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    Clinical Trial Results:
    An Extension Protocol For Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab

    Summary
    EudraCT number
    2009-010788-18
    Trial protocol
    GB   DE   BE   SE   AT   PL   CZ   NL   DK   ES   IT  
    Global end of trial date
    16 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Mar 2017
    First version publication date
    05 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMMS03409
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00930553
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly­Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    05 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the study were to examine: 1) the long term safety and efficacy of alemtuzumab in multiple sclerosis (MS) subjects who received alemtuzumab during prior company-sponsored studies CAMMS223, CAMMS323, and CAMMS324; 2) the safety and efficacy of as-needed alemtuzumab retreatment in these previously alemtuzumab-treated subjects; 3) the safety and efficacy of 2 fixed, annual, alemtuzumab courses followed by optional, as-needed, retreatment in subjects who had previously received subcutaneous (SC) interferon beta-1a (INFB-1a) during CAMMS223, CAMMS323, or CAMMS324.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Aug 2009
    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
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 59
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 100
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 53
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Russian Federation: 158
    Country: Number of subjects enrolled
    Croatia: 133
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Serbia: 62
    Country: Number of subjects enrolled
    Ukraine: 67
    Country: Number of subjects enrolled
    United States: 471
    Worldwide total number of subjects
    1314
    EEA total number of subjects
    414
    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)
    1314
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This extension study enrolled subjects from previous 3 studies: CAMMS223 (NCT00050778), CAMMS323 (NCT00530348), and CAMMS324 (NCT00548405). Subjects were enrolled in this study only after their Month 24 visit in CAMMS323 and CAMMS324. CAMMS223 subjects were enrolled within 6 months once their site received approval of extension study.

    Pre-assignment
    Screening details
    Efficacy outcome data was analysed only on CAMMS323 and CAMMS324 subjects; safety data was analysed on all subjects, as pre-specified in protocol.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]

    Arms
    Arm title
    Alemtuzumab
    Arm description
    Subjects enrolled from any of the prior studies received long-term follow-up in this study. Subjects randomised to receive interferon beta-1a (IFNB-1a) in prior studies received alemtuzumab 12 mg/day infusion intravenously (IV) once daily (QD) for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on magnetic resonance imaging [MRI]), unless they met safety-related retreatment disqualifying criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Alemtuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Alemtuzumab was administered by IV infusion over a period of at least 4 hours.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only outcome assessor was blinded in the study.
    Number of subjects in period 1
    Alemtuzumab
    Started
    1314
    Completed
    1091
    Not completed
    223
         Death
    9
         Protocol deviation
    1
         Physician decision
    39
         Lack of efficacy
    7
         Pregnancy
    1
         Adverse events
    1
         Study terminated by sponsor
    24
         Other than specified above
    28
         Consent withdrawn by subject
    88
         Lost to follow-up
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    Subjects enrolled from any of the previous studies received long-term follow-up in this study. Subjects randomised to receive IFNB-1a in any of the previous studies received alemtuzumab 12 mg/day infusion IV, QD for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on MRI), unless they met safety-related retreatment disqualifying criteria.

    Reporting group values
    Overall study Total
    Number of subjects
    1314 1314
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.7 ± 8.51 -
    Gender categorical
    Units: Subjects
        Female
    857 857
        Male
    457 457

    End points

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    End points reporting groups
    Reporting group title
    Alemtuzumab
    Reporting group description
    Subjects enrolled from any of the prior studies received long-term follow-up in this study. Subjects randomised to receive interferon beta-1a (IFNB-1a) in prior studies received alemtuzumab 12 mg/day infusion intravenously (IV) once daily (QD) for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on magnetic resonance imaging [MRI]), unless they met safety-related retreatment disqualifying criteria.

    Subject analysis set title
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received IFNB-1a in CAMMS323, were treated with alemtuzumab in CAMMS03409. IFNB-1a treatment period

    Subject analysis set title
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received IFNB-1a in CAMMS323, were treated with alemtuzumab in CAMMS03409. Alemtuzumab treatment period

    Subject analysis set title
    IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received IFNB-1a in CAMMS324, were treated with alemtuzumab in CAMMS03409. IFNB-1a treatment period

    Subject analysis set title
    IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received IFNB-1a in CAMMS324, were treated with alemtuzumab in CAMMS03409. Alemtuzumab treatment period

    Subject analysis set title
    Alemtuzumab Retreatment
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received alemtuzumab in CAMMS323 (NCT00530348) or CAMMS324 (NCT00548405), received an additional course of alemtuzumab in this study.

    Subject analysis set title
    Alemtuzumab Treatment CAMMS323 Extension
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who were randomised to alemtuzumab 12 mg/day treatment in CAMMS323 (NCT00530348) and enrolled in enrolled in this extension study (CAMMS03409).

