below table represents number of subjects in this analysis as 223.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.422
    Method
    ANCOVA
    Confidence interval

    Primary: Cognitive function: Symbol Digit Modalities Test (SDMT)

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    End point title
    Cognitive function: Symbol Digit Modalities Test (SDMT)
    End point description
    The Symbol Digit Modalities Test (SDMT) is a cognitive test for sustained attention, concentration, and information-processing speed, with a high sensitivity. Nine different geometrical symbols have one corresponding number each. One-hundred-ten symbols are presented without these numbers; the subject must find the matching number from the top line and verbalize the number to the examiner. The subject is allowed to proceed for 90 seconds, and the number of correct responses in 90 seconds is counted as the total correct score. Also, the numbers of correct responses at 30 and 60 seconds were recorded in this study. Total score ranged from 0 (worst outcome) to best (outcome). In the below table, "N" signifies number of subjects analysed who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Primary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [40]
    111 [41]
    Units: correct response
    median (inter-quartile range (Q1-Q3))
        Number of correct responses in 30 sec (N=131,85)
    19 (16 to 21)
    19 (16 to 21)
        Number of correct responses in 60 sec (N=131,85)
    34 (28 to 40)
    34 (28 to 40)
        Number of correct responses in 90 sec (N=141,92)
    53 (42 to 60)
    52.5 (44.5 to 59)
    Notes
    [40] - BENEFIT 11 set
    [41] - BENEFIT 11 set
    Statistical analysis title
    Time*Treatment (2nd interval, IFNB-1b)
    Statistical analysis description
    Parametric linear mixed-effect model including age and education status (categorized as primary school, high school diploma, vocational school diploma, collegial studies, university diploma) at BENFIT 11 in addition to time interval and initial treatment group.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7396
    Method
    Parametric linear mixed-effect model
    Parameter type
    SDMT scores
    Point estimate
    0.228
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1195
         upper limit
    1.5754
    Statistical analysis title
    Time*Treatment (3rd interval, IFNB-1b)
    Statistical analysis description
    Parametric linear mixed-effect model including age and education status (categorized as primary school, high school diploma, vocational school diploma, collegial studies, university diploma) at BENFIT 11 in addition to time interval and initial treatment group.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1352
    Method
    Parametric linear mixed-effect model
    Parameter type
    SDMT scores
    Point estimate
    -1.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3734
         upper limit
    0.3215

    Primary: Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses

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    End point title
    Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses [42]
    End point description
    A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right censored if a relapse risk period ended without relapse. Based on the Andersen Gill model the hazard ratio for recurrent relapses was estimated with actual treatment in BENEFIT (304747; i.e. IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) included in the model.
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [42] - 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: EudraCT database does not allow to report only one treatment group in statistical analyses section. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    BENEFIT 11 set
    Number of subjects analysed
    278 [43]
    Units: ratio
        number (not applicable)
    0.821
    Attachments
    Statistical Analysis_HR for Recurrent Relapses
    Notes
    [43] - BENEFIT 11 set
    No statistical analyses for this end point

    Primary: Relapse Based Efficacy Domain: Annualized Relapse Rate

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    End point title
    Relapse Based Efficacy Domain: Annualized Relapse Rate
    End point description
    The annualized relapse rate is defined as total number of relapses up to Year 11 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all subjects) in years.
    End point type
    Primary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [44]
    111 [45]
    Units: number of relapses per subject and year
        arithmetic mean (confidence interval 95%)
    0.2123 (0.192 to 0.2341)
    0.2536 (0.2264 to 0.2831)
    Notes
    [44] - BENEFIT 11 set
    [45] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Relapse rate was analyzed by a generalized linear Poisson regression model with individual relapse counts as dependent variable, covariates: actual treatment in BENEFIT (304747; i.e., IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, >=9) and offset variable natural log of time (in years) as difference between last clinical and baseline visits+1.
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0094
    Method
    generalized linear Poisson regression
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.8224
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7096
         upper limit
    0.9531

    Primary: Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

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    End point title
    Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates
    End point description
    Date of use of ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to use of ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [46]
    111 [47]
    Units: cumulative probability of device usage
        number (not applicable)
    4.2
    7.3
    Notes
    [46] - BENEFIT 11 set
    [47] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2895
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2951
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.581
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.211
         upper limit
    1.605

