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    Clinical Trial Results:
    An Open-Label, Multicenter, Extension Study to Evaluate the Safety and Tolerability of Natalizumab Following Re-Initiation of Dosing in Multiple Sclerosis Subjects Who Have Completed Study C-1801, C-1802, C-1803, or C-1808 and a Dosing Suspension Safety Evaluation

    Summary
    EudraCT number
    2005-004061-41
    Trial protocol
    GB   BE   FI   IE   DE   AT   SE   HU   DK   CZ   ES   IT   GR  
    Global end of trial date
    30 Apr 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    101-MS-321
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00297232
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives for the initial treatment period of this study are to further evaluate the safety of natalizumab monotherapy by evaluating the risk of hypersensitivity reactions and immunogenicity following re-exposure to natalizumab and confirming the safety of switching from interferon (IFN), glatiramer acetate, or other multiple sclerosis (MS) therapies to natalizumab. The primary objective for the long-term treatment period of this study is to evaluate the long-term impact of natalizumab monotherapy on the progression of disability measured by Expanded Disability Status Scale (EDSS) changes over time.
    Protection of trial subjects
    All infusions were to be administered in a clinic setting to allow for safety monitoring. Subjects were to remain in the clinic for 1 hour postinfusion for observation. An anti-natalizumab antibody sample was to be collected if an allergic reaction to natalizumab was suspected. If a subject was unable to tolerate the natalizumab dose of 300 mg intravenous (IV), the infusion was to be terminated immediately and the subject was to be discontinued from the study after follow-up procedures had been completed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Mar 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Sweden: 23
    Country: Number of subjects enrolled
    United Kingdom: 72
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 107
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 64
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Netherlands: 52
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Turkey: 29
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    United States: 356
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    New Zealand: 9
    Worldwide total number of subjects
    1094
    EEA total number of subjects
    606
    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)
    1094
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study 101-MS-321 (2005-004061-41) was initiated for subjects in Europe and the rest of the world in parallel with 101-MS-322 (NCT00306592) in North America. After 48 weeks, subjects from 101-MS-322 could enter 101-MS-321, considered the Long-Term Treatment period of 101-MS-322. The primary purpose and primary outcome for both studies are identical.

    Pre-assignment
    Screening details
    Subjects from studies 101-MS-321 (2005-004061-41) and 101-MS-322 (NCT00306592) are included in this presentation of combined final data.

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

    Arms
    Arm title
    Natalizumab
    Arm description
    300 mg IV infusions once every 4 weeks for up to 480 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Recombinant humanized anti-alpha 4 integrin antibody
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff were to refer to the Directions for Handling and Administration for specific instructions on the handling and administration of natalizumab.

    Number of subjects in period 1
    Natalizumab
    Started
    1094
    Completed
    489
    Not completed
    605
         Death
    9
         Fear of progressive multifocal leukoencephalopathy
    10
         Miscellaneous
    5
         Anti-John Cunninghan Virus Antibody Positive
    13
         Unknown
    1
         Lack of efficacy
    7
         Consent withdrawn by subject
    37
         Did Not Enroll to Week 264
    34
         Subject was noncompliant
    9
         Persistently positive antibodies
    11
         Subject relocated
    7
         Adverse event
    63
         Voluntary withdrawal
    120
         Investigator withdrew from program
    19
         Anti-natalizumab positive
    8
         Switched to Commercial Tysabri
    22
         No data available after Week 264
    161
         Disease progression
    8
         Did Not Enroll to Week 480
    17
         Lost to follow-up
    10
         Sponsor decision
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    -

    Reporting group values
    Natalizumab Total
    Number of subjects
    1094 1094
    Age categorical
    Units: Subjects
        20 to 29 years
    98 98
        30 to 39 years
    347 347
        40 to 49 years
    454 454
        50 to 59 years
    195 195
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.4 ± 8.12 -
    Gender categorical
    Units: Subjects
        Female
    755 755
        Male
    339 339

    End points

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    End points reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg IV infusions once every 4 weeks for up to 480 weeks

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) to Week 48

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious AEs (SAEs) to Week 48 [1]
    End point description
    AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in subjects administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the subject at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a subject; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. Treatment-emergent AEs: events in subjects who had received at least 1 dose of study drug, regardless of relationship to study drug.
    End point type
    Primary
    End point timeframe
    Baseline through Week 48
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    1094 [2]
    Units: subjects
        AE
    826
        Moderate or severe AE
    487
        Severe AE
    66
        AE related to study drug
    161
        SAE
    61
        SAE related to study drug
    5
        Discontinuation of study drug due to AE
    24
        Withdrawal from study due to AE
    24
    Notes
    [2] - subjects receiving at least 1 dose of study drug
    No statistical analyses for this end point