    Subject analysis set title
    Alemtuzumab Treatment CAMMS324 Extension
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who were randomised to alemtuzumab 12 mg/day treatment in CAMMS324 (NCT00548405) and enrolled in this extension study (CAMMS03409).

    Primary: Annualized Relapse Rate (ARR)

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    End point title
    Annualized Relapse Rate (ARR) [1]
    End point description
    Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of all subjects involved in certain treatment groups. ARR was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) ) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = Subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Year 3, 4, 5, 6 from the Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively)
    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: Only descriptive data was reported for this endpoint.
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    353
    391
    Units: relapses per subject per year
    number (not applicable)
        Year 3
    0.19
    0.22
        Year 4
    0.16
    0.24
        Year 5
    0.15
    0.19
        Year 6
    0.12
    0.16
    No statistical analyses for this end point

    Primary: Annualized Relapse Rate (ARR) Before and After Receiving Alemtuzumab

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    End point title
    Annualized Relapse Rate (ARR) Before and After Receiving Alemtuzumab [2]
    End point description
    Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment follow-up time of all subjects divided by the sum of total follow-up time of all subjects involved in certain treatment groups. ARR was estimated through repeated negative binomial regression with robust variance estimation and covariate adjustment for geographic region. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Primary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    Notes
    [2] - 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: Only descriptive data was reported for this endpoint.
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: relapses per subject per year
        number (confidence interval 95%)
    0.42 (0.28 to 0.64)
    0.14 (0.09 to 0.21)
    0.6 (0.45 to 0.78)
    0.15 (0.1 to 0.22)
    No statistical analyses for this end point

    Primary: Annualized Relapse Rate (ARR) Before and After Alemtuzumab Retreatment

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    End point title
    Annualized Relapse Rate (ARR) Before and After Alemtuzumab Retreatment [3]
    End point description
    Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of all subjects involved in certain treatment groups. ARR was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study.
    End point type
    Primary
    End point timeframe
    Year 1 prior to retreatment, Year 1, 2, 3 after retreatment
    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: Only descriptive data was reported for this endpoint.
    End point values
    Alemtuzumab Retreatment
    Number of subjects analysed
    321
    Units: relapses per subject per year
    number (confidence interval 95%)
        Year 1 prior to retreatment
    0.79 (0.73 to 0.87)
        Year 1 after retreatment
    0.18 (0.14 to 0.24)
        Year 2 after retreatment
    0.29 (0.23 to 0.38)
        Year 3 after retreatment
    0.3 (0.21 to 0.41)
    No statistical analyses for this end point

    Primary: Number of Subjects With Sustained Accumulation of Disability (SAD)

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    End point title
    Number of Subjects With Sustained Accumulation of Disability (SAD) [4]
    End point description
    SAD: increase of>=1.5 points in Expanded Disability Status Scale (EDSS) score for subjects with prior study baseline score (PSBS) of 0 and increase of>=1.0 point for subjects with a PSBS of 1.0 or more; persisted over a 6-month consecutive period. EDSS is ordinal scale in half-point increments, quantifying disability in subjects with MS. It assesses 7 functional systems (visual,brainstem, pyramidal, cerebellar,sensory,bowel/bladder,cerebral) and ambulation. EDSS total score ranges 0 (normal neurological examination) to 10 (death due to MS), higher scores indicating worse neurological function. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “alemtuzumab treatment CAMMS323 extension” and “alemtuzumab Treatment CAMMS324 Extension”, respectively. Subset of full analysis set (FAS -all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324.
    End point type
    Primary
    End point timeframe
    Baseline (Year 0) up to Year 6
    Notes
    [4] - 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: Statistical analysis has been provided separately as an attachment.
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    376
    426
    Units: subjects
        number (not applicable)
    79
    118
    Attachments
    Statistical Analysis 1
    No statistical analyses for this end point

    Primary: Number of Subjects With Sustained Accumulation of Disability (SAD) Before and After Alemtuzumab Treatment: 2 Year Comparison

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    End point title
    Number of Subjects With Sustained Accumulation of Disability (SAD) Before and After Alemtuzumab Treatment: 2 Year Comparison [5]
    End point description
    SAD: An increase of at least 1.5 points in EDSS score for subjects with PSBS of 0 and increase of at least 1.0 point for subjects with a PSBS of 1.0 or more; and the increase persisted over a 6-month consecutive period. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) and ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), higher scores indicating worse neurological function. Number of subjects with SAD over 2 years before and 2 years after alemtuzumab treatment were estimated by Kaplan-Meier method. The IFNB-1a/Alemtuzumab switch pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Primary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    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: Statistical analysis has been provided separately as an attachment.
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: subjects
        number (not applicable)
    13
    11
    29
    17
    Attachments
    Statistical Analysis 2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS at Year 6