    Primary: Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

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    End point title
    Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates
    End point description
    Date of dependence from ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to dependence from ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1. Cumulative probability of dependence of ambulatory device for walking represented by Kaplan-Meier estimates at Year 11.
    End point type
    Primary
    End point timeframe
    Up to Year 11 (Day 3960)
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [48]
    111 [49]
    Units: probability of subjects
        number (not applicable)
    4.2
    7.3
    Notes
    [48] - BENEFIT 11 set
    [49] - BENEFIT 11 set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2904
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    An increase in hazard is indicated by hazard ratios greater than (>) 1. Covariates included actual treatment in BENEFIT (304747; that is IFNB-1b 250 microgram versus placebo), steroid use during first event (yes versus no), onset of disease (multifocal versus monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2 - 4, 5 - 8, >=9).
    Comparison groups
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) v Initial Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2957
    Method
    PH regression
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.582
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.211
         upper limit
    1.606

    Primary: Number of Subjects With Wheelchair Use After 11 years

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    End point title
    Number of Subjects With Wheelchair Use After 11 years [50]
    End point description
    End point type
    Primary
    End point timeframe
    Year 11
    Notes
    [50] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [51]
    111 [52]
    Units: subjects
    2
    1
    Notes
    [51] - BENEFIT 11 set
    [52] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Education Status at Year 11

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    End point title
    Education Status at Year 11
    End point description
    Subjects with educational status was categorized as primary school, high school diploma, vocational diploma, collegial studies, university diploma, and missing educational status.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [53]
    111 [54]
    Units: subjects
        Missing
    1
    1
        Primary school
    17
    11
        High school diploma
    41
    34
        Vocational diploma
    28
    18
        Collegial studies
    33
    17
        University diploma
    47
    30
    Notes
    [53] - BENEFIT 11 set
    [54] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Living Conditions at Year 11

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    End point title
    Living Conditions at Year 11
    End point description
    Subjects living condition were categorized as 'living alone', 'long term care facility', living with spouse, partner, family', 'other' and 'missing'.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [55]
    111 [56]
    Units: subjects
        Missing
    1
    0
        Living alone
    20
    12
        Long term care facility
    3
    0
        Living with spouse, partner, family
    141
    98
        Other
    2
    1
    Notes
    [55] - BENEFIT 11 set
    [56] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Employment Status at Year 11

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    End point title
    Employment Status at Year 11
    End point description
    Subject's employment status was categorized as 'retired', 'homemaker', 'long term disability', 'employment less than 20 hours (hrs) per week (hrs/week)', employment more than 20 hours per week, 'early retired', 'other', and 'missing'.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [57]
    111 [58]
    Units: subjects
        Missing
    1
    0
        Retired
    0
    4
        Homemaker
    14
    9
        Long term disability
    7
    5
        Employment, less than 20 hrs/week
    14
    11
        Employment, more than 20 hrs/week
    111
    68
        Early retired
    13
    9
        Other
    7
    5
    Notes
    [57] - BENEFIT 11 set
    [58] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Multiple Sclerosis Impact on Employment at Year 11

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    End point title
    Multiple Sclerosis Impact on Employment at Year 11
    End point description
    Subject's MS impact on employment was categorized as, 'unrelated to MS condition', 'ceased work due to MS', 'never worked', 'reduced working hours', or missing.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [59]
    111 [60]
    Units: subjects
        Missing
    1
    1
        Unrelated to MS condition
    108
    71
        Ceased work due to MS
    22
    15
        Never worked
    5
    1
        Reduced working hours
    31
    23
    Notes
    [59] - BENEFIT 11 set
    [60] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Resource Use: Hospitalization During Last 12 months

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    End point title
    Resource Use: Hospitalization During Last 12 months
    End point description
    Hospitalizations were assessed at year 11 only referring to past 12 months. Number of hospitalizations per subject were categorized as, 'none', '1', '2', '3', and '6'.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [61]
    111 [62]
    Units: subjects
        Number of hospitalizations per subject: none
    154
    100
        Number of hospitalizations per subject: 1
    12
    8
        Number of hospitalizations per subject: 2
    0
    1
        Number of hospitalizations per subject: 3
    1
    1
        Number of hospitalizations per subject: 6
    0
    1
    Notes
    [61] - BENEFIT 11 set
    [62] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Resource Use: Visits to Other Specialists During Last 12 months

