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    Clinical Trial Results:
    A Randomized, Blinded, Parallel-Group, Phase 2 Study Exploring the Safety, Tolerability, and Efficacy of Multiple Regimens of Natalizumab in Adult Subjects With Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    2010-024000-10
    Trial protocol
    BE   DE   ES   IT  
    Global end of trial date
    03 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Feb 2016
    First version publication date
    15 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01405820
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to explore the effects of multiple regimens of natalizumab on disease activity and safety in participants with relapsing-remitting Multiple Sclerosis (RRMS).
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each participant was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Participants were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Italy: 109
    Worldwide total number of subjects
    290
    EEA total number of subjects
    290
    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)
    290
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility for the study was determined within approximately 4 weeks prior to study entry.

    Period 1
    Period 1 title
    Randomized Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Natalizumab 300 mg IV every 4 weeks
    Arm description
    Natalizumab 300 mg intravenous (IV) every 4 weeks for 60 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Arm title
    Natalizumab 300 mg SC every 4 weeks
    Arm description
    Natalizumab 300 mg subcutaneous (SC) every 4 weeks for 60 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for SC Injection
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Arm title
    Natalizumab 300 mg IV every 12 weeks
    Arm description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Investigational medicinal product name
    IV Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Arm title
    Natalizumab 300 mg SC every 12 weeks
    Arm description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.
    Arm type
    Experimental

    Investigational medicinal product name
    SC Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Investigational medicinal product name
    Natalizumab for SC Injection
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Arm title
    Natalizumab 150 mg IV every 12 weeks
    Arm description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Investigational medicinal product name
    IV Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Arm title
    Natalizumab 150 mg SC every 12 weeks
    Arm description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for SC Injection
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Investigational medicinal product name
    SC Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Number of subjects in period 1
    Natalizumab 300 mg IV every 4 weeks Natalizumab 300 mg SC every 4 weeks Natalizumab 300 mg IV every 12 weeks Natalizumab 300 mg SC every 12 weeks Natalizumab 150 mg IV every 12 weeks Natalizumab 150 mg SC every 12 weeks
    Started
    54
    45
    52
    54
    47
    38
    Completed
    43
    35
    9
    3
    2
    1
    Not completed
    11
    10
    43
    51
    45
    37
         Incorrect study treatment
    -
    -
    3
    -
    2
    -
         Physician decision
    -
    2
    1
    -
    -
    -
         Rescue
    -
    1
    13
    10
    8
    8
         Withdrew prior to dosing
    -
    -
    -
    1
    -
    -
         Adverse event, serious fatal
    -
    -
    -
    1
    -
    -
         Treatment arm closed
    -
    -
    20
    36
    33
    28
         Adverse event, non-fatal
    3
    3
    3
    -
    2
    1
         Consent withdrawn by subject
    6
    2
    2
    2
    -
    -
         Not Specified
    2
    2
    1
    1
    -
    -
    Period 2
    Period 2 title
    Open-Label Treatment Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Natalizumab 300 mg IV every 4 weeks
    Arm description
    Natalizumab 300 mg IV every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks.

    Arm title
    Natalizumab 300 mg SC every 4 weeks
    Arm description
    Natalizumab 300 mg SC every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks.

    Arm title
    Natalizumab 300 mg IV every 12 weeks
    Arm description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks.

    Arm title
    Natalizumab 300 mg SC every 12 weeks
    Arm description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks.

    Arm title
    Natalizumab 150 mg IV every 12 weeks
    Arm description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for IV Infusion
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks.

    Arm title
    Natalizumab 150 mg SC every 12 weeks
    Arm description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab for Subcutaneous Injection
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Investigational medicinal product name
    SC Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects received study treatment every 4 weeks. Subjects receiving natalizumab every 12 weeks received matching placebo during the intervening 4-week periods.