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    End point title
    Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS at Year 6
    End point description
    SRD was defined as a ≥1 point decrease in EDSS score lasting ≥6 months. SRD is only applicable to subjects with a baseline EDSS score of ≥2.0. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Number of subjects with SRD at Year 6 was estimated using Kaplan-Meier method and reported in this endpoint. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjectss who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0) up to Year 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    235
    321
    Units: subjects
        number (not applicable)
    74
    130
    Attachments
    Statistical Analysis 3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS (After Alemtuzumab Treatment) at Year 2 of the Extension Study

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    End point title
    Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS (After Alemtuzumab Treatment) at Year 2 of the Extension Study
    End point description
    SRD: a ≥1 point decrease in EDSS score lasting ≥6 months. SRD is only applicable to subjects with baseline EDSS score of ≥2.0. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Number of subjects with SRD at Year 2 of CAMMS03409 was estimated using Kaplan-Meier method. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Extension study (CAMMS03409) baseline up to Extension Year 2
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    65
    102
    Units: subjects
        number (not applicable)
    11
    14
    Attachments
    Statistical Analysis 4
    No statistical analyses for this end point

    Secondary: Change From Initial Study Baseline in EDSS Score at Year 3, 4, 5 and 6

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    End point title
    Change From Initial Study Baseline in EDSS Score at Year 3, 4, 5 and 6
    End point description
    EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting baseline (Month 0 of the study CAMMS323 [NCT00530348] or CAMMS324 [NCT00548405]) value from EDSS scores at specified time points. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    326
    370
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 3
    -0.08 (-0.2 to 0.04)
    -0.02 (-0.14 to 0.1)
        Change at Year 4
    -0.06 (-0.19 to 0.07)
    0.06 (-0.07 to 0.19)
        Change at Year 5
    0.06 (-0.08 to 0.19)
    0.13 (-0.01 to 0.27)
        Change at Year 6
    0.09 (-0.04 to 0.23)
    0.18 (0.03 to 0.32)
    No statistical analyses for this end point

    Secondary: Change From Initial Study Baseline in EDSS Score Before and After Alemtuzumab Treatment: 2 Year Comparison

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    End point title
    Change From Initial Study Baseline in EDSS Score Before and After Alemtuzumab Treatment: 2 Year Comparison
    End point description
    EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function.Change was calculated by subtracting baseline (Month 0 of the study CAMMS323 or CAMMS324 for pre alemtuzumab period or CAMMS03409 baseline for post alemtuzumab period) value, from EDSS scores at specified time points. The IFNB-1a/Alemtuzumab switch pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting groups. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for "CAMMS323" and "CAMMS324" subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Year 0 -2
    -0.15 (-0.32 to 0.03)
    -0.07 (-0.23 to 0.09)
    0.11 (-0.05 to 0.26)
    -0.02 (-0.18 to 0.14)
        Year 3 - 4
    -0.21 (-0.43 to 0)
    0.08 (-0.11 to 0.27)
    0.2 (-0.01 to 0.41)
    0.13 (-0.05 to 0.31)
    No statistical analyses for this end point

    Secondary: Change From Retreatment Baseline in EDSS Score After Alemtuzumab Retreatment

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    End point title
    Change From Retreatment Baseline in EDSS Score After Alemtuzumab Retreatment
    End point description
    EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function.Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study.
    End point type
    Secondary
    End point timeframe
    Retreatment baseline, Year 1, 2 and 3 after retreatment baseline
    End point values
    Alemtuzumab Retreatment
    Number of subjects analysed
    321
    Units: units on a scale
    arithmetic mean (standard deviation)
        Retreatment baseline (n = 307)
    2.89 ± 1.514
        Change at Year 1 after retreatment baseline(n=256)
    -0.22 ± 1.033
        Change at Year 2 after retreatment baseline(n=158)
    -0.13 ± 1.109
        Change at Year 3 after retreatment baseline(n=75)
    0.07 ± 1.356
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without New or Enlarging Magnetic Resonance Imaging (MRI)-T2-Hypertense Lesion Activity

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    End point title
    Percentage of Subjects Without New or Enlarging Magnetic Resonance Imaging (MRI)-T2-Hypertense Lesion Activity
    End point description
    Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    328
    356
    Units: percentage of subjects
    number (not applicable)
        Year 3 (n = 328, 356)
    72.6
    68.8
        Year 4 (n = 323, 332)
    70.3
    70.2
        Year 5 (n = 319, 321)
    70.2
    67
        Year 6 (n = 307, 312)
    66.8
    69.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Treatment

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    End point title
    Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Treatment
    End point description
    Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: percentage of subjects
    number (not applicable)
        Year 0 - 1 (n = 135, 135, 139, 138)
    57
    79.3
    44.6
    63.8
        Year 0 - 2 (n = 135, 132, 139, 131)
    60.7
    81.8
    47.5
    81.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Retreatment

