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    Clinical Trial Results:
    A Phase 3, randomized, double-blind, placebo-controlled, multicenter study of the efficacy and safety of four 12-week treatment cycles (48 weeks total) of epratuzumab in systemic lupus erythematosus subjects with moderate to severe disease

    Summary
    EudraCT number
    2010-018565-26
    Trial protocol
    HU   ES   DE   GB   IT  
    Global end of trial date
    03 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Jun 2016
    First version publication date
    18 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SL0010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01261793
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB, Inc.
    Sponsor organisation address
    1950 Lake Park Drive, Smyrna, United States, GA 30080
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to confirm the clinical efficacy of epratuzumab in the treatment of subjects with moderately to severely active Systemic Lupus Erythematosus (SLE) despite standard of care treatments (ie, corticosteroids and potentially antimalarials and immunosuppressants) continued from Baseline.
    Protection of trial subjects
    Patients were pre-medicated prior to infusion of Investigational Medicinal Product (IMP) to prevent infusion reactions. During the conduct of the study all subjects were closely monitored.
    Background therapy
    • Subjects must be receiving concomitant oral corticosteroids within the range of 5 to 60mg/day prednisone equivalents, dependent on the investigator’s assessment of disease activity, at a stable dose for at least 5 days (±1 day) prior to Week 0 (Visit 2) and the first study drug infusion. Tapering of oral corticosteroids after Week 4 (Visit 6) to a target dose of ≤7.5mg/day prednisone equivalents is encouraged during the study. • If the subject is receiving concomitant antimalarials, they must have been receiving them for at least 12 weeks prior to Screening/Baseline (Visit 1), with a stable dose regimen for at least 28 days (±1 day) prior to Week 0 (Visit 2) and the first study drug infusion. The antimalarial dose should be continued at a stable dose (same as Baseline dose) during the study. • If the subject is receiving concomitant immunosuppressants, they must be on a stable dose for at least 28 days (±1 day) prior to Week 0 (Visit 2) and the first study drug infusion. The immunosuppressants dose should be continued at a stable dose (same as Baseline dose) during the study. • Subjects receiving memantine, bromocriptine (Parlodel), danazol, dapsone, dehydroepiandrosterone, or retinoids must be on a stable dose for 28 days (±1 day) prior to Visit 2 and the first study drug infusion. The dose must remain stable during the study until Week 24 (Visit 14), after which time it may be held stable or decreased based on the investigator’s judgment of the subject’s disease activity and health status.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    22 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    Brazil: 51
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Hungary: 44
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Poland: 154
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Ukraine: 53
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 284
    Worldwide total number of subjects
    791
    EEA total number of subjects
    309
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    767
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in December 2010 and concluded in June 2015.

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

    Period 1
    Period 1 title
    Study Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Assessor, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (RS)
    Arm description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    weekly

    Arm title
    Epratuzumab 1200 mg every other week (RS)
    Arm description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Emab
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    600 mg every week, 1200 mg every other week

    Arm title
    Epratuzumab 600 mg per week (RS)
    Arm description
    600 mg infusions delivered weekly for a total of 4 weeks (cumulative dose 2400 mg) over four 12 week treatment cycles
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Emab
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    600 mg every week, 1200 mg every other week

    Number of subjects in period 1
    Placebo (RS) Epratuzumab 1200 mg every other week (RS) Epratuzumab 600 mg per week (RS)
    Started
    263
    262
    266
    Completed
    178
    171
    184
    Not completed
    85
    91
    82
         SAE(s), non-fatal and AE(s), non-serious non-fatal
    -
    1
    1
         Protocol deviation
    3
    5
    6
         AE(s), non-serious non-fatal
    4
    11
    8
         AE(s), serious fatal
    3
    1
    -
         Lack of efficacy
    44
    37
    32
         AE(s), serious non-fatal
    5
    12
    10
         Consent withdrawn by subject
    12
    14
    14
         other
    4
    7
    4
         Lost to follow-up
    10
    3
    7

    Baseline characteristics

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    Subject analysis sets

    Subject analysis set title
    Placebo (Weekly infusion)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 1200 mg every other week
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