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    End point title
    Resource Use: Visits to Other Specialists During Last 12 months
    End point description
    Visits to Other Specialists were assessed at year 11 only referring to past 12 months. The visits to other specialists were categorized as, 'missing', 'no', 'yes', 'never', and 'unsure'. The other specialists includes, neurologist, nurse clinician, home health aide, visiting nurse, physiotherapist, psychiatrist, psychologist, physician, urologist, social worker and gynecologist.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [63]
    111 [64]
    Units: subjects
        Neurologist: missing
    7
    1
        Neurologist: no
    19
    16
        Neurologist: yes
    134
    86
        Neurologist: never
    5
    6
        Neurologist: unsure
    2
    2
        Nurse clinician: missing
    14
    2
        Nurse clinician: no
    39
    30
        Nurse clinician: yes
    58
    34
        Nurse clinician: never
    55
    45
        Nurse clinician: unsure
    1
    0
        Home health aide: missing
    17
    2
        Home health aide: no
    24
    16
        Home health aide: yes
    4
    2
        Home health aide: never
    120
    89
        Home health aide: unsure
    2
    2
        Visiting nurse: missing
    17
    2
        Visiting nurse: no
    27
    19
        Visiting nurse: yes
    4
    6
        Visiting nurse: never
    119
    83
        Visiting nurse: unsure
    0
    1
        Physiotherapist: missing
    16
    2
        Physiotherapist: no
    31
    27
        Physiotherapist: yes
    37
    27
        Physiotherapist: never
    80
    52
        Physiotherapist: unsure
    3
    3
        Psychiatrist: missing
    16
    3
        Psychiatrist: no
    28
    21
        Psychiatrist: yes
    16
    13
        Psychiatrist: never
    106
    73
        Psychiatrist: unsure
    1
    1
        Psychologist: missing
    16
    2
        Psychologist: no
    34
    22
        Psychologist: yes
    12
    15
        Psychologist: never
    103
    71
        Psychologist: unsure
    2
    1
        Physician: missing
    12
    2
        Physician: no
    24
    20
        Physician: yes
    88
    60
        Physician: never
    32
    25
        Physician: unsure
    11
    4
        Urologist: missing
    16
    2
        Urologist: no
    33
    26
        Urologist: yes
    10
    12
        Urologist: never
    107
    70
        Urologist: unsure
    1
    1
        Social worker: missing
    17
    3
        Social worker: no
    25
    21
        Social worker: yes
    3
    9
        Social worker: never
    120
    77
        Social worker: unsure
    2
    1
        Gynecologist: missing
    15
    4
        Gynecologist: no
    38
    20
        Gynecologist: yes
    53
    39
        Gynecologist: never
    53
    42
        Gynecologist: unsure
    8
    6
    Notes
    [63] - BENEFIT 11 set
    [64] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services

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    End point title
    Resource Use Assessment Questionnaire: Help from Family/Regular Ambulatory Services
    End point description
    Resources use data was assessed cross-sectionally at 11 years. Supportive care was assessed as “assistance given” for the help from family members or friends with “care given” for the number f hors per week needed, as well as “ambulatory services-yes/no” with sub-categories home care, home help, day care center, meals on wheels and child care for the help from professional caregiver.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [65]
    111 [66]
    Units: subjects
        Assistance given: missing
    0
    1
        Assistance given: no
    142
    92
        Assistance given: yes
    25
    18
        Care given: missing
    1
    1
        Care given: none
    142
    92
        Care given: 1-8 hours/week
    16
    11
        Care given: 9-16 hours/week
    3
    6
        Care given: 17-24 hours/week
    2
    0
        Care given: 32-40 hours/week
    1
    1
        Care given: >40 hours/week
    2
    0
        Ambulatory services: missing
    0
    1
        Ambulatory services: no
    162
    107
        Ambulatory services: yes
    5
    3
        Home care: missing
    0
    1
        Home care: no
    167
    109
        Home care: yes
    0
    1
        Home help: missing
    0
    1
        Home help: no
    162
    108
        Home help: yes
    5
    2
        Day care center: missing
    0
    1
        Day care center: no
    167
    110
        Meals on wheels: missing
    0
    1
        Meals on wheels: no
    167
    110
        Child care: missing
    0
    1
        Child care: no
    167
    110
    Notes
    [65] - BENEFIT 11 set
    [66] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse

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    End point title
    Resource Use Assessment Questionnaire: Additional Ambulatory Services During Relapse
    End point description
    Resources use data was assessed cross-sectionally at 11 years. Additional ambulatory services during relapse were categorized as, 'missing', 'no', and 'yes'. The additional ambulatory services during relapses were home care, home help, day care center, meals on wheels, and child care.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [67]
    111 [68]
    Units: subjects
        Ambulatory services during relapse: missing
    0
    2
        Ambulatory services during relapse: no
    161
    106
        Ambulatory services during relapse: yes
    6
    3
        Home care: missing
    0
    2
        Home care: no
    167
    109
        Home help: missing
    0
    2
        Home help: no
    164
    107
        Home help: yes
    3
    2
        Day care center: missing
    0
    2
        Day care center: no
    166
    108
        Day care center: yes
    1
    1
        Meals on wheels: missing
    0
    2
        Meals on wheels: no
    166
    109
        Meals on wheels: yes
    1
    0
        Child care: missing
    0
    2
        Child care: no
    166
    109
        Child care: yes
    1
    0
    Notes
    [67] - BENEFIT 11 set
    [68] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Resource Use Assessment Questionnaire: Adaptions past 6 months

