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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled 52-Week Study to Assess Adverse Events of Special Interest in Adults with Active, Autoantibody-Positive Systemic Lupus Erythematosus Receiving Belimumab

    Summary
    EudraCT number
    		 2011-005667-25
    Trial protocol
    		 HU   LT   CZ   EE   ES   IT   PT   BG   SK   PL   RO  
    Global end of trial date
    10 Aug 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    25 Aug 2023
    First version publication date
    04 Aug 2019
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    115467
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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
    22 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study are to evaluate the following in adult Systemic Lupus Erythematosus (SLE) participants receiving belimumab plus standard therapy versus participants receiving placebo plus standard therapy: 1) Mortality and adverse events of special interest over 1 year (through 52 weeks). 2) Corticosteroid reduction during Weeks 40-52.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 Standard SLE treatment including steroids, immunomodulatory agents and/or antimalarials.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Regulatory reason
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 130
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Brazil: 451
    Country: Number of subjects enrolled
    Bulgaria: 131
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Chile: 9
    Country: Number of subjects enrolled
    Colombia: 325
    Country: Number of subjects enrolled
    Croatia: 15
    Country: Number of subjects enrolled
    Czechia: 89
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Hong Kong: 42
    Country: Number of subjects enrolled
    Hungary: 117
    Country: Number of subjects enrolled
    Indonesia: 94
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Malaysia: 17
    Country: Number of subjects enrolled
    Mexico: 292
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Peru: 83
    Country: Number of subjects enrolled
    Philippines: 138
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Portugal: 38
    Country: Number of subjects enrolled
    Romania: 30
    Country: Number of subjects enrolled
    Russian Federation: 217
    Country: Number of subjects enrolled
    Serbia: 224
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 319
    Country: Number of subjects enrolled
    Spain: 62
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Taiwan: 278
    Country: Number of subjects enrolled
    Thailand: 67
    Country: Number of subjects enrolled
    Ukraine: 123
    Country: Number of subjects enrolled
    United States: 588
    Worldwide total number of subjects
    4018
    EEA total number of subjects
    575
    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)
    3
    Adults (18-64 years)
    3859
    From 65 to 84 years
    154
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a global, multi-center, randomized, placebo-controlled double blind study that evaluated adverse events of special interest in adult participants with active, autoantibody-positive systemic lupus erythematosus (SLE) when treated with belimumab plus standard therapy versus participants who received placebo plus standard therapy for 1 year.

    Pre-assignment
    Screening details
    		 A total of 4019 participants were randomized in this study. 4003 participants who received at least one dose of study treatment contributed to the Intent-to-Treat (ITT) Population.

    Period 1
    Period 1 title
    Treatment Period (Year 1)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Placebo along with standard therapies including steroids, immunomodulatory agents and/or antimalarials during Year 1.

    Arm title
    		 Belimumab 10 mg/kg
    Arm description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Belimumab 10 milligram/kilogram along with standard therapies including steroids, immunomodulatory agents and/or antimalarials during Year 1.

    Number of subjects in period 1 [1]
    		Placebo Belimumab 10 mg/kg
    Started
    2002
    2001
    Completed
    1729
    1741
    Not completed
    273
    260
         Adverse event, serious fatal
    16
    13
         Consent withdrawn by subject
    128
    128
         Physician decision
    48
    38
         Adverse event, non-fatal
    41
    36
         Missing study conclusion form
    2
    2
         Lost to follow-up
    33
    37
         Site closure
    3
    2
         Protocol deviation
    2
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: As 15 participants were enrolled, entered into the database but did not received treatment, they were excluded from the ITT and As-Treated populations.
    Period 2
    Period 2 title
    Follow-up period (Years 2 to 5)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Placebo along with standard therapies including steroids, immunomodulatory agents and/or antimalarials during Year 1.

    Arm title
    		 Belimumab 10 mg/kg
    Arm description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Belimumab 10 milligram/kilogram along with standard therapies including steroids, immunomodulatory agents and/or antimalarials during Year 1.

