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    Clinical Trial Results:
    A phase 3, multicenter, open-label, extension study to assess the safety and tolerability of epratuzumab treatment in systemic lupus erythematosus subjects (EMBODY4)

    Summary
    EudraCT number
    2010-020859-30
    Trial protocol
    BE   ES   DE   CZ   GB   HU   BG   LT   IT   EE  
    Global end of trial date
    16 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2016
    First version publication date
    15 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SL0012
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01408576
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB, Inc.
    Sponsor organisation address
    1950 Lake Park Drive, Smyrna, United States, GA 30080
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Apr 2016
    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?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of long-term epratuzumab treatment in subjects with systemic lupus erythematosus (SLE)
    Protection of trial subjects
    Patients were pre-medicated prior to infusion of the investigational medicinal product (IMP) to prevent infusion reactions. During the conduct of the study all subjects were closely monitored.
    Background therapy
    Epratuzumab treatment is in addition to the subjects’ existing standard care of oral corticosteroids and any immunosuppressants or antimalarials continued from Baseline in the subject’s original double-blind study. In SL0012, corticosteroids are not considered to be included in the category identified as “immunosuppressants.” - Subjects who completed SL0006 or SL0008: For SL0006, the Baseline dose is defined as the dose prior to the first infusion of study drug in SL0003 or SL0004. For SL0008, the Baseline dose is defined as the dose at Visit 2 in SL0007. - Subjects who participated in SL0009 or SL0010: The Baseline dose is defined as the dose at Visit 2 in SL0009 or SL0010 for subjects completing the study, or the dose at Visit 1 in SL0012 for subjects who terminated prematurely (at Week 16 or later) due to lack of efficacy in SL0009 or SL0010.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    20 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    Ukraine: 52
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 452
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Brazil: 79
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Lithuania: 26
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Poland: 153
    Country: Number of subjects enrolled
    Romania: 47
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    1250
    EEA total number of subjects
    496
    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)
    1218
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in July 2011 and concluded in February 2016.

    Pre-assignment
    Screening details
    Participant Flow refers to the Enrolled Set.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)
    Arm description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Emab
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

    Arm title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)
    Arm description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Emab
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

    Arm title
    Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)
    Arm description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Emab
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion: 600 mg per week or 1200 mg every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles.

    Number of subjects in period 1
    Enrollment Cohort 1 Epratuzumab 600 mg per week (ES) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES) Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)
    Started
    244
    498
    508
    Completed
    56
    0
    0
    Not completed
    188
    498
    508
         AE, unknown type
    -
    1
    -
         Protocol deviation
    1
    2
    2
         Sponsor terminated study
    89
    333
    330
         Lack of efficacy
    17
    30
    48
         SAE, non-fatal
    11
    23
    14
         Other reason
    10
    16
    18
         AE, serious fatal
    4
    4
    1
         SAE, non-fatal+AE, non-serious non-fatal
    -
    1
    1
         AE, non-serious non-fatal
    12
    19
    11
         Consent withdrawn by subject
    34
    60
    66
         Lost to follow-up
    10
    9
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Reporting group values
    Enrollment Cohort 1 Epratuzumab 600 mg per week (ES) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES) Enrollment Cohort 2 Epratuzumab 600 mg per week (ES) Total
    Number of subjects
    244 498 508 1250
    Age Categorical
    Units: Subjects
        <=18 years
    0 4 3 7
        Between 18 and 65 years
    239 485 487 1211
        >=65 years
    5 9 18 32
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41 ± 12 41.9 ± 11.5 42.5 ± 11.9 -
    Gender Categorical
    Units: Subjects
        Male
    18 31 30 79
        Female
    226 467 478 1171

    End points

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    End points reporting groups
    Reporting group title
    Enrollment Cohort 1 Epratuzumab 600 mg per week (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 600 mg per week (ES)
    Reporting group description
    Enrolled Set (ES) of subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    Enrollment Cohort 1 Epratuzumab 600 mg per week
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects enrolled after approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Subject analysis set title
    Enrollment Cohort 2 Epratuzumab 600 mg per week
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects enrolled after approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    All Epratuzumab 600 mg per week
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    All subjects
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Subject analysis set title
    Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Subject analysis set title
    Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    All Epratuzumab 600 mg per week (FASS1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Subject analysis set title
    All subjects (FASS1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Subset 1 (FASS1) consisted of all subjects in the FAS who were enrolled in study SL0008, SL0009, or SL0010 prior to enrollment in SL0012. Subjects were enrolled prior to the approval of Protocol Amendment 2. Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Primary: Number of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks)