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    End point title
    Resource Use Assessment Questionnaire: Adaptions past 6 months
    End point description
    Resources use data was assessed cross-sectionally at 11 years. The kind of adaptation was categorized as “other part of living”, “star lift”. “ramps”, “alarm”, “work”, “car”, “walking aids”, “wheel chair”, “spectacles”, “special kitchen utensils”, “special hygiene utensils”, “special writing devices” and “ other” with sub-categories as 'missing', 'no', and 'yes'.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [69]
    111 [70]
    Units: subjects
        Adaptions: missing
    0
    1
        Adaptions: no
    156
    100
        Adaptions: yes
    11
    10
        Other part of living: missing
    0
    1
        Other part of living: no
    165
    106
        Other part of living: yes
    2
    4
        Stair lift: missing
    0
    1
        Stair lift: no
    167
    110
        Stair lift: yes
    0
    0
        Ramps: missing
    0
    1
        Ramps: no
    166
    110
        Ramps: yes
    1
    0
        Alarm: missing
    0
    1
        Alarm: no
    167
    110
        Work: missing
    0
    1
        Work: no
    166
    109
        Work: yes
    1
    1
        Car: missing
    0
    1
        Car: no
    162
    107
        Car: yes
    5
    3
        Walking aids: missing
    0
    1
        Walking aids: no
    163
    105
        Walking aids: yes
    4
    5
        Wheel chair: missing
    0
    1
        Wheel chair: no
    165
    109
        Wheel chair: yes
    2
    1
        Spectacles: missing
    0
    1
        Spectacles: no
    167
    110
        Special kitchen utensils: missing
    0
    1
        Special kitchen utensils: no
    165
    109
        Special kitchen utensils: yes
    2
    1
        Special hygiene utensils: missing
    0
    1
        Special hygiene utensils: no
    163
    110
        Special hygiene utensils: yes
    4
    0
        Special writing devices: missing
    0
    1
        Special writing devices: no
    167
    110
        Other: missing
    0
    1
        Other: no
    165
    109
        Other: yes
    2
    1
    Notes
    [69] - BENEFIT 11 set
    [70] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11

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    End point title
    Patient-Reported Outcomes (PRO)-based Efficacy Domain: Center of Epidemiological Studies Depression Scale (CES-D) Total Score at Year 11
    End point description
    The CES-D is a measure of depressive symptomatology. The CES-D was a self-administered questionnaire for adults comprising 20 items which evaluated the frequency and severity of depressive symptoms. Subjects were asked to recall the previous 7 days. The total score (0-60) was the sum of the scores of the 20 items. A score of >= 16 suggested a mild to moderate level of depressive symptoms; a score >21 suggested major depressive symptoms.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    165 [71]
    110 [72]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    12.44 ± 11.91
    12.12 ± 11.15
    Notes
    [71] - BENEFIT 11 set with evaluable subjects
    [72] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)

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    End point title
    PRO-based Efficacy Domain: Fatigue Scale for Sensory and Motor Functions (FSMC)
    End point description
    The cognitive and physical fatigue was assessed by the FSMC. The scale comprised of 20 questions (10 items for physical and 10 items for cognitive fatigue) and could be completed within 5 minutes. The items are rated on a 5-point Likert scale (1=does not apply at all to 5=applies completely). The FSMC total score ranges from 20 to 100 where a higher score is associated with a higher severity of fatigue.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    161 [73]
    110 [74]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    49.08 ± 22.68
    47.23 ± 23.11
    Notes
    [73] - BENEFIT 11 set with evaluable subjects
    [74] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11

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    End point title
    Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Year 11
    End point description
    The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales (mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns). FAMS-TOI is the sum of the subscale scores mobility, symptoms, thinking/fatigue, and additional concerns. The items were rated on a 5-point scale (0 to 4). Score range of FAM-TOI is 0 to 148; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    162 [75]
    108 [76]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    110.82 ± 28.09
    111.91 ± 26.08
    Notes
    [75] - BENEFIT 11 set with evaluable subjects
    [76] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11

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    End point title
    Functional Assessment of Multiple Sclerosis (FAMS) Total Score at Year 11
    End point description
    The Functional Assessment of Multiple Sclerosis (FAMS) instrument is a self-reporting, multi-dimensional, health-related QoL index for use in subjects diagnosed with MS. It comprised 58 items on 7 subscales: mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns. The items were rated on a 5-point scale (0 to 4). Total score is sum of all sub-scale scores except 14 items for "Additional concerns", ranging 0 to 176; the higher the score, the higher the quality of life. The evaluation period was the previous 7 days.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    162 [77]
    108 [78]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    133.99 ± 33.03
    134.93 ± 30.67
    Notes
    [77] - BENEFIT 11 set with evaluable subjects
    [78] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11