    Number of subjects in period 2
    Natalizumab 300 mg IV every 4 weeks Natalizumab 300 mg SC every 4 weeks Natalizumab 300 mg IV every 12 weeks Natalizumab 300 mg SC every 12 weeks Natalizumab 150 mg IV every 12 weeks Natalizumab 150 mg SC every 12 weeks
    Started
    44
    35
    42
    42
    42
    32
    Completed
    40
    33
    39
    37
    40
    30
    Not completed
    4
    2
    3
    5
    2
    2
         Physician decision
    -
    -
    1
    2
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
    -
    -
         Consent withdrawn by subject
    3
    1
    1
    1
    -
    1
         Not Specified
    1
    1
    1
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab 300 mg IV every 4 weeks
    Reporting group description
    Natalizumab 300 mg intravenous (IV) every 4 weeks for 60 weeks.

    Reporting group title
    Natalizumab 300 mg SC every 4 weeks
    Reporting group description
    Natalizumab 300 mg subcutaneous (SC) every 4 weeks for 60 weeks.

    Reporting group title
    Natalizumab 300 mg IV every 12 weeks
    Reporting group description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 300 mg SC every 12 weeks
    Reporting group description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 150 mg IV every 12 weeks
    Reporting group description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 150 mg SC every 12 weeks
    Reporting group description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.

    Reporting group values
    Natalizumab 300 mg IV every 4 weeks Natalizumab 300 mg SC every 4 weeks Natalizumab 300 mg IV every 12 weeks Natalizumab 300 mg SC every 12 weeks Natalizumab 150 mg IV every 12 weeks Natalizumab 150 mg SC every 12 weeks Total
    Number of subjects
    54 45 52 54 47 38 290
    Age, Customized
    Units: participants
        18 to 19 years
    0 1 0 0 0 0 1
        20 to 29 years
    7 11 7 7 5 11 48
        30 to 39 years
    22 15 21 24 21 14 117
        40 to 49 years
    20 16 17 17 16 9 95
        50 to 56 years
    5 2 7 6 5 4 29
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    38.4 ± 7.84 36.3 ± 8.92 38.7 ± 8.43 38.7 ± 7.85 38.7 ± 8.61 36 ± 9.03 -
    Gender, Male/Female
    Units: participants
        Female
    39 29 37 41 34 24 204
        Male
    15 16 15 13 13 14 86

    End points

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    End points reporting groups
    Reporting group title
    Natalizumab 300 mg IV every 4 weeks
    Reporting group description
    Natalizumab 300 mg intravenous (IV) every 4 weeks for 60 weeks.

    Reporting group title
    Natalizumab 300 mg SC every 4 weeks
    Reporting group description
    Natalizumab 300 mg subcutaneous (SC) every 4 weeks for 60 weeks.

    Reporting group title
    Natalizumab 300 mg IV every 12 weeks
    Reporting group description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 300 mg SC every 12 weeks
    Reporting group description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 150 mg IV every 12 weeks
    Reporting group description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Natalizumab 150 mg SC every 12 weeks
    Reporting group description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.
    Reporting group title
    Natalizumab 300 mg IV every 4 weeks
    Reporting group description
    Natalizumab 300 mg IV every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Natalizumab 300 mg SC every 4 weeks
    Reporting group description
    Natalizumab 300 mg SC every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Natalizumab 300 mg IV every 12 weeks
    Reporting group description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Natalizumab 300 mg SC every 12 weeks
    Reporting group description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Natalizumab 150 mg IV every 12 weeks
    Reporting group description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Natalizumab 150 mg SC every 12 weeks
    Reporting group description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Primary: Cumulative Number of Combined Unique Active Lesions