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    End point title
    Number of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks) [1]
    End point description
    A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.
    End point type
    Primary
    End point timeframe
    During the treatment period (through Week 96)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W Enrollment Cohort 2 Epratuzumab 600 mg per week All Epratuzumab 600 mg per week All subjects
    Number of subjects analysed
    244
    497
    507
    751
    1248
    Units: Participants
    number (not applicable)
        Number of Participants
    26
    45
    25
    51
    96
    No statistical analyses for this end point

    Primary: Percentage of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks)

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    End point title
    Percentage of subjects prematurely discontinuing due to a treatment-emergent adverse event (TEAE) during the treatment period (maximum 96 weeks) [2]
    End point description
    A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.
    End point type
    Primary
    End point timeframe
    During the treatment period (through Week 96)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W Enrollment Cohort 2 Epratuzumab 600 mg per week All Epratuzumab 600 mg per week All subjects
    Number of subjects analysed
    244
    497
    507
    751
    1248
    Units: percentage of participants
    number (not applicable)
        Percentage of Participants
    10.7
    9.1
    4.9
    6.8
    7.7
    No statistical analyses for this end point

    Primary: Number of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks)

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    End point title
    Number of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks) [3]
    End point description
    A SAE is a treatment-emergent adverse event (TEAE) that the investigator classifies as serious. This includes: • Death • Life-threatening • Significant or persistent disability/incapacity • Congenital anomaly/birth defect (including that occurring in a fetus) • Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious • Initial inpatient hospitalization or prolongation of hospitalization
    End point type
    Primary
    End point timeframe
    During the treatment period (through Week 96)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W Enrollment Cohort 2 Epratuzumab 600 mg per week All Epratuzumab 600 mg per week All subjects
    Number of subjects analysed
    244
    497
    507
    751
    1248
    Units: Participants
    number (not applicable)
        Number of Participants
    81
    119
    104
    185
    304
    No statistical analyses for this end point

    Primary: Percentage of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks)

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    End point title
    Percentage of subjects reporting at least 1 serious adverse event (SAE) during the treatment period (maximum 96 weeks) [4]
    End point description
    A SAE is a treatment-emergent adverse event (TEAE) that the investigator classifies as serious. This includes: • Death • Life-threatening • Significant or persistent disability/incapacity • Congenital anomaly/birth defect (including that occurring in a fetus) • Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious • Initial inpatient hospitalization or prolongation of hospitalization
    End point type
    Primary
    End point timeframe
    During the treatment period (through Week 96)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W Enrollment Cohort 2 Epratuzumab 600 mg per week All Epratuzumab 600 mg per week All subjects
    Number of subjects analysed
    244
    497
    507
    751
    1248
    Units: percentage of participants
    number (not applicable)
        Percentage of Participants
    33.2
    23.9
    20.5
    24.6
    24.4
    No statistical analyses for this end point

    Secondary: Number of subjects meeting treatment response criteria according to a combined response index

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    End point title
    Number of subjects meeting treatment response criteria according to a combined response index
    End point description
    Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1) Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1) All Epratuzumab 600 mg per week (FASS1) All subjects (FASS1)
    Number of subjects analysed
    230
    488
    494
    724
    1212
    Units: Participants
    number (not applicable)
        Number of Responder
    82
    146
    134
    216
    362
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting treatment response criteria according to a combined response index

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    End point title
    Percentage of subjects meeting treatment response criteria according to a combined response index
    End point description
    Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1) Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1) All Epratuzumab 600 mg per week (FASS1) All subjects (FASS1)
    Number of subjects analysed
    230
    488
    494
    724
    1212
    Units: percentage of
    number (not applicable)
        Percentage of Responder
    35.7
    29.9
    27.1
    29.8
    29.9
    No statistical analyses for this end point

    Secondary: Number of subjects meeting treatment response criteria according to a combined response index

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    End point title
    Number of subjects meeting treatment response criteria according to a combined response index
    End point description
    Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1) Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1) All Epratuzumab 600 mg per week (FASS1) All subjects (FASS1)
    Number of subjects analysed
    230
    488
    494
    724
    1212
    Units: Participants
    number (not applicable)
        Number of Responder
    74
    66
    78
    152
    218
    No statistical analyses for this end point