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    End point title
    PRO-based Efficacy Domain: European Quality of Life – 5 Dimensions (EQ-5D) Score at Year 11
    End point description
    The EQ-5D measured five state-of-health dimensions: mobility, self-care, usual activities (work, leisure, etc.), pain/discomfort, and anxiety/depression. Every item had a score of 1 (no problems), 2 (some/moderate problems), or 3 (extreme problems). An individual’s health status was defined in a combination of 5 digits. Subjects with missing answers to all questions were not considered for the respective visit.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    166 [79]
    110 [80]
    Units: subjects
        EQ-5D, question 1, mobility: missing
    1
    0
        EQ-5D, question 1, mobility: 1
    119
    79
        EQ-5D, question 1, mobility: 2
    46
    31
        EQ-5D, question 2, self care: missing
    0
    0
        EQ-5D, question 2, self care: 1
    150
    99
        EQ-5D, question 2, self care: 2
    15
    11
        EQ-5D, question 2, self care: 3
    1
    0
        EQ-5D, question 3, usual activities: missing
    0
    0
        EQ-5D, question 3, usual activities: 1
    120
    77
        EQ-5D, question 3, usual activities: 2
    44
    31
        EQ-5D, question 3, usual activities: 3
    2
    2
        EQ-5D, question 4, pain/ discomfort: missing
    0
    0
        EQ-5D, question 4, pain/ discomfort: 1
    88
    62
        EQ-5D, question 4, pain/ discomfort: 2
    71
    48
        EQ-5D, question 4, pain/ discomfort: 3
    7
    0
        EQ-5D, question 5, anxiety/ depression: missing
    0
    0
        EQ-5D, question 5, anxiety/ depression: 1
    107
    60
        EQ-5D, question 5, anxiety/ depression: 2
    52
    46
        EQ-5D, question 5, anxiety/ depression
    7
    4
    Notes
    [79] - BENEFIT 11 set with evaluable subjects
    [80] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: European Quality of Life – 5 Dimensions (EQ-5D) Health-related quality of life (HRQoL) Score at Year 11

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    End point title
    European Quality of Life – 5 Dimensions (EQ-5D) Health-related quality of life (HRQoL) Score at Year 11
    End point description
    Based on large population surveys, an algorithm was developed to combine the recordings of each of these five EQ-5D dimensions in 1 single HRQoL score, ranging from +1 (best imaginable HRQoL score) to -0.59 (worst imaginable HRQoL score). A relatively higher score represents better quality of life.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    165 [81]
    110 [82]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.7842 ± 0.2487
    0.7965 ± 0.2
    Notes
    [81] - BENEFIT 11 set with evaluable subjects
    [82] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Number of Subjects who Started Second Line Therapy at Year 11

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    End point title
    Number of Subjects who Started Second Line Therapy at Year 11
    End point description
    Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. Subjects received second line therapy as a MS treatment such as alemtuzumab, cyclophosphamide, ciclosporin, fingolimod, methotrexate, mycophenolate mitoxantrone, natalizumab, etc.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [83]
    111 [84]
    Units: subjects
    31
    24
    Notes
    [83] - BENEFIT 11 set
    [84] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Number of Subjects who Started First Disease-Modifying Treatment (DMT) other than IFNB at Year 11

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    End point title
    Number of Subjects who Started First Disease-Modifying Treatment (DMT) other than IFNB at Year 11
    End point description
    Subjects were treated exclusively at the discretion of their treating physician and according to locally applicable standards and treatment guidelines. All DMTs other than interferon beta, interferon beta-1a und interferon beta-1b were recorded as DMT other than IFNB.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [85]
    111 [86]
    Units: subjects
    54
    39
    Notes
    [85] - BENEFIT 11 set
    [86] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Magnet-Resonance Imaging (MRI): Number of Newly Active Lesions

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    End point title
    Magnet-Resonance Imaging (MRI): Number of Newly Active Lesions
    End point description
    Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Newly active lesions defined as displaying either new enhancement on T1-weighted scans, or non-enhancing on T1-weighted scan but new on T2-weighted scans.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    114 [87]
    77 [88]
    Units: subjects
        Gd-enhancing lesions on T1: missing
    6
    4
        Gd-enhancing lesions on T1: 0
    96
    69
        Gd-enhancing lesions on T1: 1
    7
    3
        Gd-enhancing lesions on T1: 2-5
    5
    1
        New lesions in T2: missing
    1
    1
        New lesions in T2: 0
    37
    26
        New lesions in T2: 1
    13
    9
        New lesions in T2: 2-5
    34
    19
        New lesions in T2: 6-9
    10
    10
        New lesions in T2: >=10
    19
    12
        Hypointense lesions on T1: missing
    2
    2
        Hypointense lesions on T1: 0
    17
    16
        Hypointense lesions on T1: 1
    16
    11
        Hypointense lesions on T1: 2-5
    33
    29
        Hypointense lesions on T1: 6-9
    13
    10
        Hypointense lesions on T1: >=10
    33
    9
        Count of cortical lesions: missing
    8
    3
        Count of cortical lesions: 0
    27
    21
        Count of cortical lesions: 1
    15
    16
        Count of cortical lesions: 2-5
    39
    23
        Count of cortical lesions: 6-9
    14
    5
        Count of cortical lesions: >=10
    11
    9
    Notes
    [87] - BENEFIT 11 set with evaluable subjects
    [88] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Magnet-Resonance Imaging (MRI): Number of Lesions on T1- and T2-Weighted Scans

