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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis, With Optional Open-Label Extension

    Summary
    EudraCT number
    2010-021978-11
    Trial protocol
    SE   GB   DE   FI   CZ   DK   BE   ES   PL   IT   IE  
    Global end of trial date
    13 Apr 2016

    Results information
    Results version number
    v3(current)
    This version publication date
    26 Aug 2017
    First version publication date
    29 Apr 2017
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Corrections made under "more information"

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS326
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01416181
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, 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
    13 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1: The primary objective of the study is to investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in participants with secondary progressive multiple sclerosis (SPMS). Part 2: The primary objective of Part 2 of the study is to evaluate the safety profile of natalizumab in participants with SPMS.
    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 subject 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. Subjects 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
    13 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 46
    Country: Number of subjects enrolled
    United Kingdom: 126
    Country: Number of subjects enrolled
    United States: 87
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 82
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Ireland: 14
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 75
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Poland: 188
    Country: Number of subjects enrolled
    Russian Federation: 55
    Worldwide total number of subjects
    889
    EEA total number of subjects
    647
    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)
    889
    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 Part 1 of the study was determined within 6 weeks prior to study entry into Part 1. Eligible subjects from Part 1 who consented to participate in Part 2 were enrolled at the Part 1 Week 96 Visit. The Part 1 Week 108 Visit served as the Baseline Visit for Part 2.

    Period 1
    Period 1 title
    Part 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    For Part 1, subjects and all study staff were blinded to the subject treatment assignments. On request, Investigators were to be notified of subject treatment assignments after finalization of the CSR for Part 1 of the study. Precautions were taken with the study treatment to maintain blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Part 1: subjects were randomized to receive placebo intravenously (IV) every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered through IV infusion. The individual preparing study treatment carefully reviewed the instructions provided in the Directions for Handling and Administration.

    Arm title
    Natalizumab 300 mg
    Arm description
    Part 1: subjects were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Natalizumab was administered through IV infusion. The individual preparing study treatment carefully reviewed the instructions provided in the Directions for Handling and Administration

    Number of subjects in period 1 [1]
    Placebo Natalizumab 300 mg
    Started
    449
    439
    Completed
    312
    326
    Not completed
    137
    113
         Ongoing in Follow-Up
    14
    8
         Lack of efficacy
    16
    8
         Adverse event, serious fatal
    -
    1
         Not specified
    10
    24
         Investigator Decision
    7
    6
         Adverse event, non-fatal
    15
    18
         Consent withdrawn by subject
    74
    47
         Lost to follow-up
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 subject withdrew prior to dosing
    Period 2
    Period 2 title
    Part 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Part 1: subjects were randomized to receive placebo IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Natalizumab was administered through IV infusion. The individual preparing study treatment carefully reviewed the instructions provided in the Directions for Handling and Administration.

    Arm title
    Natalizumab 300 mg
    Arm description
    Part 1: subjects were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Natalizumab was administered through IV infusion. The individual preparing study treatment carefully reviewed the instructions provided in the Directions for Handling and Administration.

    Number of subjects in period 2 [2]
    Placebo Natalizumab 300 mg
    Started
    274
    292
    Completed Treatment for 48 Weeks
    98
    111
    Completed Treatment for 96 Weeks
    1 [3]
    0 [4]
    Completed Treatment for > 96 Weeks
    1 [5]
    0 [6]
    Completed
    3
    6
    Not completed
    271
    286
         Lack of efficacy
    4
    1
         Investigator Decision
    6
    7
         Not specified
    234
    267
         Adverse event, non-fatal
    11
    4
         Consent withdrawn by subject
    14
    5
         Lost to follow-up
    2
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only subjects who transitioned into Part 2 of the study are presented in period 2.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones present the number of subjects who completed given number of weeks of treatment.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones present the number of subjects who completed given number of weeks of treatment.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones present the number of subjects who completed given number of weeks of treatment.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones present the number of subjects who completed given number of weeks of treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Part 1: subjects were randomized to receive placebo intravenously (IV) every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.

    Reporting group title
    Natalizumab 300 mg
    Reporting group description
    Part 1: subjects were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.

    Reporting group values
    Placebo Natalizumab 300 mg Total
    Number of subjects
    449 439 888
    Age categorical
    Units: Subjects
        20 - 29 years
    10 10 20
        30 - 39 years
    73 50 123
        40 - 49 years
    162 194 356
        ≥ 50 years
    204 185 389
    Gender, Male/Female
    Units: Subjects
        Female
    280 270 550
        Male
    169 169 338

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Part 1: subjects were randomized to receive placebo intravenously (IV) every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.

    Reporting group title
    Natalizumab 300 mg
    Reporting group description
    Part 1: subjects were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.
    Reporting group title
    Placebo
    Reporting group description
    Part 1: subjects were randomized to receive placebo IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.