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

    Subject analysis set title
    Placebo (Weekly infusion) FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 1200 mg every other week FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 600 mg per week FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    600 mg infusions delivered weekly for a total of 4 weeks (cumulative dose 2400 mg) over four 12 week treatment cycles

    Subject analysis sets values
    Placebo (Weekly infusion) Epratuzumab 1200 mg every other week Epratuzumab 600 mg per week Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects
    263
    261
    264
    263
    261
    264
    Age Categorical
    Units: Subjects
        <=18 years
    0
    4
    3
        Adults (18-64 years)
    254
    253
    251
        >=65 years
    9
    4
    10
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.1 ± 11.8
    40.8 ± 11.5
    41.2 ± 12.7
    41.2 ± 12.7
    41.2 ± 12.7
    41.2 ± 12.7
    Gender Categorical
    Units: Subjects
        Male
    18
    14
    19
        Female
    245
    247
    245

    End points

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    End points reporting groups
    Reporting group title
    Placebo (RS)
    Reporting group description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

    Reporting group title
    Epratuzumab 1200 mg every other week (RS)
    Reporting group description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

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

    Subject analysis set title
    Placebo (Weekly infusion)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 1200 mg every other week
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

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

    Subject analysis set title
    Placebo (Weekly infusion) FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 1200 mg every other week FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

    Subject analysis set title
    Epratuzumab 600 mg per week FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    600 mg infusions delivered weekly for a total of 4 weeks (cumulative dose 2400 mg) over four 12 week treatment cycles

    Primary: The percent of subjects meeting treatment response criteria at Week 48 according to a combined response index

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    End point title
    The percent of subjects meeting treatment response criteria at Week 48 according to a combined response index
    End point description
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Responder
    33.5
    34.1
    35.2
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Weekly infusion) FAS v Epratuzumab 1200 mg every other week FAS
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.899
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.477
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Weekly infusion) FAS v Epratuzumab 600 mg per week FAS
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.716
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.743
         upper limit
    1.539

    Secondary: The percent of subjects meeting treatment response criteria at Week 24 according to a combined response index

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    End point title
    The percent of subjects meeting treatment response criteria at Week 24 according to a combined response index
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Responder
    32.3
    33
    43.6
    No statistical analyses for this end point

    Secondary: The percent of subjects meeting treatment response criteria at Week 12 according to a combined response index

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    End point title
    The percent of subjects meeting treatment response criteria at Week 12 according to a combined response index
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Responder
    30
    32.2
    40.9
    No statistical analyses for this end point

    Secondary: The percent of subjects meeting treatment response criteria at Week 36 according to a combined response index

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    End point title
    The percent of subjects meeting treatment response criteria at Week 36 according to a combined response index
    End point description
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Responder
    32.7
    33
    36.7
    No statistical analyses for this end point

    Secondary: Change from Baseline in daily corticosteroid dose at Week 24

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    End point title
    Change from Baseline in daily corticosteroid dose at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Dose decreased by >50%
    4.6
    10
    8.7
        Dose decreased >0% to ≤50%
    20.9
    18
    18.2
        No change in dose
    48.3
    46.7
    52.7
        Dose increased or missing data
    26.2
    25.3
    20.5
    No statistical analyses for this end point

    Secondary: Change from Baseline in daily corticosteroid dose at Week 48

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    End point title
    Change from Baseline in daily corticosteroid dose at Week 48
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (Weekly infusion) FAS Epratuzumab 1200 mg every other week FAS Epratuzumab 600 mg per week FAS
    Number of subjects analysed
    263
    261
    264
    Units: percentage of
    number (not applicable)
        Dose decreased by >50%
    6.5
    13.8
    14.8
        Dose decreased >0% to ≤50%
    20.9
    13.4
    15.9
        No change in dose
    35.7
    35.6
    36.7
        Dose increased or missing data
    36.9
    37.2
    32.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent Adverse Events (TEAEs) were collected during the course of the study, which started in December 2010 and concluded in June 2015. The Safety Set will be utilized for TEAE reporting.
    Adverse event reporting additional description
    The Safety Set is all enrolled subjects who took at least 1 dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Placebo (Weekly infusion)
    Reporting group description
    Placebo infusions delivered weekly for a total of 4 weeks over four 12-week treatment cycles