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    End point title
    Magnet-Resonance Imaging (MRI): Number of Lesions on T1- and T2-Weighted Scans
    End point description
    Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Number of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [89]
    111 [90]
    Units: lesions
    arithmetic mean (standard deviation)
        Hypointense lesions on T1 (N=112,75)
    7.1 ± 8.9
    4.7 ± 6.6
        New lesions in T2 (N=113,76)
    6 ± 11.4
    4.9 ± 8
    Notes
    [89] - BENEFIT 11 set
    [90] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Magnet-Resonance Imaging (MRI): Volume of Lesions on T1- and T2-Weighted Scans

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    End point title
    Magnet-Resonance Imaging (MRI): Volume of Lesions on T1- and T2-Weighted Scans
    End point description
    Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Volume of lesions on T1- and T2-Weighted scans were recorded. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [91]
    111 [92]
    Units: cubic millimeter
    arithmetic mean (standard deviation)
        Gd-enhancing lesion on T1 (N=108,73)
    16.6 ± 78.7
    4.1 ± 25.5
        Hypointense lesion on T1 (N=112,75)
    1044.8 ± 2294.8
    470.9 ± 742.5
        Hyperintense lesion on T2 (N=113,76)
    4232.9 ± 5920.4
    3139.9 ± 4447.5
    Notes
    [91] - BENEFIT 11 set
    [92] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Magnet-Resonance Imaging (MRI): Normalized Brain Volume

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    End point title
    Magnet-Resonance Imaging (MRI): Normalized Brain Volume
    End point description
    Contrast-enhanced MRI (with an extracellular gadolinium-based contrast agent) technique was used for the evaluation of brain lesions in MS. Brain volume was analysed and reported.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    111 [93]
    72 [94]
    Units: cubic centimeter
        arithmetic mean (standard deviation)
    1496.6 ± 135.4
    1502.1 ± 114.2
    Notes
    [93] - BENEFIT 11 set with evaluable subjects
    [94] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Optical Coherence Tomography (OCT) Parameter - Retinal Nerve Fiber Layer (RNFL)

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    End point title
    Optical Coherence Tomography (OCT) Parameter - Retinal Nerve Fiber Layer (RNFL)
    End point description
    OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. Retinal nerve fiber layer (RNFL) thinning measured by OCT in subjects with MS occurs even in the absence of acute optic neuritis and is associated with worse scores for low-contrast letter acuity and other visual acuity tests. OCT measures peripapillary RNFL. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [95]
    111 [96]
    Units: micrometer
    arithmetic mean (standard deviation)
        Right eye: Global RNFL at 12 degree (N=41,27)
    93.8 ± 11
    89.6 ± 14.3
        Right eye: Global RNFL at 14 degree (N=42,27)
    81.3 ± 8.7
    77 ± 11.5
        Right eye: Global RNFL at 16 degree (N=43,27)
    71.3 ± 8
    67.8 ± 9.9
        Right eye: PMB RNFL at 12 degree (N=41,27)
    48.3 ± 9.6
    47.4 ± 11.1
        Right eye: PMB RNFL at 14 degree (N=42,27)
    42.5 ± 7.5
    41.9 ± 9
        Right eye: PMB RNFL at 16 degree (N=43,27)
    37.7 ± 7.2
    36.2 ± 6.9
        Right eye: Temp. RNFL at 12 degree (N=41,27)
    64.2 ± 12.4
    64 ± 14.7
        Right eye: Temp. RNFL at 14 degree (N=42,27)
    57.9 ± 10.5
    57.4 ± 12.6
        Right eye: Temp. RNFL at 16 degree (N=43,27)
    53.2 ± 9.7
    52.5 ± 10.6
        Left eye: Global RNFL at 12 degree (N=42,26)
    92 ± 11.2
    90.7 ± 15.9
        Left eye: Global RNFL at 14 degree (N=40,25)
    80 ± 9.6
    77.7 ± 14.3
        Left eye: Global RNFL at 16 degree (N=42,26)
    70.6 ± 8.2
    68.4 ± 11.8
        Left eye: PMB RNFL at 12 degree (N=42,26)
    45.3 ± 9.3
    45.2 ± 10.7
        Left eye: PMB RNFL at 14 degree (N=41,25)
    39.6 ± 7.8
    37.7 ± 8.6
        Left eye: PMB RNFL at 16 degree (N=42,26)
    35.6 ± 6.2
    34 ± 6.5
        Left eye: Temp. RNFL at 12 degree (N=42,26)
    58.9 ± 11.3
    58.9 ± 13.7
        Left eye: Temp. RNFL at 14 degree (N=41,25)
    53.2 ± 9.9
    52.1 ± 11.8
        Left eye: Temp. RNFL at 16 degree (N=42,26)
    48.8 ± 8.6
    48.6 ± 9.8
    Notes
    [95] - BENEFIT 11 set
    [96] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Optical Coherence Tomography (OCT) Parameter - Total Macular Volume (TMV)