    Reporting group title
    Natalizumab 300 mg
    Reporting group description
    Part 1: subjects were randomized to receive 300 mg of natalizumab IV every 4 weeks for 96 weeks. Part 2: subjects transitioned to receive open-label natalizumab 300 mg IV every 4 weeks for at least 96 weeks.

    Primary: Part 1: Percentage of Subjects With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT)

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    End point title
    Part 1: Percentage of Subjects With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT)
    End point description
    Confirmed disability progression, defined as ≥1 of the following criteria (confirmed at a second visit ≥6 months later and at Week 96): - Confirmed progression in EDSS (EDSS score increased from baseline [BL] by ≥1 point if BL EDSS ≤5.5 or by ≥0.5 points if BL EDSS ≥6); - Confirmed progression in T25FW (T25FW increased by ≥20% of the BL walk); - Confirmed progression in 9HPT (9HPT increased by ≥20% of the time taken at BL on either hand and confirmed on the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. The 95% confidence interval (CI) of the percentage is based on normal approximation.
    End point type
    Primary
    End point timeframe
    Up to 96 weeks (2 years)
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    448
    439
    Units: percentage of subjects
    number (confidence interval 95%)
        Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years
    48 (43.1 to 52.4)
    44 (39.8 to 49.1)
        Confirmed on EDSS at 2 years
    15 (11.7 to 18.3)
    16 (12.3 to 19.1)
        Confirmed on T25FW at 2 years
    35 (30.8 to 39.7)
    35 (30.4 to 39.3)
        Confirmed on 9HPT (either hand) at 2 years
    23 (19.3 to 27.1)
    15 (11.3 to 17.9)
        Confirmed on 9HPT (dominant hand) at 2 years
    13 (10.2 to 16.5)
    10 (7.2 to 12.8)
        Confirmed on 9HPT (non-dominant hand) at 2 years
    16 (12.5 to 19.2)
    10 (7.2 to 12.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 2 years
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2866 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.13
    Notes
    [1] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Confirmed progressors on EDSS
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.753 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.53
    Notes
    [2] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Confirmed progressors on T25FW
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9137 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.3
    Notes
    [3] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Confirmed progressors on 9HPT (either hand)
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.8
    Notes
    [4] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Confirmed progressors on 9HPT (dominant hand)
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1251 [5]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.09
    Notes
    [5] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Confirmed progressors on 9HPT (non-dominant hand)
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0091 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.87
    Notes
    [6] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).

    Primary: Number of Participants with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [7]
    End point description
    AE: any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, placed the participant at immediate risk of death (a life-threatening event); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect. An SAE may have also been any other medically important event in the opinion of the Investigator.
    End point type
    Primary
    End point timeframe
    218 weeks
    Notes
    [7] - 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 are presented, per protocol.
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: participants
        Any event
    250
    245
        Moderate or severe event
    157
    158
        Severe event
    28
    27
        Related event
    63
    56
        Serious event
    24
    39
        Discontinuation of treatment due to event
    12
    5
        Withdrawal from study due to an event
    11
    3
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Subjects With a T25FW Response

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    End point title
    Part 1: Percentage of Subjects With a T25FW Response
    End point description
    T25FW response is defined as any improvement from the best pre-dose T25FW in at least 75% of the scheduled on-treatment visits through Week 96. The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The subject is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the subject has reached the 25-foot mark. The task is immediately administered again by having the subject walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation.
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    363
    383
    Units: percentage of subjects
        number (confidence interval 95%)
    17 (12.7 to 20.3)
    19 (14.6 to 22.4)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    746
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4369 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.7
    Notes
    [8] - Based on logistic regression, adjusted for baseline EDSS (<=5.5 or >=6) and T25FW.

    Secondary: Part 1: Change from Baseline in the 12-Item MS Walking Scale (MSWS-12)

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    End point title
    Part 1: Change from Baseline in the 12-Item MS Walking Scale (MSWS-12)
    End point description
    MSWS-12 is a subject self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A negative number on change from BL value indicates an improvement in MSWS-12.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    436
    431
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.04 ± 21.061
    2.7 ± 22.11
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    867
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5409 [9]
    Method
    ANCOVA
    Confidence interval
    Notes
    [9] - p-value for comparison between the active and placebo groups at Week 96 is based on ANCOVA model, adjusted for BL EDSS (<=5.5 or >=6) and BL MSWS-12.

    Secondary: Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire

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    End point title
    Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire
    End point description
    The ABILHAND Questionnaire measures the subject’s perceived difficulty in performing everyday manual activities in the last 3 months. The subject completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability. A positive number on change from baseline value indicates an improvement in ABILHAND.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    437
    431
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.45 ± 14.739
    -2.44 ± 13.023
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    868
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2586 [10]
    Method
    ANCOVA
    Confidence interval
    Notes
    [10] - p-value for comparison between active and placebo groups at Week 96 is based on ANCOVA model, adjusted for BL EDSS (<=5.5 or >=6) and BL ABILHAND.