    Secondary: The percent of subjects meeting treatment response criteria according to a combined response index

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    End point title
    The percent of subjects meeting treatment response criteria according to a combined response index
    End point description
    Combined response index is a response variable (yes/no) incorporating the following criteria for achievement of responder status (ie, all criteria must be met to achieve responder status): (1) British Isles Lupus Activity Group (BILAG) improvement, (2) No worsening in Systemic Lupus Erythematosus Activity Index (SLEDAI), (3) No worsening in Physician’s Global Assessment of Disease, and (4) No disallowed changes in concomitant medications, with disallowed changes including mainly increases in corticosteroids, immunosuppressants, and antimalarials.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    Enrollment Cohort 1 Epratuzumab 600 mg per week (FASS1) Enrollment Cohort 2 Epratuzumab 1200 mg Q2W (FASS1) Enrollment Cohort 2 Epratuzumab 600 mg per week (FASS1) All Epratuzumab 600 mg per week (FASS1) All subjects (FASS1)
    Number of subjects analysed
    230
    488
    494
    724
    1212
    Units: percentage of
    number (not applicable)
        Percentage of Responder
    39.8
    21.6
    26.2
    31.4
    27.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Visit 1 until Safety Follow-Up Visit up to week 196
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Enrollment Cohort 1 Epratuzumab 600 mg per week
    Reporting group description
    Subjects enrolled prior to the approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 1200 mg Q2W
    Reporting group description
    Subjects enrolled after approval of Protocol Amendment 2 1200 mg infusions delivered every other week (Q2W) for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Reporting group title
    All Epratuzumab 600 mg per week
    Reporting group description
    600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Reporting group title
    All subjects
    Reporting group description
    Subjects receiving 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles and subjects receiving 1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over sixteen 12 week treatment cycles

    Reporting group title
    Enrollment Cohort 2 Epratuzumab 600 mg per week
    Reporting group description
    Subjects enrolled after approval of Protocol Amendment 2 600 mg infusions delivered weekly for a total of 4 consecutive weeks (cumulative dose 2400 mg) over sixteen 12-week treatment cycles

