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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
    2010-018563-41
    Trial protocol
    BE   ES   DE   CZ   GB   BG   LT   EE   IT  
    Global end of trial date
    15 May 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2016
    First version publication date
    29 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SL0009
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01262365
    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
    24 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 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 moderate to severe general Systemic Lupus Erythematosus (SLE) despite standard of care treatments (i.e., corticosteroids, and potentially antimalarials and immunosuppressants) continued from Baseline.
    Protection of trial subjects
    Patients were pre-medicated prior to infusion of 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
    09 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
    Australia: 43
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Bulgaria: 59
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    India: 9
    Country: Number of subjects enrolled
    Israel: 38
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Lithuania: 24
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Taiwan: 33
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 293
    Worldwide total number of subjects
    793
    EEA total number of subjects
    287
    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)
    770
    From 65 to 84 years
    23
    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 May 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
    -
    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
    -
    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
    -
    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
    266
    262
    265
    Completed
    176
    181
    171
    Not completed
    90
    81
    94
         SAE(s), non-fatal and AE(s), non-serious non-fatal
    1
    1
    1
         Protocol deviation
    3
    1
    1
         AE(s), non-serious non-fatal
    12
    5
    5
         AE(s), serious fatal
    1
    2
    1
         Lack of efficacy
    35
    30
    47
         AE(s), serious non-fatal
    13
    10
    5
         Consent withdrawn by subject
    17
    22
    22
         other
    5
    3
    6
         Lost to follow-up
    3
    7
    6

    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
    259
    264
    249
    244
    248
    Age Categorical
    Units: Subjects
        <=18 years
    2
    0
    0
        Adults (18-64 years)
    250
    254
    257
        >=65 years
    11
    5
    7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.4 ± 12.6
    42.5 ± 11.8
    42.3 ± 11.4
    42.3 ± 11.4
    42.3 ± 11.4
    42.3 ± 11.4
    Gender Categorical
    Units: Subjects
        Male
    13
    16
    22
        Female
    250
    243
    242

    End points

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    End points reporting groups
    Reporting group title
    Placebo (RS)
    Reporting group description
    -

    Reporting group title
    Epratuzumab 1200 mg every other week (RS)
    Reporting group description
    -

    Reporting group title
    Epratuzumab 600 mg per week (RS)
    Reporting group description
    -

    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Responder
    34.1
    39.8
    37.5
    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
    493
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.175
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.307
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.888
         upper limit
    1.923
    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
    497
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.442
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.164
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.714

    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Responder
    33.7
    43
    39.1
    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Responder
    31.3
    42.2
    39.9
    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Responder
    33.3
    41.8
    35.1
    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
    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Dose decreased by >50%
    9.2
    8.2
    6.9
        Dose decreased >0% to <=50%
    10.8
    16.4
    14.9
        No change in dose
    52.2
    50
    50.8
        Dose increased or missing data
    27.7
    25.4
    27.4
    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
    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
    249
    244
    248
    Units: percentage of
    number (not applicable)
        Dose decreased by >50%
    14.1
    11.9
    10.1
        Dose decreased >0% to <=50%
    10.4
    14.3
    12.5
        No chnage in dose
    38.6
    37.7
    37.9
        Dose increased or missing data
    36.9
    36.1
    37.9
    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 December in 2010 and concluded in May 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 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