    Secondary: Part 1: Change from Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score

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    End point title
    Part 1: Change from Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score
    End point description
    The 29-item MSIS-29 is a subject-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a subject’s perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    428
    430
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.34 ± 20.947
    0.61 ± 19.885
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    858
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1529 [11]
    Method
    ANCOVA
    Confidence interval
    Notes
    [11] - p-value for comparison between active & placebo groups at Wk 96 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL MSIS-29 physical score.

    Secondary: Part 1: Percentage Change from Week 24 in Whole Brain Volume at Week 96

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    End point title
    Part 1: Percentage Change from Week 24 in Whole Brain Volume at Week 96
    End point description
    Whole brain volume as measured by MRI.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 96
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    265
    287
    Units: percentage change
        arithmetic mean (standard deviation)
    -0.72 ± 0.656
    -0.66 ± 0.596
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    552
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.2424 [13]
    Method
    ANCOVA
    Confidence interval
    Notes
    [12] - Only subjects with BL brain volume are included in the p-value calculation.
    [13] - natalizumab subjects had a baseline after 6 months of treatment and the placebo-to-natalizumab group had a baseline of initiation of treatment

    Secondary: Part 1: Percentage of Subjects Defined as Confirmed Progressors on EDSS Functional System Scores

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    End point title
    Part 1: Percentage of Subjects Defined as Confirmed Progressors on EDSS Functional System Scores
    End point description
    The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Subjects with confirmed progression of disability in EDSS physical functional system scores were defined as those who met one of the following criteria: - an increase of ≥ 1 point from baseline system score of ≥ 1 or an increase of ≥ 2 points from baseline system score of 0 in at least 2 physical functional systems, or - an increase of ≥ 2 points from baseline system score of ≥ 1 or an increase of ≥ 3 points from baseline system score of 0 in any 1 physical functional system. A confirmed progressor was defined as a participant who met the criteria for disability progression at any given visit and at the 6-Month Confirmation Visit. The 95% CIs are based on normal approximation.
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    448
    439
    Units: percentage of subjects
        number (confidence interval 95%)
    29 (25.2 to 33.7)
    25 (20.6 to 28.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1052 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.05
    Notes
    [14] - Based on logistic regression, adjusted for baseline EDSS (<=5.5 or >=6).

    Secondary: Part 2: Percentage of Subjects With Disability Worsening at 156 Weeks

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    End point title
    Part 2: Percentage of Subjects With Disability Worsening at 156 Weeks
    End point description
    Percentage of subjects with disability worsening at each scheduled efficacy visit in Part 2, defined as one or more of the following: • ≥ 20% worsening from Part 1 baseline in T25FW; • ≥ 20% worsening from Part 1 baseline in 9HPT; • Worsening from Part 1 baseline in EDSS (≥ 1 point increase if Part 1 baseline EDSS ≤ 5.5 or ≥ 0.5 point increase if Part 1 baseline EDSS > 5.5). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the subject is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. 95% CIs of percentages are based on normal approximation.
    End point type
    Secondary
    End point timeframe
    Week 156
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: percentage of subjects
    number (confidence interval 95%)
        Confirmed on ≥1 of EDSS, T25FW, 9HPT at 156 weeks
    61 (55.2 to 66.7)
    52 (45.8 to 57.3)
        Confirmed on EDSS at 156 weeks
    23 (18.3 to 28.4)
    18 (13.8 to 22.6)
        Confirmed on T25FW at 156 weeks
    46 (40.1 to 51.9)
    41 (35.2 to 46.5)
        Confirmed on 9HPT (either hand) at 156 weeks
    28 (23.1 to 33.8)
    19 (14.4 to 23.4)
        Confirmed on 9HPT (dominant hand) at 156 weeks
    18 (13 to 22)
    12 (8 to 15.4)
        Confirmed on 9HPT (non-dominant hand) at 156 weeks
    18 (13 to 22)
    13 (9.2 to 16.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Confirmed progressors on ≥ 1 of EDSS, T25FW, or 9HPT at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0205 [15]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    0.94
    Notes
    [15] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Confirmed progressors on EDSS at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1305 [16]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.1
    Notes
    [16] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Confirmed progressors on T25FW at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1988 [17]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.12
    Notes
    [17] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Confirmed progressors on 9HPT (either hand) at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0093 [18]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.88
    Notes
    [18] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Confirmed progressors onm 9HPT (dominant hand) at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.054 [19]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.01
    Notes
    [19] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Confirmed progressors on 9HPT (non-dominant hand) at 156 weeks
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.141 [20]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.12
    Notes
    [20] - Based on logistic regression, adjusted for Baseline EDSS (<=5.5 or >=6) and/or T25FW and/or 9HPT (either hand).