    Serious adverse events
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W All Epratuzumab 600 mg per week All subjects Enrollment Cohort 2 Epratuzumab 600 mg per week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 244 (33.20%)
    119 / 497 (23.94%)
    185 / 751 (24.63%)
    304 / 1248 (24.36%)
    104 / 507 (20.51%)
         number of deaths (all causes)
    4
    4
    5
    9
    1
         number of deaths resulting from adverse events
    1
    0
    1
    1
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nail avulsion
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Biopsy liver
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood cortisol decreased
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Factor VII deficiency
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 3
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    1 / 751 (0.13%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic cyst
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    4 / 751 (0.53%)
    6 / 1248 (0.48%)
    4 / 507 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 5
    1 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 497 (0.00%)
    6 / 751 (0.80%)
    6 / 1248 (0.48%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 6
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    4 / 751 (0.53%)
    4 / 1248 (0.32%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 497 (0.60%)
    1 / 751 (0.13%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    1 / 751 (0.13%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    1 / 751 (0.13%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 497 (0.60%)
    0 / 751 (0.00%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lupus encephalitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropsychiatric lupus
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculitis brachial
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure anoxic
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus headache
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thecal sac compression
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic outlet syndrome
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transverse sinus thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amaurosis fugax
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising retinitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panophthalmitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 244 (0.41%)
    3 / 497 (0.60%)
    4 / 751 (0.53%)
    7 / 1248 (0.56%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    1 / 5
    2 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 497 (0.60%)
    3 / 751 (0.40%)
    6 / 1248 (0.48%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 3
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 244 (0.41%)
    3 / 497 (0.60%)
    2 / 751 (0.27%)
    5 / 1248 (0.40%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 2
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 497 (0.20%)
    3 / 751 (0.40%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    1 / 4
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 497 (0.60%)
    1 / 751 (0.13%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilic colitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal motility disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    2 / 244 (0.82%)
    3 / 497 (0.60%)
    3 / 751 (0.40%)
    6 / 1248 (0.48%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    1 / 3
    2 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis membranoproliferative
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney fibrosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blister
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic cutaneous lupus erythematosus
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus generalised
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus rash
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Troponin increased
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    7 / 244 (2.87%)
    13 / 497 (2.62%)
    19 / 751 (2.53%)
    32 / 1248 (2.56%)
    12 / 507 (2.37%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 15
    1 / 19
    3 / 34
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 497 (0.40%)
    3 / 751 (0.40%)
    5 / 1248 (0.40%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    3 / 751 (0.40%)
    4 / 1248 (0.32%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondromalacia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enthesopathy
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fasciitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SLE arthritis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis stenosans
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 244 (2.46%)
    7 / 497 (1.41%)
    15 / 751 (2.00%)
    22 / 1248 (1.76%)
    9 / 507 (1.78%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 7
    7 / 16
    7 / 23
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 244 (1.23%)
    3 / 497 (0.60%)
    7 / 751 (0.93%)
    10 / 1248 (0.80%)
    4 / 507 (0.79%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
    4 / 8
    4 / 11
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 244 (0.41%)
    4 / 497 (0.80%)
    4 / 751 (0.53%)
    8 / 1248 (0.64%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 6
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 244 (0.82%)
    3 / 497 (0.60%)
    4 / 751 (0.53%)
    7 / 1248 (0.56%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 4
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 497 (0.40%)
    1 / 751 (0.13%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 1
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 3
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 497 (0.00%)
    5 / 751 (0.67%)
    5 / 1248 (0.40%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 5