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

    Reporting group title
    Epratuzumab 1200 mg every other week
    Reporting group description
    1200 mg infusions delivered every other week for a total of 4 weeks (cumulative dose 2400 mg) over four 12-week treatment cycles and placebo infusions delivered every other week for a total of 4 weeks over four 12-week treatment cycles

    Serious adverse events
    Placebo (Weekly infusion) Epratuzumab 600 mg per week Epratuzumab 1200 mg every other week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 263 (17.11%)
    50 / 264 (18.94%)
    45 / 261 (17.24%)
         number of deaths (all causes)
    3
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy on contraceptive
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 263 (0.76%)
    3 / 264 (1.14%)
    4 / 261 (1.53%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised anxiety disorder
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine decreased
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus myocarditis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Talipes
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 263 (0.00%)
    4 / 264 (1.52%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus pleurisy
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus pneumonitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 264 (0.76%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Antiphospholipid syndrome
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus encephalitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis cerebral
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Noninfectious myelitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Necrotising retinitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal degeneration
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 263 (1.14%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    7 / 263 (2.66%)
    6 / 264 (2.27%)
    6 / 261 (2.30%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 263 (1.14%)
    4 / 264 (1.52%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 263 (0.76%)
    3 / 264 (1.14%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis infected
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 264 (0.38%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 264 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye infection toxoplasmal
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 264 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Weekly infusion) Epratuzumab 600 mg per week Epratuzumab 1200 mg every other week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    159 / 263 (60.46%)
    163 / 264 (61.74%)
    154 / 261 (59.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 263 (4.56%)
    17 / 264 (6.44%)
    14 / 261 (5.36%)
         occurrences all number
    12
    17
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 263 (4.56%)
    16 / 264 (6.06%)
    12 / 261 (4.60%)
         occurrences all number
    12
    19
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    45 / 263 (17.11%)
    34 / 264 (12.88%)
    29 / 261 (11.11%)
         occurrences all number
    71
    51
    39
    Dizziness
         subjects affected / exposed
    13 / 263 (4.94%)
    15 / 264 (5.68%)
    10 / 261 (3.83%)
         occurrences all number
    20
    17
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 263 (5.32%)
    15 / 264 (5.68%)
    15 / 261 (5.75%)
         occurrences all number
    17
    18
    31
    Pyrexia
         subjects affected / exposed
    17 / 263 (6.46%)
    14 / 264 (5.30%)
    8 / 261 (3.07%)
         occurrences all number
    19
    19
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    15 / 263 (5.70%)
    9 / 264 (3.41%)
    10 / 261 (3.83%)
         occurrences all number
    16
    12
    11
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    36 / 263 (13.69%)
    25 / 264 (9.47%)
    32 / 261 (12.26%)
         occurrences all number
    52
    38
    41
    Diarrhoea
         subjects affected / exposed
    20 / 263 (7.60%)
    25 / 264 (9.47%)
    15 / 261 (5.75%)
         occurrences all number
    25
    41
    15
    Vomiting
         subjects affected / exposed
    17 / 263 (6.46%)
    16 / 264 (6.06%)
    12 / 261 (4.60%)
         occurrences all number
    20
    24
    14
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    12 / 263 (4.56%)
    12 / 264 (4.55%)
    13 / 261 (4.98%)
         occurrences all number
    13
    15
    15
    Back pain
         subjects affected / exposed
    19 / 263 (7.22%)
    14 / 264 (5.30%)
    14 / 261 (5.36%)
         occurrences all number
    20
    14
    16
    Arthralgia
         subjects affected / exposed
    14 / 263 (5.32%)
    11 / 264 (4.17%)
    10 / 261 (3.83%)
         occurrences all number
    17
    11
    12
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 263 (14.07%)
    37 / 264 (14.02%)
    38 / 261 (14.56%)
         occurrences all number
    46
    47
    49
    Nasopharyngitis
         subjects affected / exposed
    21 / 263 (7.98%)
    24 / 264 (9.09%)
    15 / 261 (5.75%)
         occurrences all number
    23
    31
    23
    Urinary tract infection
         subjects affected / exposed
    46 / 263 (17.49%)
    38 / 264 (14.39%)
    37 / 261 (14.18%)
         occurrences all number
    68
    57
    45
    Sinusitis
         subjects affected / exposed
    19 / 263 (7.22%)
    20 / 264 (7.58%)
    12 / 261 (4.60%)
         occurrences all number
    23
    23
    17
    Bronchitis
         subjects affected / exposed
    23 / 263 (8.75%)
    11 / 264 (4.17%)
    13 / 261 (4.98%)
         occurrences all number
    24
    13
    13