    Secondary: Part 2: Absolute Change From Baseline (Part 1) in T25FW

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    End point title
    Part 2: Absolute Change From Baseline (Part 1) in T25FW
    End point description
    The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The subject is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Lower scores on time taken to reach 25 foot mark reflects a better outcome. Values are presented for the overall group, as well as the confirmed progressor (CP, defined in the primary endpoint description above) and non-progressor (NP) subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    255
    264
    Units: seconds
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=255, 264
    12.8 ± 35.111
    7.78 ± 21.251
        Overall: Change from BL to Week 204; n=39, 38
    25.01 ± 56.582
    9.01 ± 22.507
        CP Group: Change from BL to Week 156; n=156, 135
    21.67 ± 42.51
    16.26 ± 26.943
        CP Group: Change from BL to Week 204; n=25, 18
    40.06 ± 66.275
    20.89 ± 28.2
        NP Group: Change from BL to Week 156; n=99, 129
    -1.17 ± 3.804
    -1.09 ± 3.593
        NP Group: Change from BL to Week 204; n=14, 20
    -1.88 ± 5.917
    -1.67 ± 4.613
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0273 [21]
    Method
    ANCOVA
    Confidence interval
    Notes
    [21] - p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW.

    Secondary: Part 2: Percentage change from Baseline (Part 1) in T25FW

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    End point title
    Part 2: Percentage change from Baseline (Part 1) in T25FW
    End point description
    The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The subject is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the subject has reached the 25-foot mark. The task is immediately repeated; the score for the T25FW is the average of the two completed trials. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    255
    264
    Units: percentage change
    arithmetic mean (standard deviation)
        Overall: Change from BL at Week 156; n=255, 264
    75.52 ± 166.191
    55.91 ± 130.286
        Overall: Change from BL at Week 204; n=39, 38
    130.72 ± 272.117
    71.09 ± 177.668
        CP Group: Change from BL at Week 156; n=156, 135
    127.05 ± 195.138
    113.51 ± 160.857
        CP Group: Change from BL at Week 204; n=25, 18
    206.78 ± 316.344
    158.91 ± 228.458
        NP Group: Change from BL at Week 156; n=99, 129
    -5.68 ± 21.708
    -4.37 ± 25.05
        NP Group: Change from BL at Week 204; n=14, 20
    -5.09 ± 26.591
    -7.94 ± 29.856
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.096 [22]
    Method
    ANCOVA
    Confidence interval
    Notes
    [22] - p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL T25FW.

    Secondary: Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand)

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    End point title
    Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand)
    End point description
    The 9HPT is a brief, standardized, quantitative test of upper extremity function. The subject picks up 9 pegs, puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    257
    271
    Units: seconds
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n= 257, 271
    5.22 ± 27.728
    2.12 ± 16.719
        Overall: Change from BL to Week 204; n=39, 38
    0.56 ± 7.923
    2.65 ± 16.001
        CP Group: Change from BL to Week 156; n=158, 138
    10.12 ± 33.675
    5.01 ± 20.625
        CP Group: Change from BL to Week 204; n=24, 19
    2.36 ± 9.187
    6.03 ± 21.994
        NP Group: Change from BL to Week 156; n=99, 133
    -2.6 ± 9.543
    -0.89 ± 10.602
        NP Group: Change from BL to Week 204; n=15, 19
    -2.32 ± 4.153
    -0.73 ± 4.292
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall, Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1119 [23]
    Method
    ANCOVA
    Confidence interval
    Notes
    [23] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand).

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand)

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand)
    End point description
    The 9HPT is a brief, standardized, quantitative test of upper extremity function. The subject picks up 9 pegs, puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    257
    271
    Units: percentage change
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=257, 271
    14.32 ± 59.727
    5.25 ± 32.649
        Overall: Change from BL to Week 204; n=39, 38
    2.27 ± 19.193
    6.87 ± 32.333
        CP Group: Change from BL to Week 156; n=158, 138
    25.87 ± 72.621
    12.84 ± 40.232
        CP Group: Change from BL to Week 204; n=24, 19
    8.43 ± 20.247
    16.25 ± 41.317
        NP Group: Change from BL to Week 156; n=99, 133
    -4.1 ± 17.661
    -2.63 ± 19.436
        NP Group: Change from BL to Week 204; n=15, 19
    -7.57 ± 12.56
    -2.52 ± 15.998
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0261 [24]
    Method
    ANCOVA
    Confidence interval
    Notes
    [24] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (dominant hand).