    Number of subjects in period 2 [2]
    		Placebo Belimumab 10 mg/kg
    Started
    1670
    1695
    Completed
    1474
    1514
    Not completed
    196
    181
         Consent withdrawn by subject
    44
    36
         Death
    58
    38
         Lost to follow-up
    75
    89
         Missing
    19
    18
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1670 participants from Placebo arm and 1695 from Belimumab arm entered in the Year 2 to 5 follow-up period from the Year 1 - treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Reporting group values
    		 Placebo Belimumab 10 mg/kg Total
    Number of subjects
    		 2002 2001 4003
    Age categorical
    Baseline characteristics were reported for ITT Population.
    Units: Participants
        All Participants
    		 2002 2001 4003
    Age Continuous
    Baseline characteristics were reported for ITT Population.
    Units: years
        arithmetic mean (standard deviation)
    		 40.8 ( 12.74 ) 40.4 ( 12.75 ) -
    Sex: Female, Male
    Baseline characteristics were reported for ITT Population.
    Units: Participants
        Female
    		 1853 1848 3701
        Male
    		 149 153 302
    Race/Ethnicity, Customized
    Baseline characteristics were reported for ITT Population.
    Units: Subjects
        White/Caucasian-European Heritage
    		 1070 1080 2150
        White/Caucasian-Arabic/North African Heritage
    		 19 16 35
        Mixed White Race
    		 1 0 1
        Asian-East Asian Heritage
    		 310 307 617
        Asian-South East Asian Heritage
    		 172 168 340
        Asian-Central/South Asian Heritage
    		 8 6 14
        Asian-Japanese Heritage
    		 2 1 3
        Mixed Asian Race
    		 0 1 1
        African American/African Heritage
    		 155 175 330
        Alaskan Native or American Indian
    		 257 228 485
        Native Hawaiian or Other Pacific Islander
    		 2 5 7
        Missing
    		 6 14 20

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Subject analysis set title
    Belimumab 10 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Primary: Number of deaths - On treatment period (Week 52)

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    End point title
    		 Number of deaths - On treatment period (Week 52)
    End point description
    Number of participants who died during on-treatment period (Week 52) is reported. The on-treatment period was defined as first dose to last dose + 28 days (or death). The As-Treated Population was defined as all participants who were randomized and received at least one dose of study agent, grouped according to the actual treatment administered for the majority (greater than [>]50 percent [%]) of the time. The on-treatment period was the primary analysis period for safety analyses. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    End point type
    Primary
    End point timeframe
    Up to Week 52 (On-treatment period)
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [1]
    2001 [2]
    Units: Participants
        number (not applicable)
    10
    8
    Notes
    [1] - As-Treated Population.
    [2] - As-Treated Population.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.51
    Notes
    [3] - 95% Confidence Interval was calculated using simple asymptotic Chi-Square (Pearson) method.

    Primary: Number of participants who reported protocol defined adverse events of special interest (AESI): On-treatment period (Week 52)

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    End point title
    		 Number of participants who reported protocol defined adverse events of special interest (AESI): On-treatment period (Week 52)
    End point description
    A summary of protocol defined AESIs including serious infections, opportunistic infections and other infections of interest (serious and non-serious), non-melanoma skin cancer (NMSC), malignancies (excluding NMSC), psychiatric events suggesting serious mood disorders and anxiety (serious depression), suicidality (using Columbia-Suicide Severity Rating Scale [C-SSRS]) and serious infusion and hypersensitivity reactions (SIHR) is reported. The on-treatment period (Week 52) was defined as first dose to last dose + 28 days (or death). The on-treatment period was the primary analysis period for safety analyses. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    Up to Week 52 (On-treatment period)
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [4]
    2001 [5]
    Units: Participants
    number (not applicable)
        Serious Infections, n=2001, 2002
    75
    82
        Opportunistic Infections, n=2001, 2002
    36
    50
        Malignancies (Excluding NMSC), n=2001, 2002
    5
    5
        NMSC, n=2001, 2002
    4
    3
        Serious depression, n=2001, 2002
    7
    1
        Suicidality (C-SSRS), n=1986, 1972
    28
    23
        SIHR, n=2001, 2002
    8
    2
    Notes
    [4] - As-Treated Population
    [5] - As-Treated Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.55
         upper limit
    		 0.85
    Notes
    [6] - 95% CI for serious infections was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 0.2
    Notes
    [7] - 95% CI for opportunistic infections and other infections of interest (serious and non-serious) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.31
    Notes
    [8] - 95% CI for malignancies (excluding NMSC) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.31
    Notes
    [9] - 95% CI for NMSC was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.58
    Notes
    [10] - 95% CI for psychiatric events suggesting serious mood disorders and anxiety (serious depression) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 0.96
    Notes
    [11] - 95% CI for suicidality (C-SSRS) was calculated using simple asymptotic Chi-Square (Pearson) method. The total number of participants analyzed were n=3958.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.61
    Notes
    [12] - 95% CI for SIHR was calculated using simple asymptotic Chi-Square (Pearson) method.