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    End point title
    Cumulative Number of Combined Unique Active Lesions [1]
    End point description
    Cumulative number of combined unique active lesions (sum of the number of new gadolinium (Gd)-enhancing lesions and new or newly enlarging T2 hyperintense lesions not associated with Gd-enhancement on T1 weighted scans) based on brain magnetic resonance imaging (MRI) scans up to Week 60. Modified intent-to-treat (mITT) population: all randomized subjects who received at least 1 dose of study drug, had at least 1 efficacy assessment, and had no statistical protocol deviations.
    End point type
    Primary
    End point timeframe
    Up to Week 60
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were planned for this endpoint, and are presented here.
    End point values
    Natalizumab 300 mg IV every 4 weeks Natalizumab 300 mg SC every 4 weeks Natalizumab 300 mg IV every 12 weeks Natalizumab 300 mg SC every 12 weeks Natalizumab 150 mg IV every 12 weeks Natalizumab 150 mg SC every 12 weeks
    Number of subjects analysed
    52
    44
    45
    50
    35
    32
    Units: lesions
        arithmetic mean (standard deviation)
    0.23 ± 1.262
    0.02 ± 0.151
    3.84 ± 8.054
    3.08 ± 8.216
    6.09 ± 15.424
    6.44 ± 11.285
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were analyzed during the randomized and open-label periods separately. Randomized period: AEs, after 1st randomized dose on Day 0 and prior to open-label infusion of natalizumab at Week 60 (±5 days); SAEs also between Screening and dosing on Day 0.
    Adverse event reporting additional description
    Open-label period: on or after open-label infusion of natalizumab at Week 60 through to Week 72 (±2 weeks). If participant did not receive natalizumab infusions during the open-label period (Week 60 to Week 72), all events with an onset date after Day 0 were considered as occurring during the randomized treatment period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Randomized Period: Natalizumab 300 mg IV every 4 weeks
    Reporting group description
    Natalizumab 300 mg IV every 4 weeks for 60 weeks.

    Reporting group title
    Randomized Period: Natalizumab 300 mg SC every 4 weeks
    Reporting group description
    Natalizumab 300 mg SC every 4 weeks for 60 weeks.

    Reporting group title
    Randomized Period: Natalizumab 300 mg IV every 12 weeks
    Reporting group description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Randomized Period: Natalizumab 300 mg SC every 12 weeks
    Reporting group description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.

    Reporting group title
    Randomized Period: Natalizumab 150 mg IV every 12 weeks
    Reporting group description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods.

    Reporting group title
    Randomized Period: Natalizumab 150 mg SC every 12 weeks
    Reporting group description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods.

    Reporting group title
    Open-label Period: Natalizumab 300 mg IV every 4 weeks
    Reporting group description
    Natalizumab 300 mg IV every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Open-label Period: Natalizumab 300 mg SC every 4 weeks
    Reporting group description
    Natalizumab 300 mg SC every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Open-label Period: Natalizumab 300 mg IV every 12 weeks
    Reporting group description
    Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Open-label Period: Natalizumab 300 mg SC every 12 weeks
    Reporting group description
    Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Open-label Period: Natalizumab 150 mg IV every 12 weeks
    Reporting group description
    Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Reporting group title
    Open-label Period: Natalizumab 150 mg SC every 12 weeks
    Reporting group description
    Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68.

