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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus Standard of Care in Adult Subjects with Active Lupus Nephritis

    Summary
    EudraCT number
    2011-004570-28
    Trial protocol
    HU   DE   GB   BE   ES   CZ   NL   FR  
    Global end of trial date
    12 Mar 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jun 2020
    First version publication date
    27 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BEL114054
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    10 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy, safety, and tolerability of belimumab in adult patients with active lupus nephritis.
    Protection of trial subjects
    Not Applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 34
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 32
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    China: 79
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 43
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Philippines: 45
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Thailand: 25
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 76
    Worldwide total number of subjects
    448
    EEA total number of subjects
    77
    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)
    446
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a Phase 3, multi-center, multi-national, randomized, double-blind, placebo-controlled study that evaluated safety and efficacy of intravenous (IV) belimumab 10 milligrams per kilogram (mg/kg) plus standard of care (SoC) compared to placebo plus SoC in adult participants with active lupus nephritis.The study was conducted in 21 countries.

    Pre-assignment
    Screening details
    A total of 797 participants were screened for the study of which 448 participants were enrolled. The results presented are for the primary analysis (double blind treatment period)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants were randomized to receive matching placebo IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (high dose cortiocsteroids [HDCS] plus Cyclophosphamide [CYC] versus [vs.] HDCS plus Mycophenolate Mofetil [MMF]) and race.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered with Placebo intravenously (IV) along with standard of care (SoC) on Days 0, 14, 28, and then every 28 days thereafter through Week 100, with a final evaluation at Week 104.

    Arm title
    Belimumab 10 mg/kg
    Arm description
    Participants were randomized to receive Belimumab 10 mg/kg IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (HDCS plus CYC vs. HDCS plus MMF) and race.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered with Belimumab 10 milligrams per kilograms (mg/kg) IV along with SoC on Days 0, 14, 28, and then every 28 days thereafter through Week 100, with a final evaluation at Week 104.

    Number of subjects in period 1
    Placebo Belimumab 10 mg/kg
    Started
    224
    224
    Completed
    170
    186
    Not completed
    54
    38
         Protocol deviation
    -
    2
         Physician decision
    11
    5
         Lack of efficacy
    2
    1
         Adverse event, serious fatal
    5
    6
         Adverse event, non-fatal
    5
    1
         Consent withdrawn by subject
    26
    19
         Lost to follow-up
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were randomized to receive matching placebo IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (high dose cortiocsteroids [HDCS] plus Cyclophosphamide [CYC] versus [vs.] HDCS plus Mycophenolate Mofetil [MMF]) and race.

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were randomized to receive Belimumab 10 mg/kg IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (HDCS plus CYC vs. HDCS plus MMF) and race.

    Reporting group values
    Placebo Belimumab 10 mg/kg Total
    Number of subjects
    224 224 448
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    222 224 446
        From 65-84 years
    2 0 2
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    33.0 ± 10.64 33.7 ± 10.73 -
    Sex: Female, Male
    Units: Participants
        Female
    196 198 394
        Male
    28 26 54
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian (AI) or Alaska Native (AN)
    6 4 10
        Asian-Central/South Asian Heritage (H)
    2 3 5
        Asian-Japanese/East Asian/Southeast Asian H
    107 112 219
        Mixed Asian
    1 0 1
        Black or African American (AA)
    31 30 61
        White/Caucasian/European H
    71 72 143
        White/Caucasian/Arabic/North African H
    4 1 5
        Multiple-AA/African H and AI or AN and White
    1 1 2
        Multiple-Asian and White
    1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were randomized to receive matching placebo IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (high dose cortiocsteroids [HDCS] plus Cyclophosphamide [CYC] versus [vs.] HDCS plus Mycophenolate Mofetil [MMF]) and race.

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were randomized to receive Belimumab 10 mg/kg IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (HDCS plus CYC vs. HDCS plus MMF) and race.

    Primary: Percentage of participants with primary efficacy renal response (PERR) at Week 104

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    End point title
    Percentage of participants with primary efficacy renal response (PERR) at Week 104
    End point description
    PERR is defined as urinary protein creatinine ratio <=0.7, estimated glomerular filtration rate (eGFR) was not more than 20 percent (%) below the pre-flare value or >=60 milliliters per minute per 1.73 square meter (mL/min/1.73m^2) and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates of induction regimen (CYC vs. MMF), race (Black vs. Non-Black), Baseline urine protein-creatinine ratio (uPCR) and Baseline eGFR. Modified Intent-to-treat (MITT) Population consisted of all randomized participants who received at least one dose of study treatment and were not in one of 2 sites excluded due to GCP compliance. Percentage of participants with PERR at Week 104 has been presented.
    End point type
    Primary
    End point timeframe
    Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    223 [1]
    223 [2]
    Units: Percentage of participants
        number (not applicable)
    32.3
    43.0
    Notes
    [1] - mITT Population
    [2] - mITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Belimumab 10 mg/kg v Placebo
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.0311 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    2.32
    Notes
    [3] - Treatment comparison between Belimumab 10 mg/kg and placebo using odds ratio and its corresponding 95% confidence interval has been presented.
    [4] - P-value was calculated using logistic regression model. Test 1 of 5 in a step-down sequential testing procedure.