    Primary: Number of participants with serious adverse events (SAEs) reported during on-treatment period (Week 52)

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    End point title
    		 Number of participants with serious adverse events (SAEs) reported during on-treatment period (Week 52) [13]
    End point description
    An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. The on-treatment period (Week 52) was defined as first dose to last dose + 28 days (or death) and was the primary analysis period for safety analyses. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    End point type
    Primary
    End point timeframe
    Up to Week 52 (On-treatment period)
    Notes
    [13] - 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: This endpoint was descriptive; hence no statistical analysis to report.
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [14]
    2001 [15]
    Units: Participants
        number (not applicable)
    220
    222
    Notes
    [14] - As-Treated Population.
    [15] - As-Treated Population.
    No statistical analyses for this end point

    Secondary: Number of deaths reported - On-study period (Week 52)

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    End point title
    		 Number of deaths reported - On-study period (Week 52)
    End point description
    Number of participants who died during on-study period (Week 52) is reported. The on-study period (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death). The on-study period was a supportive analysis period for safety analysis. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    End point type
    Secondary
    End point timeframe
    Up to Week 52 (On-study period)
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [16]
    2001 [17]
    Units: Participants
        number (not applicable)
    13
    22
    Notes
    [16] - As-Treated Population.
    [17] - As-Treated Population.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.13
    Notes
    [18] - 95% CI was calculated using simple asymptotic Chi-Square (Pearson) method.

    Secondary: Number of participants who reported protocol defined AESI: On-study period (Week 52)

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    End point title
    		 Number of participants who reported protocol defined AESI: On-study period (Week 52)
    End point description
    A summary of protocol defined AESIs including serious infections, opportunistic infections and other infections of interest (serious and non-serious), NMSC, malignancies (excluding NMSC), psychiatric events suggesting serious mood disorders and anxiety (serious depression), suicidality (using C-SSRS) and SIHR is reported. The on-study period (Week 52) (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death). The on-study period was a supportive analysis period for safety analysis. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    End point type
    Secondary
    End point timeframe
    Up to Week 52 (On-study period)
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [19]
    2001 [20]
    Units: Participants
    number (not applicable)
        Serious Infectionsn n=2001, 2002
    80
    95
        Opportunistic Infections, n=2001, 2002
    39
    59
        Malignancies (Excluding NMC), n=2001, 2002
    5
    7
        NMSC, n=2001, 2002
    4
    3
        Serious depression, n=2001, 2002
    7
    1
        Suicidality (C-SSRS), n=1988, 1974
    31
    25
        SIHR, n=2001, 2002
    8
    2
    Notes
    [19] - As-Treated Population.
    [20] - As-Treated Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 0.51
    Notes
    [21] - 95% CI for serious infections was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.96
         upper limit
    		 -0.04
    Notes
    [22] - 95% CI for opportunistic infections and other infections of interest (serious and non-serious) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 0.24
    Notes
    [23] - 95% CI for malignancies (excluding NMSC) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.31
    Notes
    [24] - 95% CI for NMSC was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 [25]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.58
    Notes
    [25] - 95% CI for psychiatric events suggesting serious mood disorders and anxiety (serious depression) was calculated using simple asymptotic Chi-Square (Pearson) method.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 1.05
    Notes
    [26] - 95% CI for suicidality (C-SSRS) was calculated using simple asymptotic Chi-Square (Pearson) method. The total number of participants analyzed were n=3962.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    4003
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    Method
    Parameter type
    		 Difference in percentage versus placebo
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.61
    Notes
    [27] - 95% CI for SIHR was calculated using simple asymptotic Chi-Square (Pearson) method.

    Secondary: Number of participants with SAEs reported during on-study period (Week 52)

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    End point title
    		 Number of participants with SAEs reported during on-study period (Week 52)
    End point description
    A SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. The on-study period (Week 52) (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death) and was a supportive analysis period for safety analyses. One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    End point type
    Secondary
    End point timeframe
    Up to Week 52 (On-study period)
    End point values
    		 Belimumab 10 mg/kg Placebo
    Number of subjects analysed
    2002 [28]
    2001 [29]
    Units: Participants
        number (not applicable)
    233
    241
    Notes
    [28] - As-Treated Population.
    [29] - As-Treated Population.
    No statistical analyses for this end point

    Secondary: Percentage of participants whose average prednisone (or equivalent) dose to treat SLE has been reduced by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52