    Serious adverse events
    Randomized Period: Natalizumab 300 mg IV every 4 weeks Randomized Period: Natalizumab 300 mg SC every 4 weeks Randomized Period: Natalizumab 300 mg IV every 12 weeks Randomized Period: Natalizumab 300 mg SC every 12 weeks Randomized Period: Natalizumab 150 mg IV every 12 weeks Randomized Period: Natalizumab 150 mg SC every 12 weeks Open-label Period: Natalizumab 300 mg IV every 4 weeks Open-label Period: Natalizumab 300 mg SC every 4 weeks Open-label Period: Natalizumab 300 mg IV every 12 weeks Open-label Period: Natalizumab 300 mg SC every 12 weeks Open-label Period: Natalizumab 150 mg IV every 12 weeks Open-label Period: Natalizumab 150 mg SC every 12 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 54 (12.96%)
    4 / 45 (8.89%)
    4 / 52 (7.69%)
    3 / 53 (5.66%)
    4 / 47 (8.51%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    1 / 35 (2.86%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    2 / 32 (6.25%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Nuclear Magnetic Resonance Imaging Abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    1 / 52 (1.92%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoma In Situ
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    1 / 52 (1.92%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma Metastatic
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple Sclerosis Relapse
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 45 (4.44%)
    1 / 52 (1.92%)
    0 / 53 (0.00%)
    2 / 47 (4.26%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    1 / 47 (2.13%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Insufficiency
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    1 / 52 (1.92%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    1 / 35 (2.86%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I Disorder
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Gambling
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Automatic Bladder
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    1 / 47 (2.13%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis Enteroviral
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    1 / 52 (1.92%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Progressive Multifocal Leukoencephalopathy
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    1 / 35 (2.86%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Randomized Period: Natalizumab 300 mg IV every 4 weeks Randomized Period: Natalizumab 300 mg SC every 4 weeks Randomized Period: Natalizumab 300 mg IV every 12 weeks Randomized Period: Natalizumab 300 mg SC every 12 weeks Randomized Period: Natalizumab 150 mg IV every 12 weeks Randomized Period: Natalizumab 150 mg SC every 12 weeks Open-label Period: Natalizumab 300 mg IV every 4 weeks Open-label Period: Natalizumab 300 mg SC every 4 weeks Open-label Period: Natalizumab 300 mg IV every 12 weeks Open-label Period: Natalizumab 300 mg SC every 12 weeks Open-label Period: Natalizumab 150 mg IV every 12 weeks Open-label Period: Natalizumab 150 mg SC every 12 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 54 (74.07%)
    31 / 45 (68.89%)
    31 / 52 (59.62%)
    34 / 53 (64.15%)
    31 / 47 (65.96%)
    17 / 38 (44.74%)
    2 / 44 (4.55%)
    4 / 35 (11.43%)
    2 / 42 (4.76%)
    0 / 42 (0.00%)
    4 / 42 (9.52%)
    6 / 32 (18.75%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 45 (2.22%)
    3 / 52 (5.77%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Nuclear Magnetic Resonance Imaging Abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    2 / 38 (5.26%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 45 (2.22%)
    1 / 52 (1.92%)
    4 / 53 (7.55%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    1
    1
    4
    0
    1
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Multiple Sclerosis Relapse
         subjects affected / exposed
    8 / 54 (14.81%)
    6 / 45 (13.33%)
    13 / 52 (25.00%)
    17 / 53 (32.08%)
    12 / 47 (25.53%)
    5 / 38 (13.16%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    2 / 32 (6.25%)
         occurrences all number
    9
    6
    14
    18
    15
    5
    0
    0
    1
    0
    3
    2
    Headache
         subjects affected / exposed
    4 / 54 (7.41%)
    9 / 45 (20.00%)
    7 / 52 (13.46%)
    5 / 53 (9.43%)
    3 / 47 (6.38%)
    4 / 38 (10.53%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    12
    18
    6
    4
    5
    0
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 45 (2.22%)
    2 / 52 (3.85%)
    3 / 53 (5.66%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    2
    2
    4
    0
    0
    0
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 45 (2.22%)
    3 / 52 (5.77%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 54 (11.11%)
    6 / 45 (13.33%)
    4 / 52 (7.69%)
    1 / 53 (1.89%)
    2 / 47 (4.26%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    6
    6
    4
    1
    2
    1
    0
    0
    0
    0
    0
    0
    Injection Site Pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    3 / 53 (5.66%)
    0 / 47 (0.00%)
    3 / 38 (7.89%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    4
    0
    7
    0