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 497 (0.60%)
    0 / 751 (0.00%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint arthroplasty
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymedication
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Shoulder operation
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    Bladder cancer
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myeloproliferative disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Cerebral infarction
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 497 (0.00%)
    4 / 751 (0.53%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 4
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 244 (0.41%)
    4 / 497 (0.80%)
    9 / 751 (1.20%)
    13 / 1248 (1.04%)
    8 / 507 (1.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    1 / 10
    1 / 14
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 2
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    1 / 751 (0.13%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug interaction
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 497 (0.20%)
    3 / 751 (0.40%)
    4 / 1248 (0.32%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 497 (0.20%)
    2 / 751 (0.27%)
    3 / 1248 (0.24%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenomyosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 244 (0.41%)
    3 / 497 (0.60%)
    2 / 751 (0.27%)
    5 / 1248 (0.40%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 497 (0.40%)
    0 / 751 (0.00%)
    2 / 1248 (0.16%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 497 (0.40%)
    2 / 751 (0.27%)
    4 / 1248 (0.32%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    3 / 751 (0.40%)
    3 / 1248 (0.24%)
    3 / 507 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    2 / 751 (0.27%)
    2 / 1248 (0.16%)
    2 / 507 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis migration
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 497 (0.20%)
    0 / 751 (0.00%)
    1 / 1248 (0.08%)
    0 / 507 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 244 (0.00%)
    0 / 497 (0.00%)
    1 / 751 (0.13%)
    1 / 1248 (0.08%)
    1 / 507 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Enrollment Cohort 1 Epratuzumab 600 mg per week Enrollment Cohort 2 Epratuzumab 1200 mg Q2W All Epratuzumab 600 mg per week All subjects Enrollment Cohort 2 Epratuzumab 600 mg per week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 244 (72.54%)
    296 / 497 (59.56%)
    483 / 751 (64.31%)
    779 / 1248 (62.42%)
    306 / 507 (60.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 244 (6.97%)
    26 / 497 (5.23%)
    43 / 751 (5.73%)
    69 / 1248 (5.53%)
    26 / 507 (5.13%)
         occurrences all number
    19
    28
    46
    74
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 244 (8.61%)
    30 / 497 (6.04%)
    53 / 751 (7.06%)
    83 / 1248 (6.65%)
    32 / 507 (6.31%)
         occurrences all number
    25
    31
    68
    99
    43
    Oropharyngeal pain
         subjects affected / exposed
    15 / 244 (6.15%)
    9 / 497 (1.81%)
    29 / 751 (3.86%)
    38 / 1248 (3.04%)
    14 / 507 (2.76%)
         occurrences all number
    24
    11
    40
    51
    16
    Urticaria
         subjects affected / exposed
    13 / 244 (5.33%)
    7 / 497 (1.41%)
    17 / 751 (2.26%)
    24 / 1248 (1.92%)
    4 / 507 (0.79%)
         occurrences all number
    20
    7
    24
    31
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    46 / 244 (18.85%)
    67 / 497 (13.48%)
    103 / 751 (13.72%)
    170 / 1248 (13.62%)
    57 / 507 (11.24%)
         occurrences all number
    66
    84
    146
    230
    80
    Dizziness
         subjects affected / exposed
    20 / 244 (8.20%)
    23 / 497 (4.63%)
    43 / 751 (5.73%)
    66 / 1248 (5.29%)
    23 / 507 (4.54%)
         occurrences all number
    26
    30
    51
    81
    25
    Hypoaesthesia
         subjects affected / exposed
    13 / 244 (5.33%)
    9 / 497 (1.81%)
    25 / 751 (3.33%)
    34 / 1248 (2.72%)
    12 / 507 (2.37%)
         occurrences all number
    15
    9
    28
    37
    13
    Psychiatric disorders
    Depression
         subjects affected / exposed
    16 / 244 (6.56%)
    23 / 497 (4.63%)
    31 / 751 (4.13%)
    54 / 1248 (4.33%)
    15 / 507 (2.96%)
         occurrences all number
    17
    23
    33
    56
    16
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    39 / 244 (15.98%)
    59 / 497 (11.87%)
    101 / 751 (13.45%)
    160 / 1248 (12.82%)
    62 / 507 (12.23%)
         occurrences all number
    80
    86
    159
    245
    79
    Diarrhoea
         subjects affected / exposed
    27 / 244 (11.07%)
    47 / 497 (9.46%)
    47 / 751 (6.26%)
    108 / 1248 (8.65%)
    34 / 507 (6.71%)
         occurrences all number
    41
    58
    61
    146
    47
    Vomiting
         subjects affected / exposed
    22 / 244 (9.02%)
    32 / 497 (6.44%)
    51 / 751 (6.79%)
    83 / 1248 (6.65%)
    29 / 507 (5.72%)
         occurrences all number
    45
    43
    83
    126
    38
    Fatigue
         subjects affected / exposed
    17 / 244 (6.97%)
    19 / 497 (3.82%)
    38 / 751 (5.06%)
    57 / 1248 (4.57%)
    21 / 507 (4.14%)
         occurrences all number
    24
    22
    46
    68
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 244 (9.84%)
    36 / 497 (7.24%)
    54 / 751 (7.19%)
    90 / 1248 (7.21%)
    30 / 507 (5.92%)
         occurrences all number
    40
    44
    78
    122
    38
    Back pain
         subjects affected / exposed
    34 / 244 (13.93%)
    31 / 497 (6.24%)
    66 / 751 (8.79%)
    97 / 1248 (7.77%)
    32 / 507 (6.31%)
         occurrences all number
    47
    32
    79
    111
    32
    Systemic lupus erythematosus
         subjects affected / exposed
    15 / 244 (6.15%)
    18 / 497 (3.62%)
    38 / 751 (5.06%)
    56 / 1248 (4.49%)
    23 / 507 (4.54%)
         occurrences all number
    19
    26
    49
    75
    30