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    End point title
    		 Percentage of participants whose average prednisone (or equivalent) dose to treat SLE has been reduced by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52
    End point description
    Average daily prednisone dose during Weeks 40 to 52 is sum of all prednisone doses to treat SLE from the day following Week 40 visit date including Week 52 study completion date (SCD)/no. of days between Week 40 visit and SCD. Percentage of participants whose average prednisone dose reduced by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52 in participants with average prednisone use >7.5 mg/day at Baseline was compared using logistic regression including treatment group, Baseline prednisone dose, screening safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score (<=9 vs.>=10) and region. Baseline is the value at Day 1. Only participants with Baseline prednisone>7.5 mg/day were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Week 40 to Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    990 [30]
    986 [31]
    Units: Percentage of Participants
        number (not applicable)
    16.2
    19.9
    Notes
    [30] - ITT Population
    [31] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    1976
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.0284
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio versus placebo
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.65
    Notes
    [32] - 95% CI and P-value was calculated from a logistic regression model for the comparison between belimumab and placebo including treatment group, Baseline prednisone dose, screening SELENA SLEDAI score (<=9 versus >=10) and region.

    Secondary: Number of Participants With All-cause Mortality During Years 2 to 5

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    End point title
    		 Number of Participants With All-cause Mortality During Years 2 to 5 [33]
    End point description
    Number of participants with all-cause mortality during years 2 to 5 has been presented. As-Treated Any Year 2-5 Follow-up Population consisted of all participants in the As-Treated population who completed at least one post-treatment follow-up visit for Year 2 to 5.
    End point type
    Secondary
    End point timeframe
    From 2 years to 5 years
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoints are different for the different parts of the study.
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    1670 [34]
    1695 [35]
    Units: Participants
    58
    38
    Notes
    [34] - As-Treated Any Year 2-5 Follow-up Population
    [35] - As-Treated Any Year 2-5 Follow-up Population
    No statistical analyses for this end point

    Secondary: Number of Participants With New Primary Malignancies During Years 2 to 5

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    End point title
    		 Number of Participants With New Primary Malignancies During Years 2 to 5 [36]
    End point description
    Number of participants with new primary malignancies during years 2 to 5 has been presented.
    End point type
    Secondary
    End point timeframe
    From 2 years to 5 years
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoints are different for the different parts of the study.
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    1670 [37]
    1695 [38]
    Units: Participants
    22
    24
    Notes
    [37] - As-Treated Any Year 2-5 Follow-up Population.
    [38] - As-Treated Any Year 2-5 Follow-up Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AESIs and all SAEs were collected up to Week 52 (On-study period), all-cause mortality was collected up to end of study (up to 5 years)
    Adverse event reporting additional description
    All-cause mortality, AESIs and SAEs are summarized for the As-Treated Population. Only AESIs and SAEs were collected up to Week 52, but not all AEs. All-cause mortality was collected up to end of study (up to 5 years). One participant in placebo group who received belimumab >50% of the time was reported in the belimumab group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received belimumab 10 milligrams per kilogram (mg/kg) on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo via the intravenous route on Days 0, 14, 28 and every 28 days through Week 48 with a final visit conducted at Week 52. Participants continued to receive standard SLE treatment and were followed up until end of study (up to 5 years).