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    End point title
    Optical Coherence Tomography (OCT) Parameter - Total Macular Volume (TMV)
    End point description
    OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [97]
    111 [98]
    Units: cubic millimeter
    arithmetic mean (standard deviation)
        Right eye: TMV (N=48,28)
    7.798 ± 1.836
    8.044 ± 1.538
        Left eye: TMV (N=45,28)
    7.775 ± 1.929
    8.002 ± 1.536
    Notes
    [97] - BENEFIT 11 set
    [98] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Optical Coherence Tomography (OCT) Parameter - Pupillo Macular Bundle (PMB)

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    End point title
    Optical Coherence Tomography (OCT) Parameter - Pupillo Macular Bundle (PMB)
    End point description
    OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [99]
    111 [100]
    Units: micrometer
    arithmetic mean (standard deviation)
        Right eye: PMB (N=47,26)
    309.4 ± 19
    306.7 ± 15
        Left eye: PMB (N=45,28)
    307.4 ± 17.3
    303.8 ± 18.9
    Notes
    [99] - BENEFIT 11 set
    [100] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Optical Coherence Tomography (OCT) Parameter – Ganglion Cell Inner Plexiform Layer

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    End point title
    Optical Coherence Tomography (OCT) Parameter – Ganglion Cell Inner Plexiform Layer
    End point description
    OCT is a noninvasive ocular imaging recognized in MS as a marker of axonal loss. OCT is a potential method for capturing neuronal in addition to axonal degeneration in MS. In the below table, "N" signifies subjects who were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [101]
    111 [102]
    Units: micrometer
    arithmetic mean (standard deviation)
        Right eye (N=47,31)
    78.9 ± 10.1
    77.6 ± 10.5
        Left eye (N=44,29)
    78.6 ± 9.7
    76.8 ± 13.2
    Notes
    [101] - BENEFIT 11 set
    [102] - BENEFIT 11 set
    No statistical analyses for this end point

    Secondary: Ophthalmological examination – Optic Nerve Head

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    End point title
    Ophthalmological examination – Optic Nerve Head
    End point description
    Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    51 [103]
    32 [104]
    Units: subjects
        Right eye: Optic nerve head-normal
    48
    27
        Right eye: Optic nerve head-abnormal
    3
    5
        Left eye: Optic nerve head-normal
    46
    27
        Left eye: Optic nerve head-abnormal
    5
    5
    Notes
    [103] - BENEFIT 11 set with evaluable subjects
    [104] - BENEFIT 11 set with evaluable subjects
    No statistical analyses for this end point

    Secondary: Ophthalmological examination - Slit lamp Biomicroscopy

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    End point title
    Ophthalmological examination - Slit lamp Biomicroscopy
    End point description
    Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings. Ocular medical and surgical history, visual acuity (Early Treatment Diabetic Retinopathy Study Chart), low-contrast letter acuity (Sloan charts), and eye examination through slit-lamp biomicroscopy were assessed.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    50 [105]
    34 [106]
    Units: subjects
        Right: Anterior segment and vitreous body-missing
    1
    1
        Right: Anterior segment and vitreous body-normal
    48
    31
        Right: Anterior segment and vitreous body-abnormal
    1
    2
        Right: Pupil-missing
    0
    0
        Right: Pupil-normal
    46
    33
        Right: Pupil-abnormal
    4
    1
        Left: Anterior segment and vitreous body-missing
    1
    1
        Left: Anterior segment and vitreous body-normal
    47
    31
        Left: Anterior segment and vitreous body-abnormal
    2
    2
        Left: Pupil-missing
    1
    0
        Left: Pupil-normal
    49
    33
        Left: Pupil-abnormal
    0
    1
    Notes
    [105] - Subjects with ophthalmological examination from BENEFIT 11 set.
    [106] - Subjects with ophthalmological examination from BENEFIT 11 set.
    No statistical analyses for this end point