    Secondary: Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)

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    End point title
    Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
    End point description
    The 9HPT is a brief, standardized, quantitative test of upper extremity function. The subject picks up 9 pegs, puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    254
    269
    Units: seconds
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=254, 269
    5.24 ± 32.91
    4.62 ± 30.333
        Overall: Change from BL to Week 204; n=40, 40
    1.41 ± 16.952
    4.91 ± 33.808
        CP Group: Change from BL to Week 156; n=155, 137
    11.25 ± 39.513
    11.25 ± 38.296
        CP Group: Change from BL to Week 204; n=25, 20
    5.87 ± 17.474
    17.2 ± 34.632
        NP Group: Change from BL to Week 156; n=99, 132
    -4.17 ± 13.999
    -2.26 ± 16.311
        NP Group: Change from BL to Week 204; n=15, 20
    -6.04 ± 13.491
    -7.39 ± 28.78
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.723 [25]
    Method
    ANCOVA
    Confidence interval
    Notes
    [25] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand).

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
    End point description
    The 9HPT is a brief, standardized, quantitative test of upper extremity function. The subjec picks up 9 pegs, puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    254
    269
    Units: percentage change
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=254, 269
    13.87 ± 64.959
    11.04 ± 47.942
        Overall: Change from BL to Week 204; n=40, 40
    3.67 ± 28.755
    18.57 ± 62.537
        CP Group: Change from BL to Week 156; n=155, 137
    26.33 ± 79.957
    23.51 ± 60.074
        CP Group: Change from BL to Week 204; n=25, 20
    11.87 ± 31.05
    43.12 ± 80.639
        NP Group: Change from BL to Week 156; n=99, 132
    -5.63 ± 14.765
    -1.89 ± 24.987
        NP Group: Change from BL to Week 204; n=15, 20
    -9.98 ± 18.188
    -5.98 ± 16.005
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5051 [26]
    Method
    ANCOVA
    Confidence interval
    Notes
    [26] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6) & BL 9HPT (non-dominant hand).

    Secondary: Part 2: Absolute Change from Baseline (Part 1) in EDSS

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    End point title
    Part 2: Absolute Change from Baseline (Part 1) in EDSS
    End point description
    The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    260
    275
    Units: units on a scale
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=260, 275
    0.11 ± 0.746
    0.06 ± 0.797
        Overall: Change from BL to Week 204; n=40, 40
    -0.01 ± 0.895
    0.15 ± 0.928
        CP Group: Change from BL to Week 156; n=162, 141
    0.38 ± 0.631
    0.36 ± 0.703
        CP Group: Change from BL to Week 204; n=25, 20
    0.28 ± 0.542
    0.68 ± 0.634
        NP Group: Change from BL to Week 156; n=98, 134
    -0.33 ± 0.718
    -0.25 ± 0.775
        NP Group: Change from BL to Week 204; n=15, 20
    -0.5 ± 1.15
    -0.38 ± 0.887
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.433 [27]
    Method
    ANCOVA
    Confidence interval
    Notes
    [27] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6).

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in EDSS

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in EDSS
    End point description
    The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. Values are presented for the overall group, as well as the CP (defined in the primary endpoint description above) and NP subgroups.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    260
    275
    Units: percentage change
    arithmetic mean (standard deviation)
        Overall: Change from BL to Week 156; n=260, 275
    2.07 ± 15.188
    1.65 ± 16.53
        Overall: Change from BL to Week 204; n=40, 40
    -0.63 ± 17.889
    2.91 ± 18.656
        CP Group Change from BL to Week 156; n=162, 141
    7.23 ± 13.513
    7.3 ± 15.728
        CP Group Change from BL to Week 204; n=25, 20
    5.31 ± 10.711
    13.18 ± 13.957
        NP Group Change from BL to Week 156; n=98, 134
    -6.47 ± 13.951
    -4.29 ± 15.266
        NP Group Change from BL to Week 204; n=15, 20
    -10.53 ± 22.953
    -7.35 ± 17.26
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall: Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7225 [28]
    Method
    ANCOVA
    Confidence interval
    Notes
    [28] - p-value for comparison between active & placebo groups at Week 156 based on ANCOVA, adjusted for BL EDSS (≤5.5 or ≥6).

    Secondary: Part 2: Absolute change from Baseline (Part 1) in the 6-Minute Walk Test (6MWT)

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    End point title
    Part 2: Absolute change from Baseline (Part 1) in the 6-Minute Walk Test (6MWT)
    End point description
    The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    272
    290
    Units: meters
    arithmetic mean (standard deviation)
        Change from BL to Week 156; n=272, 289
    -32.1 ± 117.55
    -40.4 ± 219.6
        Change from BL to Week 204; n=272, 290
    -33.3 ± 119.4
    -40.7 ± 219.58
    No statistical analyses for this end point

    Secondary: Part 2: Percentage Change from Baseline (Part 1) in the 6MWT

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    End point title
    Part 2: Percentage Change from Baseline (Part 1) in the 6MWT
    End point description
    The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    0 [29]
    0 [30]
    Units: percentage change
    Notes
    [29] - Due to sparse data up to Week 204 the analysis was not done.
    [30] - Due to sparse data up to Week 204 the analysis was not done.
    No statistical analyses for this end point

    Secondary: Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score

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    End point title
    Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score
    End point description
    The 29-item MSIS-29 is a subject-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a subject’s perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change from BL to Week 156
    0.32 ± 20.943
    0.05 ± 20.843
        Change to from BL Week 204
    0.91 ± 21.018
    -0.28 ± 20.596
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7084 [31]
    Method
    ANCOVA
    Confidence interval
    Notes
    [31] - p-value for comparison between active & placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (≤5.5 or ≥6) & BL MSIS-29 physical score.