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    End point title
    Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Retreatment
    End point description
    Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. Retreatment baseline was the annual visit prior to the retreatment start date. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Retreatment Baseline, Year 1, 2 and 3 after retreatment
    End point values
    Alemtuzumab Retreatment
    Number of subjects analysed
    321
    Units: percentage of subjects
    number (not applicable)
        Retreatment baseline (n = 315)
    49.2
        Year 1 after retreatment baseline (n = 301)
    64.1
        Year 2 after retreatment baseline (n = 197)
    66
        Year 3 after retreatment baseline (n = 113)
    60.2
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in MRI-T2-Hypertense Lesion Volumes at Year 3, 4, 5, 6

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    End point title
    Percentage Change From Baseline in MRI-T2-Hypertense Lesion Volumes at Year 3, 4, 5, 6
    End point description
    Lesion volume was quantitatively assessed by hyperintensity on T2-weighted MRI scans. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    332
    364
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Year 3 (n = 332, 364)
    -6.57 ± 29.96
    1.69 ± 31.62
        Change at Year 4 (n = 327, 339)
    -5.04 ± 32.88
    4.97 ± 41.11
        Change at Year 5 (n = 324, 336)
    -4.09 ± 36.99
    12.37 ± 80.74
        Change at Year 6 (n = 309, 319)
    -2.68 ± 42.92
    11.46 ± 73.91
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without New Gadolinium-enhancing MRI Lesion Activity

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    End point title
    Percentage of Subjects Without New Gadolinium-enhancing MRI Lesion Activity
    End point description
    Analysis of new gadolinium-enhancing lesions that appear on MRI scans performed annually. Baseline was the prior annual visit. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    330
    356
    Units: percentage of subjects
    number (not applicable)
        Year 3 (n = 330, 356)
    90.6
    86.5
        Year 4 (n = 325, 331)
    87.1
    88.8
        Year 5 (n = 321, 321)
    87.5
    89.4
        Year 6 (n = 308, 310)
    86.7
    90
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Brain Parenchymal Fractions (BPF) at Year 3, 4, 5 and 6

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    End point title
    Percent Change From Baseline in Brain Parenchymal Fractions (BPF) at Year 3, 4, 5 and 6
    End point description
    Brain parenchymal fraction (calculated as the ratio of brain parenchymal volume to total intradural volume), is a sensitive indicator of brain atrophy. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    325
    355
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Year 3 (n = 325, 355)
    -1.068 ± 1.185
    -0.761 ± 1.24
        Change at Year 4 (n = 323, 331)
    -1.251 ± 1.228
    -0.949 ± 1.341
        Change at Year 5 (n = 321, 317)
    -1.437 ± 1.317
    -0.983 ± 1.374
        Change at Year 6 (n = 308, 315)
    -1.601 ± 1.37
    -1.051 ± 1.472
    No statistical analyses for this end point

    Secondary: Percentage of Relapse Free Subjects

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    End point title
    Percentage of Relapse Free Subjects
    End point description
    Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    353
    391
    Units: percentage of subjects
    number (not applicable)
        Year 3
    84.14
    80.56
        Year 4
    86.84
    79.27
        Year 5
    87.35
    83.29
        Year 6
    88.96
    86.86
    No statistical analyses for this end point

    Secondary: Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey at Year 3, 4, 5 and 6

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    End point title
    Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey at Year 3, 4, 5 and 6
    End point description
    SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of first four health aspects (1 - 4) were aggregated to derive the PCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “alemtuzumab treatment CAMMS323 extension group”, “alemtuzumab Treatment CAMMS324 Extension” group, respectively),Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    340
    375
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 3
    1.9 (0.85 to 2.95)
    1.72 (0.84 to 2.6)
        Change at Year 4
    2.15 (1.1 to 3.2)
    1.34 (0.4 to 2.28)
        Change at Year 5
    1.85 (0.75 to 2.94)
    1.34 (0.39 to 2.29)
        Change at Year 6
    1.65 (0.56 to 2.74)
    1 (-0.03 to 2.03)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey (Before and After Alemtuzumab Treatment): 2 Year Comparison

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    End point title
    Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey (Before and After Alemtuzumab Treatment): 2 Year Comparison
    End point description
    SF-36 is a standardised survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health. Scores of first four health aspects (1 - 4) were aggregated to derive the PCS ranging from 0 (worst) to 100 (best), higher scores indicating good health. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab group consisted of same subjects as those in corresponding post alemtuzumab group. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “CAMMS323” and “CAMMS324” subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Year 1
    1.16 (-0.48 to 2.81)
    2 (0.43 to 3.57)
    0.79 (-0.34 to 1.93)
    1.56 (0.38 to 2.75)
        Year 2
    1.2 (-0.54 to 2.95)
    0.41 (-1.21 to 2.04)
    0.45 (-0.86 to 1.76)
    1.31 (0.14 to 2.48)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) at Year 3, 4, 5, and 6