    Primary: Number of Subjects with Hypersensitivity-related Adverse Events to Week 48

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    End point title
    Number of Subjects with Hypersensitivity-related Adverse Events to Week 48 [3]
    End point description
    For purposes of this analysis, the terms 'hypersensitivity' and 'drug hypersensitivity' were categorized by their temporal relationship to study drug infusion (within 2 hours of the start of the infusion), and were considered equivalent. Hypersensitivity reactions are defined as infusion reactions with the following preferred terms: hypersensitivity not otherwise specified (NOS), anaphylactic reaction, anaphylactoid reaction, dermatitis allergic, drug hypersensitivity, urticaria NOS, vasoconstriction, urticaria generalised, hypersensitivity, urticaria.
    End point type
    Primary
    End point timeframe
    Baseline to Week 48
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    1094 [4]
    Units: subjects
    8
    Notes
    [4] - subjects receiving at least 1 dose of study drug
    No statistical analyses for this end point

    Primary: Number of Subjects with Antibodies to Natalizumab to Week 24

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    End point title
    Number of Subjects with Antibodies to Natalizumab to Week 24 [5]
    End point description
    ‘Positive with unknown persistence’ is defined as a positive result (≥0.5 micrograms/mL) at one timepoint only with no confirmatory re-test available at least 42 days later. ‘Transient positive’ is defined as a positive at one timepoint but negative upon re-test at least 42 days later. ‘Persistent positive’ is defined as positive at 2 or more timepoints separated by at least 42 days. The threshold for classifying a sample as 'antibody positive' was set at the lowest level of reactivity that had a measurable impact on drug serum concentrations.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0), Week 4, Week 24 (test was repeated after 8 weeks if positive, to confirm persistence)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    1043 [6]
    Units: subjects
        Antibody negative
    1004
        Antibody positive with unknown persistence
    15
        Antibody transient positive
    8
        Antibody persistent positive
    16
    Notes
    [6] - subjects with a negative baseline antibody result and ≥ 1 antibody result after the first dose
    No statistical analyses for this end point

    Primary: Time to 24-week Confirmed Expanded Disability Status Scale (EDSS) Progression

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    End point title
    Time to 24-week Confirmed Expanded Disability Status Scale (EDSS) Progression [7]
    End point description
    Time to 24-week confirmed EDSS progression in subjects with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS progression is defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and < 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 24 weeks.
    End point type
    Primary
    End point timeframe
    up to 480 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 data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    220 [8]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    121.9 (67.9 to 216.1)
    Notes
    [8] - subjects with EDSS progression (regardless of length of follow-up) sustained for 24 weeks
    No statistical analyses for this end point

    Primary: Time to 48-week Confirmed EDSS Progression

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    End point title
    Time to 48-week Confirmed EDSS Progression [9]
    End point description
    Time to 48-week confirmed EDSS progression in subjects with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 48-week EDSS progression is defined as ≥ 0.5 point increase from a baseline EDSS ≥ 6.0, or ≥ 1.0 point increase from a baseline EDSS ≥ 1.0 and < 6.0, or ≥ 1.5 point increase from a baseline EDSS of 0, all sustained for 48 weeks.
    End point type
    Primary
    End point timeframe
    up to 480 weeks
    Notes
    [9] - 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 data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    181 [10]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    130.1 (72.4 to 216.1)
    Notes
    [10] - subjects with EDSS progression (regardless of length of follow-up) sustained for 48 weeks
    No statistical analyses for this end point

    Primary: Time to 24-week Confirmed EDSS Improvement Where Baseline ≥ 2.0

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    End point title
    Time to 24-week Confirmed EDSS Improvement Where Baseline ≥ 2.0 [11]
    End point description
    Time to 24-week confirmed EDSS improvement in subjects with at least 2 post-baseline milestone EDSS assessments. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was reported. Confirmed 24-week EDSS improvement is defined as >=1.0 point decrease from baseline sustained for 24 weeks.
    End point type
    Primary
    End point timeframe
    up to 480 weeks
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data for this endpoint was collected and is presented here, per protocol.
    End point values
    Natalizumab
    Number of subjects analysed
    173 [12]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    48.1 (24.1 to 119.9)
    Notes
    [12] - subjects with EDSS improvement (regardless of length of follow-up) sustained for 24 weeks
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) were collected from Screening through the follow-up (492 weeks). Non-serious AEs were collected from baseline through Week 264.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg IV infusions once every 4 weeks for up to 480 weeks