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score
    End point description
    The 29-item MSIS-29 is a subject-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a subject’s perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. A negative number on change from baseline value indicates an improvement in MSIS-29.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156, 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    0 [32]
    0 [33]
    Units: percentage change
    Notes
    [32] - Due to sparse data up to Week 204 the analysis was not done.
    [33] - Due to sparse data up to Week 204 the analysis was not done.
    No statistical analyses for this end point

    Secondary: Part 2: Absolute Change from Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT)

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    End point title
    Part 2: Absolute Change from Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT)
    End point description
    SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). Missing values were imputed using last observation carried forward.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    273
    291
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change from BL to Week 108
    13.6 ± 14.19
    15.5 ± 13.82
        Change from BL to Week 112
    14.4 ± 13.72
    15.1 ± 13.5
        Change from BL to Week 116
    14.1 ± 13.84
    15.3 ± 13.51
        Change from BL to Week 120
    14.3 ± 14.23
    15.3 ± 13.68
        Change from BL to Week 124
    14.4 ± 14.02
    15.7 ± 13.69
        Change from BL to Week 128
    15.1 ± 14.49
    15.7 ± 13.72
        Change from BL to Week 132
    15.1 ± 14.52
    15.6 ± 13.63
        Change from BL to Week 136
    14.8 ± 14.56
    16.3 ± 13.75
        Change from BL to Week 140
    15.4 ± 14.98
    16.4 ± 14.29
        Change from BL to Week 144
    15.7 ± 15.23
    16.2 ± 14.22
        Change from BL to Week 148
    15.5 ± 15.34
    16.3 ± 14.35
        Change from BL to Week 152
    15.5 ± 14.98
    16.3 ± 14.25
        Change from BL to Week 156
    11.2 ± 13.1
    12.3 ± 14.59
        Change from BL to Week 160
    15.2 ± 14.92
    16.2 ± 14.61
        Change from BL to Week 164
    15.6 ± 15.21
    16.3 ± 14.64
        Change from BL to Week 168
    15.8 ± 15.52
    16.4 ± 14.78
        Change from BL to Week 172
    15.6 ± 15.4
    16.3 ± 14.64
        Change from BL to Week 176
    15.5 ± 15.58
    16.3 ± 14.91
        Change from BL to Week 180
    15.5 ± 15.23
    16.4 ± 14.89
        Change from BL to Week 184
    15.6 ± 15.34
    16.3 ± 14.81
        Change from BL to Week 188
    15.6 ± 15.38
    16.4 ± 14.77
        Change from BL to Week 192
    15.6 ± 15.46
    16.3 ± 14.79
        Change from BL to Week 196
    15.7 ± 15.45
    16.3 ± 14.69
        Change from BL to Week 200
    15.7 ± 15.47
    16.3 ± 14.69
        Change from BL to Week 204
    15.7 ± 15.43
    16.3 ± 14.69
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 156
    Comparison groups
    Placebo v Natalizumab 300 mg
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3465 [34]
    Method
    ANCOVA
    Confidence interval
    Notes
    [34] - p-value for comparison between active and placebo at Week 156 based on ANCOVA model, adjusted for BL EDSS (<=5.5 or>=6) and BL SDMT.

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in the SDMT

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in the SDMT
    End point description
    SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best).
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    0 [35]
    0 [36]
    Units: percentage change
    Notes
    [35] - Due to sparse data up to Week 204 the analysis was not done.
    [36] - Due to sparse data up to Week 204 the analysis was not done.
    No statistical analyses for this end point

    Secondary: Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment – Multiple Sclerosis (WPAI-MS) Questionnaire

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    End point title
    Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment – Multiple Sclerosis (WPAI-MS) Questionnaire
    End point description
    The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (percentage of overall work impairment [absenteeism plus presenteeism]) 4. Activity Impairment (percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    272
    291
    Units: percentage of impairment
    arithmetic mean (standard deviation)
        Absenteeism: Week 108
    2.6 ± 12.8
    1.4 ± 8.24
        Absenteeism: Week 156
    3 ± 14.61
    4.1 ± 17.36
        Absenteeism: Week 204
    3 ± 14.61
    4.2 ± 16.89
        Presenteeism: Week 108
    30.6 ± 12.1
    30.9 ± 11.71
        Presenteeism: Week 156
    30.8 ± 12.17
    33 ± 14.23
        Presenteeism: Week 204
    31 ± 12.29
    32.2 ± 13.78
        Work Productivity Loss: Week 108
    30.9 ± 12.36
    31.2 ± 11.7
        Work Productivity Loss: Week 156
    31.6 ± 13.54
    33.9 ± 15.75
        Work Productivity Loss: Week 204
    31.9 ± 13.66
    33.3 ± 15.61
        Activity Impairment: Week 108
    56.1 ± 24.78
    58 ± 24.84
        Activity Impairment: Week 156
    56.8 ± 26.49
    58.5 ± 24.08
        Activity Impairment: Week 204
    57.2 ± 25.15
    59.8 ± 23.6
    No statistical analyses for this end point