    7
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    3 / 47 (6.38%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    1
    3
    1
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 45 (6.67%)
    0 / 52 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 45 (8.89%)
    2 / 52 (3.85%)
    1 / 53 (1.89%)
    4 / 47 (8.51%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    5
    2
    1
    4
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 54 (5.56%)
    4 / 45 (8.89%)
    2 / 52 (3.85%)
    2 / 53 (3.77%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    4
    2
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 54 (1.85%)
    4 / 45 (8.89%)
    0 / 52 (0.00%)
    2 / 53 (3.77%)
    1 / 47 (2.13%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    0
    2
    1
    0
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    3 / 47 (6.38%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    1
    0
    1
    3
    0
    0
    0
    0
    0
    0
    0
    Abdominal Pain
         subjects affected / exposed
    1 / 54 (1.85%)
    4 / 45 (8.89%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 45 (0.00%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 45 (6.67%)
    2 / 52 (3.85%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    3
    2
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 45 (4.44%)
    3 / 52 (5.77%)
    1 / 53 (1.89%)
    2 / 47 (4.26%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    2
    3
    1
    2
    1
    0
    0
    0
    0
    0
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 45 (6.67%)
    2 / 52 (3.85%)
    2 / 53 (3.77%)
    2 / 47 (4.26%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    3
    2
    3
    2
    1
    0
    0
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    3 / 54 (5.56%)
    4 / 45 (8.89%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    3 / 47 (6.38%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    4
    0
    1
    3
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 54 (24.07%)
    8 / 45 (17.78%)
    8 / 52 (15.38%)
    9 / 53 (16.98%)
    8 / 47 (17.02%)
    4 / 38 (10.53%)
    2 / 44 (4.55%)
    1 / 35 (2.86%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    19
    8
    14
    16
    8
    4
    2
    1
    1
    0
    0
    2
    Urinary Tract Infection
         subjects affected / exposed
    8 / 54 (14.81%)
    5 / 45 (11.11%)
    3 / 52 (5.77%)
    4 / 53 (7.55%)
    4 / 47 (8.51%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    10
    7
    4
    5
    6
    4
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 45 (4.44%)
    1 / 52 (1.92%)
    2 / 53 (3.77%)
    8 / 47 (17.02%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    1 / 35 (2.86%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    3 / 32 (9.38%)
         occurrences all number
    4
    3
    1
    2
    9
    0
    0
    1
    0
    0
    1
    3
    Pharyngitis
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 45 (2.22%)
    1 / 52 (1.92%)
    1 / 53 (1.89%)
    4 / 47 (8.51%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    1
    1
    1
    4
    1
    0
    0
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 45 (6.67%)
    0 / 52 (0.00%)
    4 / 53 (7.55%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    2 / 35 (5.71%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    5
    0
    4
    0
    1
    0
    2
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 45 (6.67%)
    2 / 52 (3.85%)
    2 / 53 (3.77%)
    0 / 47 (0.00%)
    1 / 38 (2.63%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    6
    2
    2
    0
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 45 (0.00%)
    3 / 52 (5.77%)
    2 / 53 (3.77%)
    2 / 47 (4.26%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    4
    2
    2
    0
    0
    0
    0
    0
    0
    0
    Oral Herpes
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 45 (2.22%)
    0 / 52 (0.00%)
    1 / 53 (1.89%)
    1 / 47 (2.13%)
    0 / 38 (0.00%)
    0 / 44 (0.00%)
    0 / 35 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    6
    1
    0
    1
    2
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2011
    The primary reason for this amendment was the addition of optional exploratory pharmacogenomic analysis using DNA samples derived from whole blood collected at Baseline. The purpose of the analysis was to explore identification of genetic variation associated with study treatment response and to explore host genetic mutations that may increase individual subjects’ susceptibility or resistance to developing PML.
    28 Feb 2012
    The primary reason for this amendment was to align the safety information in the protocol related to the risk factors for the development of PML with the established risk factors described in the Patient Information Sheet and the ICF.
    16 Nov 2012
    The primary reason for this amendment was to revise the frequency of anti-JCV antibody testing in subjects who were anti-JCV antibody negative to align with the current safety recommendations for Tysabri.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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