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    End point title
    Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) at Year 3, 4, 5, and 6
    End point description
    SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of last four health aspects (5 - 8) were aggregated to derive the MCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    340
    375
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 3
    2.43 (1.07 to 3.78)
    1.96 (0.85 to 3.07)
        Change at Year 4
    3.17 (1.85 to 4.49)
    1.91 (0.77 to 3.05)
        Change at Year 5
    2.54 (1.23 to 3.85)
    1.75 (0.59 to 2.92)
        Change at Year 6
    2.41 (1.01 to 3.8)
    1.58 (0.35 to 2.82)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) Before and After Alemtuzumab Treatment: 2 Year Comparison

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    End point title
    Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) Before and After Alemtuzumab Treatment: 2 Year Comparison
    End point description
    SF-36 is a standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health. Scores of last four health aspects (5 - 8) were aggregated to derive the MCS ranging from 0 (worst) to 100 (best), higher scores indicating good health. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab group consisted of same subjects as those in corresponding post alemtuzumab group. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “CAMMS323” and “CAMMS324” subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 1
    2.88 (0.49 to 5.27)
    1.98 (-0.46 to 4.43)
    1.83 (0.3 to 3.36)
    1.21 (-0.31 to 2.74)
        Change at Year 2
    2.32 (-0.11 to 4.74)
    2.08 (-0.38 to 4.54)
    1.65 (0.05 to 3.25)
    1.65 (-0.01 to 3.31)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score at Year 3, 4, 5 and 6

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    End point title
    Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score at Year 3, 4, 5 and 6
    End point description
    FAMS comprised of 58 items on 7 subscales: mobility (7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 items, these are not scored). Subjects provided their response based on the recall of past week. Each item was rated on a 5-point scale ranges from 0 (poor) to 4 (best), where higher scores indicated higher/better quality of life. Scores from 44 calculable items were summed to provide FAMS total score. FAMS total score ranges from 0 (poor) to 176 (best), where higher scores indicated higher/better quality of life. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    340
    372
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 3
    5.28 (2.03 to 8.52)
    4.55 (1.89 to 7.21)
        Change at Year 4
    6.81 (3.55 to 10.08)
    3.65 (0.98 to 6.32)
        Change at Year 5
    4.82 (1.55 to 8.1)
    3.57 (0.78 to 6.37)
        Change at Year 6
    4.4 (1.03 to 7.78)
    3.16 (0.07 to 6.25)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score Before and After Alemtuzumab Treatment: 2 Year Comparison

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    End point title
    Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score Before and After Alemtuzumab Treatment: 2 Year Comparison
    End point description
    FAMS comprised of 58 items on 7 subscales: mobility (7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 items, these are not scored). Subjects provided their response based on the recall of past week. Each item was rated on a 5-point scale ranges from 0 (poor) to 4 (best), where higher scores indicated higher/better quality of life. Scores from 44 calculable items were summed to provide FAMS total score. FAMS total score ranges from 0 (poor) to 176 (best), where higher scores indicated higher/better quality of life. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 1
    4.27 (-1.17 to 9.72)
    4.82 (0.1 to 9.53)
    3.19 (-0.12 to 6.51)
    5.83 (2.74 to 8.92)
        Change at Year 2
    1.88 (-3.63 to 7.38)
    3.1 (-2.16 to 8.35)
    0.93 (-2.86 to 4.71)
    4.66 (1.07 to 8.24)
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score at Year 3, 4, 5 and 6

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    End point title
    Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score at Year 3, 4, 5 and 6
    End point description
    EQ-5D is a standardized instrument for measuring health status and consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was measured on 3 levels (no problem, some problems and extreme problems). These 5-dimensional 3-level measurements were converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state.Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
    End point values
    Alemtuzumab Treatment CAMMS323 Extension Alemtuzumab Treatment CAMMS324 Extension
    Number of subjects analysed
    337
    374
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Year 3
    3.505 (1.438 to 5.572)
    2.859 (1.008 to 4.71)
        Change at Year 4
    5.144 (3.078 to 7.21)
    2.992 (1.145 to 4.838)
        Change at Year 5
    4.409 (2.303 to 6.515)
    3.034 (1.169 to 4.898)
        Change at Year 6
    4.134 (1.946 to 6.323)
    3.155 (0.933 to 5.377)
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score Before and After Alemtuzumab Treatment: 2 Year Comparison