    Serious adverse events
    Natalizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    231 / 1094 (21.12%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous stenosis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Peripheral nerve decompression
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal laminectomy
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid nodule removal
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular graft
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    5 / 1094 (0.46%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    5 / 1094 (0.46%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    5 / 1094 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma of salivary gland
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bile duct adenocarcinoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellopontine angle tumour
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobular breast carcinoma in situ
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Meningioma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Teratoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    11 / 1094 (1.01%)
         occurrences causally related to treatment / all
    9 / 12
         deaths causally related to treatment / all
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foetal death
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage in pregnancy
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Premature baby
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 1094 (0.37%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Completed suicide
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Mania
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obsessive-compulsive disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Uterine polyp
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast hyperplasia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast mass
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 1094 (0.64%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    4 / 1094 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Animal bite
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthropod bite
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyomavirus test positive
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial fibrosis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Congenital anomaly
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coombs negative haemolytic anaemia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal polyps
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Obstructive airways disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    21 / 1094 (1.92%)
         occurrences causally related to treatment / all
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Amnesia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal tear
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal fissure
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Flatulence
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Functional gastrointestinal disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurogenic bladder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    5 / 1094 (0.46%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melanocytic hyperplasia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    5 / 1094 (0.46%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint instability
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint stiffness
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    18 / 1094 (1.65%)
         occurrences causally related to treatment / all
    18 / 18
         deaths causally related to treatment / all
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    13 / 1094 (1.19%)
         occurrences causally related to treatment / all
    1 / 18
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 1094 (0.37%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 1094 (0.27%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 1094 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 1094 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Natalizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    752 / 1094 (68.74%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    61 / 1094 (5.58%)
         occurrences all number
    83
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    164 / 1094 (14.99%)
         occurrences all number
    193
    Headache
         subjects affected / exposed
    157 / 1094 (14.35%)
         occurrences all number
    303
    Dizziness
         subjects affected / exposed
    62 / 1094 (5.67%)
         occurrences all number
    74
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    102 / 1094 (9.32%)
         occurrences all number
    112
    Psychiatric disorders
    Depression
         subjects affected / exposed
    72 / 1094 (6.58%)
         occurrences all number
    81
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    80 / 1094 (7.31%)
         occurrences all number
    118
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    113 / 1094 (10.33%)
         occurrences all number
    149
    Arthralgia
         subjects affected / exposed
    86 / 1094 (7.86%)
         occurrences all number
    114
    Pain in extremity
         subjects affected / exposed
    62 / 1094 (5.67%)
         occurrences all number
    86
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    256 / 1094 (23.40%)
         occurrences all number
    618
    Upper respiratory tract infection
         subjects affected / exposed
    192 / 1094 (17.55%)
         occurrences all number
    394
    Urinary tract infection
         subjects affected / exposed
    162 / 1094 (14.81%)
         occurrences all number
    381
    Influenza
         subjects affected / exposed
    122 / 1094 (11.15%)
         occurrences all number
    159
    Sinusitis
         subjects affected / exposed
    82 / 1094 (7.50%)
         occurrences all number
    110
    Bronchitis
         subjects affected / exposed
    67 / 1094 (6.12%)
         occurrences all number
    96

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2006
    • Changes to exclusion criteria • Addition of pregnancy precautions • Additional follow-up visits added
    29 Jan 2007
    • Long-term Follow-Up, extension of the study
    23 Mar 2007
    • Addition of Canadian sites • Antibody testing for allergic reaction
    12 Mar 2010
    • Addition of blood and urine samples for John Cunningham Virus (JCV) research • Addition of annual magnetic resonance imaging (MRI) • Permission for pregnant patients to return to study
    10 Jan 2011
    • Extension of the study to 480 weeks (This amendment was not implemented; the changes detailed in this version were included in Protocol Version 7 [04 March 2011].)
    04 Mar 2011
    • Extended the study by 216 weeks to give a total study duration of 480 weeks • Addition of anti-JCV antibody testing every 12 weeks if JCV antibody is positive • Progressive multifocal leukoencephalopathy samples and genetic samples • Axial fluid-attenuated inversion recovery MRI
    14 Feb 2013
    • Removed requirement for anti-JCV antibody positive patients to provide samples every 12 weeks. All patients to provide samples every 24 weeks • Removed MRI substudy • Added exploratory analysis of long-term MRI changes • Specified 12-week Telephone Follow-Up only required for subjects discontinuing treatment with natalizumab

    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.
    Sponsor decided to terminate the study prior to all subjects reaching Week 480 as the primary objective was deemed to have been met and only approximately 45% of the original STRATA population remained in the study at the time of study termination.
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