    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

    Serious adverse events
    Placebo (Weekly infusion) Epratuzumab 1200 mg every other week Epratuzumab 600 mg per week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 263 (18.25%)
    44 / 259 (16.99%)
    45 / 264 (17.05%)
         number of deaths (all causes)
    1
    2
    2
         number of deaths resulting from adverse events
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Arteriosclerosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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 vasculitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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 / 259 (0.00%)
    1 / 264 (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)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    1 / 264 (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
    Colon adenoma
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 259 (0.00%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pyrexia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 259 (0.00%)
    0 / 264 (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
    Serositis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Psychiatric disorders
    Delirium tremens
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Suicidal ideation
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Bipolar I disorder
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Depression
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Reproductive system and breast disorders
    Breast ulceration
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Endometriosis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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 cyst ruptured
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    0 / 264 (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
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Ankle fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Fibula fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Foot fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Weight decreased
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Haemoglobin decreased
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pericarditis lupus
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pericarditis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Cerebrovascular arteriovenous malformation
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 259 (0.77%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Asthma
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pleural effusion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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 failure
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 259 (0.77%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pancytopenia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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 / 259 (0.00%)
    1 / 264 (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
    Splenomegaly
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery thrombosis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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 encephalitis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Hemiparesis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Hypoaesthesia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Mononeuropathy multiplex
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Retinal detachment
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    3 / 264 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Impaired gastric emptying
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Nausea
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Vomiting
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Abdominal discomfort
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Bezoar
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Diarrhoea
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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%)
    2 / 259 (0.77%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 259 (0.77%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    1 / 264 (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 / 1
    Nephrolithiasis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Proteinuria
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Renal failure acute
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Renal impairment
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Urinary retention
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 259 (0.00%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 259 (0.77%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus hepatitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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%)
    0 / 259 (0.00%)
    1 / 264 (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
    Hidradenitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Swelling face
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    3 / 263 (1.14%)
    5 / 259 (1.93%)
    3 / 264 (1.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Haemarthrosis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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 chest pain
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Osteonecrosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Osteoporotic fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Back pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Hypophosphataemia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Obesity
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Hyperglycaemia
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 259 (0.00%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 259 (1.16%)
    3 / 264 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 259 (1.16%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    4 / 264 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 259 (0.39%)
    2 / 264 (0.76%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    1 / 264 (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
    Abscess neck
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Bronchopneumonia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Diverticulitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Erysipelas
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    1 / 264 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Herpes zoster
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Herpes zoster meningitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Influenza
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Localised infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Lymphangitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Myringitis bullous
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pyelonephritis acute
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    0 / 264 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 259 (0.39%)
    0 / 264 (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
    Pyomyositis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 259 (0.39%)
    0 / 264 (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
    Septic shock
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Bronchitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Diarrhoea infectious
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Viral infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 259 (0.00%)
    0 / 264 (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
    Appendicitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 259 (0.00%)
    1 / 264 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Weekly infusion) Epratuzumab 1200 mg every other week Epratuzumab 600 mg per week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    222 / 263 (84.41%)
    228 / 259 (88.03%)
    211 / 264 (79.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 263 (4.18%)
    20 / 259 (7.72%)
    14 / 264 (5.30%)
         occurrences all number
    12
    21
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 263 (4.56%)
    13 / 259 (5.02%)
    12 / 264 (4.55%)
         occurrences all number
    16
    14
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 263 (11.03%)
    34 / 259 (13.13%)
    38 / 264 (14.39%)
         occurrences all number
    38
    42
    58
    Dizziness
         subjects affected / exposed
    11 / 263 (4.18%)
    9 / 259 (3.47%)
    16 / 264 (6.06%)
         occurrences all number
    11
    10
    18
    Migraine
         subjects affected / exposed
    3 / 263 (1.14%)
    16 / 259 (6.18%)
    7 / 264 (2.65%)
         occurrences all number
    4
    19
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 263 (3.80%)
    17 / 259 (6.56%)
    12 / 264 (4.55%)
         occurrences all number
    10
    20
    17
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 263 (8.75%)
    30 / 259 (11.58%)
    39 / 264 (14.77%)
         occurrences all number
    28
    44
    50
    Diarrhoea
         subjects affected / exposed
    18 / 263 (6.84%)
    21 / 259 (8.11%)
    19 / 264 (7.20%)
         occurrences all number
    20
    24
    28
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 263 (1.90%)
    14 / 259 (5.41%)
    8 / 264 (3.03%)
         occurrences all number
    5
    16
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 263 (5.32%)
    20 / 259 (7.72%)
    14 / 264 (5.30%)
         occurrences all number
    21
    28
    24
    Back pain
         subjects affected / exposed
    11 / 263 (4.18%)
    19 / 259 (7.34%)
    15 / 264 (5.68%)
         occurrences all number
    15
    20
    17
    Pain in extremity
         subjects affected / exposed
    11 / 263 (4.18%)
    14 / 259 (5.41%)
    9 / 264 (3.41%)
         occurrences all number
    13
    18
    9
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 263 (11.41%)
    32 / 259 (12.36%)
    32 / 264 (12.12%)
         occurrences all number
    36
    38
    38
    Urinary tract infection
         subjects affected / exposed
    30 / 263 (11.41%)
    25 / 259 (9.65%)
    30 / 264 (11.36%)
         occurrences all number
    41
    29
    45
    Nasopharyngitis
         subjects affected / exposed
    21 / 263 (7.98%)
    20 / 259 (7.72%)
    22 / 264 (8.33%)
         occurrences all number
    26
    21
    29
    Sinusitis
         subjects affected / exposed
    13 / 263 (4.94%)
    24 / 259 (9.27%)
    15 / 264 (5.68%)
         occurrences all number
    14
    24
    17
    Bronchitis
         subjects affected / exposed
    21 / 263 (7.98%)
    12 / 259 (4.63%)
    15 / 264 (5.68%)
         occurrences all number
    24
    14
    18

    More information

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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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