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    End point title
    Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score Before and After Alemtuzumab Treatment: 2 Year Comparison
    End point description
    EQ-5D is a standardized instrument for measuring health status and consisting of EQ-5D descriptive system and VAS. EQ-5D descriptive system comprised of 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was measured on 3 levels (no problem, some problems and extreme problems). These 5-dimensional 3-level measurements were converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
    End point type
    Secondary
    End point timeframe
    Baseline (Year 0 of initial studies) up to Year 4
    End point values
    IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab) IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
    Number of subjects analysed
    139
    139
    143
    143
    Units: units on scale
    arithmetic mean (confidence interval 95%)
        Change at Year 1
    4.165 (0.639 to 7.691)
    4.576 (1.419 to 7.733)
    1.663 (-0.893 to 4.219)
    4.337 (1.1614 to 7.059)
        Change at Year 2
    2.359 (-1.319 to 6.037)
    4.515 (1.407 to 7.622)
    -0.712 (-3.552 to 2.129)
    3.346 (0.324 to 6.368)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form in the extension study up to the end of extension study visit (up to Year 6) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent adverse events (TEAEs), AEs that developed/worsened during or at any time after first alemtuzumab treatment. Alemtuzumab TEAEs were defined as AEs with start dates and start times on or after the date and time of the first alemtuzumab treatment in CAMMS03409 or in prior studies (CAMMS223, CAMMS323, or CAMMS324).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Alemtuzumab
    Reporting group description
    Subjects enrolled in any of the previous studies who had received alemtuzumab. Subjects enrolled in any of the previous studies who had received IFNB-1a, who received alemtuzumab 12 mg/day infusion in this study.