    Secondary: Ophthalmological examination - Visual Acuity

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    End point title
    Ophthalmological examination - Visual Acuity
    End point description
    Standard clinical ophthalmic examination and test were applied for visual assessment and the differential diagnosis of OCT-related findings. Ocular medical and surgical history, visual acuity (Early Treatment Diabetic Retinopathy Study Chart), low-contrast letter acuity (Sloan charts), and eye examination through slit-lamp biomicroscopy were assessed.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    49 [107]
    30 [108]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Right eye
    86.5 ± 6.9
    87.3 ± 7.1
        Left eye
    86.3 ± 5.7
    83.9 ± 8.7
    Notes
    [107] - Subjects with ophthalmological examination from BENEFIT 11 set.
    [108] - Subjects with ophthalmological examination from BENEFIT 11 set.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Vitamin D Intake

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    End point title
    Number of Subjects with Vitamin D Intake
    End point description
    Number of subjects with intake of Vitamin D were categorized as, 'since beginning of the BENEFIT study', and 'within the past 12 months'.
    End point type
    Secondary
    End point timeframe
    Year 11
    End point values
    Initial Interferon Beta-1b (IFNB-1b, Betaseron, BAY86-5046) Initial Placebo
    Number of subjects analysed
    167 [109]
    111 [110]
    Units: subjects
        Since beginning of the BENEFIT study: missing
    2
    0
        Since beginning of the BENEFIT study: no
    136
    102
        Since beginning of the BENEFIT study: yes
    29
    9
        Within the past 12 months: missing
    21
    11
        Within the past 12 months: no
    100
    68
        Within the past 12 months: yes
    46
    32
    Notes
    [109] - BENEFIT 11 set
    [110] - BENEFIT 11 set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After signing the informed consent form up to the end of study (approximately 1 year)
    Adverse event reporting additional description
    The death reported in this study was not considered an AE or an SAE as per the definitions provided in the protocol, but rather was categorized under “Medical history.”
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    This overall reporting group includes both of the reporting groups below: Initial Interferon Beta-1b: Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 microgram administered subcutaneously every other day in original BENEFIT (304747 / 92012 / NCT00185211) study. Initial Placebo: Initial placebo treatment administered in original BENEFIT study; Betaferon/Betaseron, 250 microgram administered subcutaneous every other day offered in BENEFIT Follow-up (305207 / 91031) phase. At the time of study 16401 subjects were on any MS disease modifying or on no therapy.

    Serious adverse events
    Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 278 (0.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 278 (8.63%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    3 / 278 (1.08%)
         occurrences all number
    3
    MICROANGIOPATHY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Pregnancy, puerperium and perinatal conditions
    PREGNANCY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    General disorders and administration site conditions
    INJECTION SITE INFLAMMATION
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    2
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 278 (1.08%)
         occurrences all number
    3
    FATIGUE
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    PYREXIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Psychiatric disorders
    DYSTHYMIC DISORDER
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    ANXIETY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    DEPRESSION
         subjects affected / exposed
    4 / 278 (1.44%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    RIB FRACTURE
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    LIGAMENT SPRAIN
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    FALL
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Cardiac disorders
    TACHYCARDIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    RHINITIS ALLERGIC
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    ASTHMA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    LEUKOPENIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Nervous system disorders
    EPILEPSY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    DIABETIC NEUROPATHY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    MULTIPLE SCLEROSIS RELAPSE
         subjects affected / exposed
    6 / 278 (2.16%)
         occurrences all number
    11
    PRESYNCOPE
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    GLAUCOMA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Gastrointestinal disorders
    HYPERCHLORHYDRIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    ECZEMA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    PSORIASIS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    LIPOATROPHY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    SKIN REACTION
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    MENISCAL DEGENERATION
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    2 / 278 (0.72%)
         occurrences all number
    2
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    ABNORMAL LOSS OF WEIGHT
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    VITAMIN B12 DEFICIENCY
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    HYPERLIPIDAEMIA
         subjects affected / exposed
    2 / 278 (0.72%)
         occurrences all number
    2
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    Infections and infestations
    FUNGAL SKIN INFECTION
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    SINUSITIS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    PERIODONTITIS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    1 / 278 (0.36%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2013
    This amendment was included following change: - modifications were made to provide clearer study procedures and provide greater consistency; generalized contrast agent procedure guidance instead of confining to Gadobutrol administration; removed references to magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) imaging procedures; clarification of Adverse events reporting details
    05 Dec 2013
    The enrollment date as extended to increase the number of subjects.

    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.
    Results of the DNA, RNA and Biomarkers were not reported as they would be reported in a separate report, as planned.
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