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Nov 2011
    The protocol was amended for the following reasons: - To change the name and contact information of the Clinical Trial Biostatistician and Study Physician - To add additional exploratory endpoints for assessment of the SF-36 and flares - To clarify the guidance for use of oral corticosteroids for the investigator - To add the sampling time points for overall B and T cell levels during the study and to add a body weight measurement at Week 48. These were inadvertently omitted from the original protocol - To modify Inclusion Criterion #5 for female subjects to allow abstinence alone and condoms/diaphragm use without adjunct spermicide - To modify Exclusion Criterion #15 to clarify that subjects who had previously received Emab treatment were excluded from participation in this study - To update the withdrawal criteria list: subjects who received a live vaccine during the study must have been withdrawn - To increase the Wash-Out Period for the prohibited concomitant treatment TACI-Ig (Atacicept®) from 3 months to 10 months based on recently reported data. The screening window had been increased from 2 days to 5 days, to allow the Screening Period to be extended after discussion with and approval of the medical monitor if it was in the best interest of the subject, and to allow rescreening of subjects on a case-by-case basis at the discretion of the medical monitor - To add additional details to the description of the SF-36 assessment - To include a list of Anticipated SAEs in compliance with the recent US FDA guidance on safety reporting requirements for studies conducted under an open Investigational New Drug Application (Food and Drug Administration [FDA], Guidance for Industry and Investigators, 2010) - To modify the definition of the Pharmacokinetic Set (PKS) to include the requirement of at least 1 Emab plasma concentration measurement In addition, a few clarifications, inconsistencies, and typographical errors had been made/corrected within the protocol text
    09 May 2014
    The protocol was amended at the request of the German Regulatory Authority PEI to clarify details of the BILAG assessment, to introduce a list of adverse events (AEs) of special interest, and to clarify further actions after identification of an AE of special interest. Additional changes were as follows: - Updated study contact information - Updated SAE reporting information - Revised the exploratory endpoints for assessment of flares and for assessment of the SLICC/ACR Damage score - Added an additional safety variable (incidence of hospitalizations/emergency room [ER] visits) - Clarified the guidance for use of oral corticosteroids for the investigator to note that subjects with increases in oral corticosteroids above the allowed levels for an SLE-related indication are considered nonresponders - Corrected the visit numbers cited in Exclusion Criterion #14 - Updated Steroid conversion table with additional corticosteroids - Updated the text “Preparation and administration of Emab and placebo” in order to clarify that it is recommended, but not mandatory, that subjects be premedicated before receiving an iv infusion - Updated the text “Handling and storage requirements” in order to clarify the process to follow in case of out-of-range temperatures - Updated the version number of the European Quality of Life-5 Dimensions questionnaire to European Quality of Life-5 Dimensions 3 level version - Modified the generalized estimating equation (GEE) sensitivity analysis in order to avoid known violations of the missing completely at random assumption, and to be consistent with the current SAP. The original plan for assessing the impact of missing data on the primary endpoint has not changed - Modified the text “Safety analyses” to state that infection TEAEs will be identified by including all events in the coded SOC “Infections and infestations” rather than via a review of all AE terms prior to study unblinding, as originally planned

    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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