    Serious adverse events
    Alemtuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    376 / 1314 (28.61%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cartilage Injury
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cervical Vertebral Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrostomy Failure
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incision Site Oedema
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Intentional Overdose
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic Injury
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Fistula
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Lumbar Puncture Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural Nausea
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull Fractured Base
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Column Injury
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural Pain
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic Rupture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urine Ketone Body Present
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bradycardia Foetal
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia Neonatal
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bundle Branch Block Right
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Congestive Cardiomyopathy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus Bradycardia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Foetal Cystic Hygroma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Acquired Haemophilia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Autoimmune Haemolytic Anaemia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune Pancytopenia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemolytic Anaemia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune Thrombocytopenic Purpura
         subjects affected / exposed
    16 / 1314 (1.22%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Altered State Of Consciousness
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal Ganglia Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Dizziness
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Complex Partial Seizures
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depressed Level Of Consciousness
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolic Stroke
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    7 / 1314 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Intraventricular Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Optic Neuritis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    67 / 1314 (5.10%)
         occurrences causally related to treatment / all
    0 / 115
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    9 / 1314 (0.68%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Tension Headache
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Uhthoff's Phenomenon
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine Ophthalmopathy
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Optic Atrophy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision Blurred
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    11 / 1314 (0.84%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Impaired Gastric Emptying
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 1314 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancreatic Fistula
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic Pseudocyst
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peptic Ulcer
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Automatic Bladder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Calculus Bladder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Calculus Ureteric
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glomerulonephritis Membranous
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal Mass
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Retention
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal Tubular Necrosis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema Nodosum
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polymorphic Eruption Of Pregnancy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash Generalised
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chondropathy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Costochondritis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Flank Pain
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint Effusion
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint Instability
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint Range Of Motion Decreased
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle Spasms
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal Stiffness
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain In Jaw
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plantar Fasciitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sapho Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Pain
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Temporomandibular Joint Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Autoimmune Hypothyroidism
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune Thyroiditis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Basedow's Disease
         subjects affected / exposed
    39 / 1314 (2.97%)
         occurrences causally related to treatment / all
    0 / 40
         deaths causally related to treatment / all
    0 / 0
    Goitre
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    14 / 1314 (1.07%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Hyperparathyroidism
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrolyte Imbalance
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 1 Diabetes Mellitus
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess Bacterial
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic Hepatitis C
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    7 / 1314 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Bacterial
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    10 / 1314 (0.76%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Helicobacter Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hiv Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious Colitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective Myositis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lung Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreas Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 1314 (0.99%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Oral Herpes
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Legionella
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Fungal
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Tract Infection Viral
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Scrotal Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 1314 (0.61%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Subcutaneous Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubo-Ovarian Abscess
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    7 / 1314 (0.53%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varicella Zoster Virus Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pallor
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Surgical and medical procedures
    Thyroidectomy
         subjects affected / exposed
    1 / 1314 (0.08%)
         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)
    Anogenital Warts
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    B-Cell Lymphoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Benign Hydatidiform Mole
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Benign Neoplasm Of Thyroid Gland
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Castleman's Disease
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cervix Carcinoma Stage Ii
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Insulinoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive Lobular Breast Carcinoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningioma Benign
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant Melanoma In Situ
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic Malignant Melanoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm Skin
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian Adenoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Small Cell Lung Cancer
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Papillary Thyroid Cancer
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Parathyroid Tumour Benign
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic Neuroendocrine Tumour
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pituitary Tumour
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid Cancer
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    5 / 1314 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Vulval Cancer Stage 0
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactoid Reaction
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abortion Missed
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Foetal Death
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foetal Cardiac Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hellp Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foetal-Maternal Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripartum Cardiomyopathy
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Low Birth Weight Baby
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Placental Insufficiency
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pre-Eclampsia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Premature Separation Of Placenta
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Catheter Site Pain
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chills
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device Dislocation
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Perforated Ulcer
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Affective Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adjustment Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Completed Suicide
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Bipolar Ii Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypomania
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Major Depression
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Post-Traumatic Amnestic Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychogenic Pain Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychogenic Tremor
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Schizoaffective Disorder Bipolar Type
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Self Injurious Behaviour
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Cystocele
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Adnexa Uteri Mass
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial Hyperplasia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometriosis
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menorrhagia
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ovarian Haemorrhage
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    6 / 1314 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Pelvic Adhesions
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parovarian Cyst
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectocele
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vulvar Dysplasia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Apnoea Neonatal
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 1314 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Eosinophilic Pneumonia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Biliary Dyskinesia
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    2 / 1314 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 1314 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatitis Acute
         subjects affected / exposed
    1 / 1314 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sphincter Of Oddi Dysfunction
         subjects affected / exposed
    1 / 1314 (0.08%)
         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
    Alemtuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1225 / 1314 (93.23%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    92 / 1314 (7.00%)
         occurrences all number
    109
    Flushing
         subjects affected / exposed
    79 / 1314 (6.01%)
         occurrences all number
    119
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    280 / 1314 (21.31%)
         occurrences all number
    357
    Pain
         subjects affected / exposed
    85 / 1314 (6.47%)
         occurrences all number
    120
    Pyrexia
         subjects affected / exposed
    228 / 1314 (17.35%)
         occurrences all number
    318
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    133 / 1314 (10.12%)
         occurrences all number
    150
    Depression
         subjects affected / exposed
    154 / 1314 (11.72%)
         occurrences all number
    180
    Insomnia
         subjects affected / exposed
    231 / 1314 (17.58%)
         occurrences all number
    278
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    141 / 1314 (10.73%)
         occurrences all number
    322
    Fall
         subjects affected / exposed
    87 / 1314 (6.62%)
         occurrences all number
    244
    Investigations
    Protein Urine Present
         subjects affected / exposed
    78 / 1314 (5.94%)
         occurrences all number
    135
    Blood Creatinine Increased
         subjects affected / exposed
    68 / 1314 (5.18%)
         occurrences all number
    85
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    86 / 1314 (6.54%)
         occurrences all number
    114
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    91 / 1314 (6.93%)
         occurrences all number
    116
    Cough
         subjects affected / exposed
    127 / 1314 (9.67%)
         occurrences all number
    168
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    130 / 1314 (9.89%)
         occurrences all number
    168
    Headache
         subjects affected / exposed
    437 / 1314 (33.26%)
         occurrences all number
    783
    Hypoaesthesia
         subjects affected / exposed
    176 / 1314 (13.39%)
         occurrences all number
    299
    Multiple Sclerosis
         subjects affected / exposed
    70 / 1314 (5.33%)
         occurrences all number
    82
    Multiple Sclerosis Relapse
         subjects affected / exposed
    508 / 1314 (38.66%)
         occurrences all number
    947
    Paraesthesia
         subjects affected / exposed
    168 / 1314 (12.79%)
         occurrences all number
    260
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    75 / 1314 (5.71%)
         occurrences all number
    94
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    72 / 1314 (5.48%)
         occurrences all number
    87
    Constipation
         subjects affected / exposed
    104 / 1314 (7.91%)
         occurrences all number
    125
    Diarrhoea
         subjects affected / exposed
    170 / 1314 (12.94%)
         occurrences all number
    234
    Dyspepsia
         subjects affected / exposed
    71 / 1314 (5.40%)
         occurrences all number
    83
    Nausea
         subjects affected / exposed
    206 / 1314 (15.68%)
         occurrences all number
    323
    Vomiting
         subjects affected / exposed
    130 / 1314 (9.89%)
         occurrences all number
    182
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    122 / 1314 (9.28%)
         occurrences all number
    239
    Haematuria
         subjects affected / exposed
    92 / 1314 (7.00%)
         occurrences all number
    217
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    96 / 1314 (7.31%)
         occurrences all number
    135
    Rash Generalised
         subjects affected / exposed
    110 / 1314 (8.37%)
         occurrences all number
    173
    Rash
         subjects affected / exposed
    208 / 1314 (15.83%)
         occurrences all number
    333
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    216 / 1314 (16.44%)
         occurrences all number
    300
    Back Pain
         subjects affected / exposed
    205 / 1314 (15.60%)
         occurrences all number
    262
    Muscle Spasms
         subjects affected / exposed
    132 / 1314 (10.05%)
         occurrences all number
    182
    Muscular Weakness
         subjects affected / exposed
    113 / 1314 (8.60%)
         occurrences all number
    167
    Musculoskeletal Pain
         subjects affected / exposed
    75 / 1314 (5.71%)
         occurrences all number
    87
    Pain In Extremity
         subjects affected / exposed
    189 / 1314 (14.38%)
         occurrences all number
    320
    Myalgia
         subjects affected / exposed
    80 / 1314 (6.09%)
         occurrences all number
    96
    Endocrine disorders
    Basedow's Disease
         subjects affected / exposed
    165 / 1314 (12.56%)
         occurrences all number
    170
    Hyperthyroidism
         subjects affected / exposed
    142 / 1314 (10.81%)
         occurrences all number
    158
    Autoimmune Thyroiditis
         subjects affected / exposed
    67 / 1314 (5.10%)
         occurrences all number
    67
    Hypothyroidism
         subjects affected / exposed
    140 / 1314 (10.65%)
         occurrences all number
    151
    Metabolism and nutrition disorders
    Vitamin D Deficiency
         subjects affected / exposed
    83 / 1314 (6.32%)
         occurrences all number
    85
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    81 / 1314 (6.16%)
         occurrences all number
    100
    Bronchitis
         subjects affected / exposed
    133 / 1314 (10.12%)
         occurrences all number
    199
    Herpes Zoster
         subjects affected / exposed
    123 / 1314 (9.36%)
         occurrences all number
    145
    Gastroenteritis Viral
         subjects affected / exposed
    85 / 1314 (6.47%)
         occurrences all number
    112
    Influenza
         subjects affected / exposed
    155 / 1314 (11.80%)
         occurrences all number
    195
    Nasopharyngitis
         subjects affected / exposed
    382 / 1314 (29.07%)
         occurrences all number
    949
    Oral Herpes
         subjects affected / exposed
    78 / 1314 (5.94%)
         occurrences all number
    147
    Upper Respiratory Tract Infection
         subjects affected / exposed
    272 / 1314 (20.70%)
         occurrences all number
    501
    Pharyngitis
         subjects affected / exposed
    68 / 1314 (5.18%)
         occurrences all number
    86
    Sinusitis
         subjects affected / exposed
    186 / 1314 (14.16%)
         occurrences all number
    322
    Urinary Tract Infection
         subjects affected / exposed
    360 / 1314 (27.40%)
         occurrences all number
    938