    Serious adverse events
    		 Belimumab 10 mg/kg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    233 / 2002 (11.64%)
    241 / 2001 (12.04%)
         number of deaths (all causes)
    51
    80
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 2002 (0.00%)
    4 / 2001 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of adrenal gland
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enchondromatosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucoepidermoid carcinoma
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus vasculitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis necrotising
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    5 / 2002 (0.25%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 2002 (0.10%)
    6 / 2001 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 2002 (0.00%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Oedema due to renal disease
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenomyosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adhesion
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovulation pain
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 2002 (0.10%)
    7 / 2001 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus pneumonitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus pleurisy
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Shrinking lung syndrome
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    6 / 2002 (0.30%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    4 / 2002 (0.20%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    4 / 2002 (0.20%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Anomalous pulmonary venous connection
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    3 / 2002 (0.15%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Acute myocardial infarction
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bundle branch block left
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 2002 (0.05%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system vasculitis
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lupus
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis transverse
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropsychiatric lupus
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 2002 (0.15%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 2002 (0.05%)
    5 / 2001 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 2002 (0.00%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 2002 (0.15%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antiphospholipid syndrome
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital swelling
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiploic appendagitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus enteritis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 2002 (0.00%)
    4 / 2001 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice extrahepatic obstructive
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    3 / 2002 (0.15%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus rash
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blister
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyshidrotic eczema
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitic ulcer
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    6 / 2002 (0.30%)
    11 / 2001 (0.55%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 2002 (0.10%)
    6 / 2001 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    5 / 2002 (0.25%)
    11 / 2001 (0.55%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 2002 (0.00%)
    4 / 2001 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SLE arthritis
         subjects affected / exposed
    1 / 2002 (0.05%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    16 / 2002 (0.80%)
    8 / 2001 (0.40%)
         occurrences causally related to treatment / all
    8 / 17
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    18 / 2002 (0.90%)
    27 / 2001 (1.35%)
         occurrences causally related to treatment / all
    9 / 18
    12 / 28
         deaths causally related to treatment / all
    3 / 5
    0 / 2
    Gastroenteritis
         subjects affected / exposed
    4 / 2002 (0.20%)
    11 / 2001 (0.55%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    7 / 2002 (0.35%)
    8 / 2001 (0.40%)
         occurrences causally related to treatment / all
    2 / 7
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 2002 (0.20%)
    4 / 2001 (0.20%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 5
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    Appendicitis
         subjects affected / exposed
    3 / 2002 (0.15%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 2002 (0.05%)
    5 / 2001 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 2002 (0.15%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 2002 (0.20%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
         deaths causally related to treatment / all
    3 / 4
    1 / 3
    Pyelonephritis acute
         subjects affected / exposed
    3 / 2002 (0.15%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    2 / 2002 (0.10%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 2002 (0.05%)
    4 / 2001 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dengue haemorrhagic fever
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    3 / 2001 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholinitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus mucocutaneous ulcer
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis viral
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hookworm infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint tuberculosis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdiaphragmatic abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis gastrointestinal
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 2002 (0.10%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chikungunya virus infection
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 2002 (0.00%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 2002 (0.00%)
    2 / 2001 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 2002 (0.05%)
    1 / 2001 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 2002 (0.05%)
    0 / 2001 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Belimumab 10 mg/kg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 2002 (0.85%)
    31 / 2001 (1.55%)
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    17 / 2002 (0.85%)
    31 / 2001 (1.55%)
         occurrences all number
    17
    33

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2012
    Amendment No.1: Inclusion and exclusion criteria for the study were modified, including clarification of SLE diagnosis, adding a screening pregnancy test, and clarifying contraceptive use. The screening period was reduced from 90 to 30 days to better fit use of the Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) was moved from screening to Baseline to avoid unnecessary efforts assessing SLICC on screen failures. Participants who required hemodialysis or high dose prednisone were excluded if these happened within 90 days prior to screening. Use of concomitant medications was updated to include mepacrine an antimalarial, and capture of dose and frequency of all SLE concomitant medications was added. Clarifications to the use of concomitant SLE medications and commercial belimumab were made. Commercial belimumab remained prohibited during year 1, however a participant could receive it during the follow up period. Assessment of serious infusion or hypersensitivity reactions was removed from the Week 52 visit as no Week 52 study drug was administered. The major efficacy endpoint of steroid reduction was clarified to include patients with involuntary reductions in concomitant immunomodulators. Amendment 01 clarified that participants could participate in the main study without participating in the pharmacogenetic sub-study. As a protocol addition, participants that withdrew their consent to participate in the study were asked to consent to a Week 52 survival status assessment and annual contacts in Years 2 to 5. Further clarification was also provided on the definition of ‘opportunistic infection’ and ‘infections of interest’ were expanded to include Hepatitis B, Hepatitis C, and herpes zoster.
    15 Mar 2013
    Lithuanian Local Amendment: Exclusion criteria were expanded to include participants with hypogammaglobulinaemia, a deficiency in immunoglobulin A, any renal, major organ or stem cell/marrow transplant, and if the participant had a history of recurrent or chronic infection. The exclusion criteria were also expanded to include cyclophosphamide use within 90 days of screening, and cyclophosphamide use during the study.
    13 Jul 2016
    Amendment No.2: This amendment to the protocol was enacted to include detail of interim analyses, to update language surrounding contraceptive use in line with GSK standards, and to modify safety language to ensure alignment with belimumab program standard text. Clarification was also provided on the study design, and typographical errors were fixed.
    22 May 2017
    Amendment No.3: This amendment was enacted to reduce the target number of randomized participants from 5,000 to 4,000, and to update marketing, safety information on belimumab studies, and delivery method of commercial belimumab. The study design was also further updated and clarified, the location of the Study Procedures Manual was included, and remaining typographical errors were fixed.
    25 Nov 2020
    Amendment 4 was implemented during the follow-up period and prior to the Year 3 interim report; the protocol was amended to change the Sponsor from Human Genome Sciences, Inc. to GlaxoSmithKline.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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