    Pain in extremity
         subjects affected / exposed
    15 / 244 (6.15%)
    15 / 497 (3.02%)
    34 / 751 (4.53%)
    49 / 1248 (3.93%)
    19 / 507 (3.75%)
         occurrences all number
    21
    17
    42
    59
    21
    Muscle spasms
         subjects affected / exposed
    13 / 244 (5.33%)
    18 / 497 (3.62%)
    19 / 751 (2.53%)
    37 / 1248 (2.96%)
    6 / 507 (1.18%)
         occurrences all number
    14
    20
    21
    41
    7
    Bursitis
         subjects affected / exposed
    15 / 244 (6.15%)
    9 / 497 (1.81%)
    22 / 751 (2.93%)
    31 / 1248 (2.48%)
    7 / 507 (1.38%)
         occurrences all number
    24
    11
    31
    42
    7
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    66 / 244 (27.05%)
    76 / 497 (15.29%)
    148 / 751 (19.71%)
    224 / 1248 (17.95%)
    82 / 507 (16.17%)
         occurrences all number
    140
    126
    260
    386
    120
    Urinary tract infection
         subjects affected / exposed
    56 / 244 (22.95%)
    61 / 497 (12.27%)
    118 / 751 (15.71%)
    179 / 1248 (14.34%)
    62 / 507 (12.23%)
         occurrences all number
    124
    88
    214
    302
    90
    Nasopharyngitis
         subjects affected / exposed
    38 / 244 (15.57%)
    42 / 497 (8.45%)
    83 / 751 (11.05%)
    125 / 1248 (10.02%)
    45 / 507 (8.88%)
         occurrences all number
    56
    65
    123
    188
    67
    Bronchitis
         subjects affected / exposed
    34 / 244 (13.93%)
    35 / 497 (7.04%)
    69 / 751 (9.19%)
    104 / 1248 (8.33%)
    35 / 507 (6.90%)
         occurrences all number
    38
    38
    79
    117
    41
    Sinusitis
         subjects affected / exposed
    25 / 244 (10.25%)
    41 / 497 (8.25%)
    63 / 751 (8.39%)
    104 / 1248 (8.33%)
    38 / 507 (7.50%)
         occurrences all number
    40
    48
    88
    136
    48
    Influenza
         subjects affected / exposed
    15 / 244 (6.15%)
    22 / 497 (4.43%)
    36 / 751 (4.79%)
    58 / 1248 (4.65%)
    21 / 507 (4.14%)
         occurrences all number
    16
    24
    39
    63
    23
    Gastroenteritis
         subjects affected / exposed
    14 / 244 (5.74%)
    19 / 497 (3.82%)
    31 / 751 (4.13%)
    50 / 1248 (4.01%)
    17 / 507 (3.35%)
         occurrences all number
    14
    21
    37
    58
    23
    Conjunctivitis
         subjects affected / exposed
    14 / 244 (5.74%)
    15 / 497 (3.02%)
    22 / 751 (2.93%)
    37 / 1248 (2.96%)
    8 / 507 (1.58%)
         occurrences all number
    16
    17
    24
    41
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2011
    The protocol was amended to allow subjects completing the Phase 2, Open-Label-Extension (OLE) studies, SL0006 and SL0008, to enroll in SL0012. In addition, a few clarifications, inconsistencies, and typographical errors were made/corrected within the protocol text.
    03 Feb 2012
    The protocol was amended for the following reasons: - To add an additional treatment arm of epratuzumab 1200mg every other week (QOW) to collect long-term safety data on this dose in a Phase 3 open-label study, in addition to safety data currently being collected in the Phase 3, placebo-controlled, double-blind studies (ie, in SL0009 and SL0010). - To update the statistical considerations (Section 14.2 and Section 14.8 of the protocol) in accordance with addition of the epratuzumab 1200mg QOW treatment arm. - To clarify the guidance for concomitant corticosteroid use in Section 7.8.1.1 of the protocol. The previous text allowed corticosteroid increases for up to 1 month. The revised text specified that corticosteroid increases were allowed for up to 30 consecutive days or up to a total of 30 days per study year. - To update criterion 4 of the primary efficacy variable in Section 4.1.1 of the protocol regarding concomitant corticosteroid use, so that it was consistent with the updated text in Section 7.8.1.1 of the protocol described above. The previous text allowed corticosteroid increases for up to 1 month. The revised text specified that corticosteroid increases were allowed for up to 30 consecutive days or up to a total of 30 days per study year. - To add an additional exploratory endpoint for assessment of flares. - To include a list of anticipated serious adverse events (SAEs) in compliance with the recent Food and Drug Administration (FDA) final rule on safety reporting requirements for studies conducted under an open Investigational New Drug Application (FDA, Guidance for Industry and Investigators, 2011). - To change the name and contact information of the Clinical Trial Biostatistician and Study Physician. In addition, a few clarifications, inconsistencies, and typographical errors were made/corrected within the protocol text.
    25 Mar 2013
    The protocol was amended for the following reasons: - To extend the study duration for an additional 2 years - To update study contact information - To update SAE reporting information - To update information pertaining to SL0006, SL0008, SL0009, and SL0010 Minor typographical errors were corrected throughout the protocol.
    12 May 2014
    The protocol was amended at the request of the German Regulatory Authority, Paul Ehrlich Institute to clarify details of the physical examination within the scope of the BILAG assessment, to introduce a list of adverse events (AEs) of special interest that were identified for epratuzumab, and to clarify further actions after identification of an AE of special interest. Additional changes to the protocol were as follows: - Updated study contact information and SAE reporting information - Revised the exploratory endpoints for assessment of flares - Added an additional safety variable (incidence of hospitalizations/emergency room [ER] visits) - Clarified in Exclusion criterion 10 that the laboratory results from SL0009 and SL0010 should not be older than 28 days - Updated the text in Section 7.2.1 of the protocol (Preparation and administration of epratuzumab and pla