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2010
    • Allowed use of disease modifying therapies including follow-up. • Revision to allow female subjects to become pregnant 6 months after infusion. • Addition of substudy to evaluate effect of alemtuzumab on cardiac repolarization via QT assessments. • Allowed one-time blood sample collection for future genotyping.
    26 Aug 2010
    • Addition of one time point for a PK sample and triplicate electrocardiogram (ECG) collection on study Day 6 or 8 in order to assess any potential delayed alemtuzumab effects on QT.
    18 Apr 2012
    • To extend study by 1 additional year; from 3 years (36 months) to 4 years (48 months).
    26 Jun 2013
    • Study extended to allow subjects to remain in the study through the time of drug approval or until long term care was available. • Added collection of vital signs during alemtuzumab infusion.
    20 Jun 2014
    • Medical events of interest (MEOI) table revised to list specific examples and reporting times. • To specify that an enrolled subject could remain in the Extension Study for a minimum of 48 months from study entry • To specify assessment of rater blinding to include annual visits after 24 months. • Clarification of ITP (immune thrombocytopenic purpura) and anti-glomerular basement membrane (GBM) surveillance monitoring. • To revise that last completion of CARE-MS monthly monitoring survey occurred at the end of the study. • Added Section 9.4.19 to define symptomatic overdose with Investigational Medicinal Product. • Duration of the study was extended to allow subjects in the United States to remain on the study until a follow-up study was available or through Month 72, whichever occurred first. • MEOI table revised to list specific examples and reporting times. • Revised number of Months (from 59 to 71) that subjects would have to qualify and receive treatment after enrollment. • Protocol updated throughout to add monthly visits for Months 61 through 71, accordingly. • Clarification of ITP and Anti-GBM surveillance monitoring. • Revised Section 9.4.19 to clarify symptomatic overdose with IMP. • Revised that last completion of CARE-MS monthly monitoring survey occurred at the end of the study. • Specified assessment of rater blinding to be done at Month 72 visit.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/18946064
    http://www.ncbi.nlm.nih.gov/pubmed/16044212
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