    Secondary: Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire

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    End point title
    Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire
    End point description
    The WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (percentage of work time missed) 2. Presenteesism (percentage of impairment at work/reduced on-the-job effectiveness) 3. Work productivity loss (WPL; percentage of overall work impairment [absenteeism plus presenteeism]) 4. Activity Impairment (AI; percentage of overall activity impairment). WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: percentage change
    arithmetic mean (standard deviation)
        Absenteeism: Change at Week 156; n=18,17
    -10.3 ± 116.81
    -7.4 ± 95.77
        Absenteeism: Change at Week 204; n=18, 17
    -6.6 ± 116.9
    151.5 ± 457.29
        Presenteeism: Change at Week 156; n=264, 285
    4 ± 50.08
    14.4 ± 90.39
        Presenteeism: Change at Week 204; n=264, 285
    5.3 ± 51.23
    7.4 ± 58.95
        WPL: Change at Week 156; n=264,286
    4.7 ± 51.73
    16.8 ± 95.43
        WPL: Change at Week 204; n=264, 286
    5.9 ± 53.44
    10.6 ± 69.34
        AI: Change at Week 156; n=264, 284
    16 ± 95.68
    15.7 ± 83.7
        AI: Change at Week 204; n=264, 284
    16.1 ± 88.56
    20.4 ± 99.54
    No statistical analyses for this end point

    Secondary: Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume

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    End point title
    Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume
    End point description
    Whole brain volume as measured by MRI.
    End point type
    Secondary
    End point timeframe
    Week 24 (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: percentage change
    arithmetic mean (standard deviation)
        Change from Week 24 to Week 156; n=155, 175
    -1.164 ± 0.8228
    -0.948 ± 0.7193
        Change from Week 24 to Week 204; n=28, 24
    -1.687 ± 1.2872
    -1.517 ± 0.8412
    No statistical analyses for this end point

    Secondary: Part 2: Percentage Change from Baseline (Part 1) in Whole Gray Matter Brain Volume

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    End point title
    Part 2: Percentage Change from Baseline (Part 1) in Whole Gray Matter Brain Volume
    End point description
    Whole grey matter brain volume as measured by MRI.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: percentage change
    arithmetic mean (standard deviation)
        Change from Baseline to Week 156; n=149, 170
    -1.566 ± 0.9303
    -1.514 ± 0.8969
        Change from Baseline to Week 204; n=26, 20
    -1.883 ± 1.4222
    -2.086 ± 0.9068
    No statistical analyses for this end point

    Secondary: Part 2: Summary of New/Enlarging T2 Lesion Counts

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    End point title
    Part 2: Summary of New/Enlarging T2 Lesion Counts
    End point description
    New or enlarging T2 lesions as measured by MRI.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) up to Week 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    274
    291
    Units: lesions
    arithmetic mean (standard deviation)
        At Week 24 compared to BL; n=272, 287
    2.1 ± 4.24
    0.6 ± 3.27
        At Week 48 compared to Week 24; n=272, 289
    1.8 ± 4.47
    0 ± 0.37
        At Week 72 compared to Week 48; n=271, 287
    1.6 ± 3.76
    0 ± 0.19
        At Week 96 compared to Week 72; n=269, 284
    1.8 ± 4.33
    0 ± 0
        At Week 108 compared to Week 96; n=269, 288
    1.2 ± 3.38
    0 ± 0.13
        At Week 156 compared to Week 108; n=245, 258
    0.2 ± 0.79
    0 ± 0.2
        At Week 204 compared to Week 156; n=50, 47
    0 ± 0.2
    0 ± 0.15
        Cumulative count from BL to Week 204; n=274, 291
    8.6 ± 16.04
    0.7 ± 3.53
    No statistical analyses for this end point

    Secondary: Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions

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    End point title
    Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions
    End point description
    New or enlarging T2 lesions as measured by MRI.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1) and Weeks 156 and 204
    End point values
    Placebo Natalizumab 300 mg
    Number of subjects analysed
    0 [37]
    0 [38]
    Units: percentage change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [37] - Due to sparse data up to Week 204 the analysis was not done.
    [38] - Due to sparse data up to Week 204 the analysis was not done.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are captured through the last study visit; subjects were followed through Week 228, or 24 weeks following last dose of study treatment, or premature withdrawal.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Natalizumab 300 mg
    Reporting group description
    -

    Serious adverse events
    Placebo Natalizumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    100 / 449 (22.27%)
    90 / 439 (20.50%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 449 (0.00%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Joint surgery
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus operation
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb operation
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrectomy
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Signet-ring cell carcinoma
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tonsil cancer
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 449 (0.00%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 449 (0.00%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 449 (0.22%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear injury
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 449 (0.67%)
    6 / 439 (1.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 449 (0.45%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pelvic kidney
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral venous thrombosis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical myelopathy
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    5 / 449 (1.11%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    28 / 449 (6.24%)
    21 / 439 (4.78%)
         occurrences causally related to treatment / all
    0 / 37
    1 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    0 / 449 (0.00%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary progressive multiple sclerosis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    3 / 449 (0.67%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurogenic bladder
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urge incontinence
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture nonunion
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Insulin-requiring type 2 diabetes mellitus
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 449 (0.45%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 449 (0.00%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1n1 influenza
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 449 (0.45%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 449 (1.11%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 449 (0.22%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 449 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    12 / 449 (2.67%)
    5 / 439 (1.14%)
         occurrences causally related to treatment / all
    0 / 13
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 449 (0.22%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 449 (0.22%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Natalizumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    347 / 449 (77.28%)
    325 / 439 (74.03%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    17 / 449 (3.79%)
    26 / 439 (5.92%)
         occurrences all number
    19
    36
    Fall
         subjects affected / exposed
    85 / 449 (18.93%)
    82 / 439 (18.68%)
         occurrences all number
    212
    198
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 449 (4.45%)
    24 / 439 (5.47%)
         occurrences all number
    23
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 449 (11.14%)
    66 / 439 (15.03%)
         occurrences all number
    92
    126
    Dizziness
         subjects affected / exposed
    35 / 449 (7.80%)
    22 / 439 (5.01%)
         occurrences all number
    43
    28
    Muscle spasticity
         subjects affected / exposed
    27 / 449 (6.01%)
    17 / 439 (3.87%)
         occurrences all number
    27
    20
    Multiple sclerosis relapse
         subjects affected / exposed
    116 / 449 (25.84%)
    68 / 439 (15.49%)
         occurrences all number
    166
    79
    Paraesthesia
         subjects affected / exposed
    13 / 449 (2.90%)
    22 / 439 (5.01%)
         occurrences all number
    16
    26
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    53 / 449 (11.80%)
    59 / 439 (13.44%)
         occurrences all number
    61
    91
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    31 / 449 (6.90%)
    33 / 439 (7.52%)
         occurrences all number
    55
    38
    Constipation
         subjects affected / exposed
    26 / 449 (5.79%)
    21 / 439 (4.78%)
         occurrences all number
    31
    22
    Nausea
         subjects affected / exposed
    23 / 449 (5.12%)
    34 / 439 (7.74%)
         occurrences all number
    30
    42
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    40 / 449 (8.91%)
    43 / 439 (9.79%)
         occurrences all number
    55
    48
    Back pain
         subjects affected / exposed
    50 / 449 (11.14%)
    45 / 439 (10.25%)
         occurrences all number
    63
    56
    Muscle spasms
         subjects affected / exposed
    21 / 449 (4.68%)
    23 / 439 (5.24%)
         occurrences all number
    26
    29
    Muscular weakness
         subjects affected / exposed
    39 / 449 (8.69%)
    28 / 439 (6.38%)
         occurrences all number
    48
    41
    Pain in extremity
         subjects affected / exposed
    42 / 449 (9.35%)
    42 / 439 (9.57%)
         occurrences all number
    52
    82
    Infections and infestations
    Influenza
         subjects affected / exposed
    33 / 449 (7.35%)
    32 / 439 (7.29%)
         occurrences all number
    38
    38
    Cystitis
         subjects affected / exposed
    16 / 449 (3.56%)
    22 / 439 (5.01%)
         occurrences all number
    19
    35
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 449 (6.68%)
    48 / 439 (10.93%)
         occurrences all number
    37
    63
    Nasopharyngitis
         subjects affected / exposed
    73 / 449 (16.26%)
    98 / 439 (22.32%)
         occurrences all number
    136
    157
    Urinary tract infection
         subjects affected / exposed
    103 / 449 (22.94%)
    100 / 439 (22.78%)
         occurrences all number
    216
    226

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2011
    The primary reason for this amendment to 101MS326 is to add stratification by EDSS score to subject enrollment
    27 Feb 2013
    The primary reason for this amendment to Protocol 101MS326 was to revise the frequency of anti-JCV virus (JCV) antibody testing and to add an open-label Extension Phase (Part 2) for subjects who complete the Placebo-controlled Phase (Part 1), are eligible, and choose to participate.

    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.
    The ASCEND Study did not achieve statistical significance on the primary or secondary endpoints and was terminated early.
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