    Secondary: Percentage of participants with complete renal response (CRR) at Week 104

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    End point title
    Percentage of participants with complete renal response (CRR) at Week 104
    End point description
    CRR is defined as urinary protein creatinine ratio <0.5, eGRF was not more than 10% below the pre-flare value or >=90 mL/min/1.73m^2 and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates of induction regimen (CYC vs. MMF), race (Black vs. Non-Black), Baseline uPCR and Baseline eGFR. Percentage of participants with CRR at Week 104 has been presented.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    223 [5]
    223 [6]
    Units: Percentage of participants
        number (not applicable)
    19.7
    30.0
    Notes
    [5] - mITT Population.
    [6] - mITT Population.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.0167 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.11
         upper limit
    2.74
    Notes
    [7] - Treatment comparison between Belimumab 10 mg/kg and placebo using odds ratio and its corresponding 95% confidence interval has been presented.
    [8] - P-value was calculated using logistic regression model. Test 2 of 5 in a step-down sequential testing procedure.

    Secondary: Percentage of participants with PERR at Week 52

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    End point title
    Percentage of participants with PERR at Week 52
    End point description
    PERR is defined as urinary protein creatinine ratio <=0.7, eGRF was not more than 20% below the pre-flare value or >=60 mL/min/1.73m^2 and was not a treatment failure. Analysis was performed using a logistic regression model for the comparison between Belimumab and Placebo with covariates of induction regimen (CYC vs. MMF), race (Black vs. Non-Black), uPCR and Baseline eGFR. Percentage of participants with PERR at Week 52 has been presented.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    223 [9]
    223 [10]
    Units: Percentage of participants
        number (not applicable)
    35.4
    46.6
    Notes
    [9] - mITT Population
    [10] - mITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.0245 [12]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    2.38
    Notes
    [11] - Treatment comparison between Belimumab 10 mg/kg and placebo using odds ratio and its corresponding 95% confidence interval has been presented.
    [12] - P-value was calculated using logistic regression model. Test 3 of 5 in a step-down sequential testing procedure.

    Secondary: Number of participants with time to death or renal related event

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    End point title
    Number of participants with time to death or renal related event
    End point description
    Events are defined as the first event experienced among the following: death, progression to end stage renal disease, doubling of serum creatinine from Baseline, renal worsening or renal-related treatment failure. Participants who discontinued randomized treatment, withdrawn from the study, or are lost to follow-up were censored on the date of the event. Participants who completed the 104-week treatment period were censored at the Week 104 visit. Time to event is defined as event date minus treatment start date plus one. Analysis was performed using Cox proportional hazards model for the comparison between Belimumab and Placebo adjusting for induction regimen, race, baseline uPCR, and Baseline eGFR. Number of participants with time to death or renal related event up to Week 104 has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    223 [13]
    223 [14]
    Units: Participants
    63
    35
    Notes
    [13] - mITT Population
    [14] - mITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.0014 [16]
    Method
    Cox proportional hazards model
    Parameter type
    Cox proportional hazard
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.77
    Notes
    [15] - Treatment comparison between Belimumab 10 mg/kg and placebo using Cox proportional hazards ratio and its corresponding 95% confidence interval has been presented.
    [16] - P-value was calculated using Cox proportional hazards model. Test 4 of 5 in a step-down sequential testing procedure

    Secondary: Percentage of participants with ordinal renal response (ORR) at Week 104

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    End point title
    Percentage of participants with ordinal renal response (ORR) at Week 104
    End point description
    ORR is defined with respect to reproducible responses that included CRR, partial RR (PRR) and non responder. CRR is reported when uPCR was <0.5, eGFR was not more than 10% below pre-flare GFR or within normal range and not a treatment failure. PRR is >=50% decrease from Baseline in uPCR and one of the following: value <1 if Baseline <=3, or value <3 if the Baseline was >3, eGFR not more than 10% below Baseline GFR or within normal range and not a treatment failure and not a CRR. Non responder is reported when neither CRR nor PRR criteria was met. Percentage of participants reporting CRR, PRR and non responders at Week 104 has been presented.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    223 [17]
    223 [18]
    Units: Percentage of participants
    number (not applicable)
        CRR
    19.7
    30.0
        PRR
    17.0
    17.5
        Non responder
    63.2
    52.5
    Notes
    [17] - mITT Population
    [18] - mITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0096 [19]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [19] - P-value is rank analysis of covariance model comparing Belimumab and Placebo with covariates for treatment group, induction regimen(CYC vs MMF),race(Black vs Non-black), Baseline uPCR, and eGFR. Test 5 of 5 in step-down sequential testing procedure.

    Other pre-specified: Number of participants reporting on-treatment adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    Number of participants reporting on-treatment adverse events (AEs) and serious adverse events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose: resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with on-treatment AE/ SAE has been reported. Safety Population comprises of all randomized participants who received at least one dose of study treatment.
    End point type
    Other pre-specified
    End point timeframe
    Up to Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    224 [20]
    224 [21]
    Units: Participants
        Any AE
    211
    214
        Any SAE
    67
    58
    Notes
    [20] - Safety Population.
    [21] - Safety Population.
    No statistical analyses for this end point

    Other pre-specified: Number of participants reporting on-treatment adverse events of special interest (AESI)

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    End point title
    Number of participants reporting on-treatment adverse events of special interest (AESI)
    End point description
    An AESI is one of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by investigator to sponsor can be appropriate. A summary of protocol defined AESIs include malignant neoplasms including and excluding non-melanoma skin cancer (NMSC), post-infusion systemic reactions (PISR), all infections of special interest (opportunistic infections [OI], Herpes Zoster [HZ], tuberculosis [TB], and sepsis), depression (including mood disorders and anxiety)/suicide/self-injury and deaths (On-treatment AE with death occurring anytime). Number of participants reporting on-treatment AESI has been presented.
    End point type
    Other pre-specified
    End point timeframe
    Up to Week 104
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    224 [22]
    224 [23]
    Units: Participants
        Malignancies excluding NMSC
    0
    2
        Malignancies including NMSC
    0
    3
        PISR
    29
    26
        All infections of special interest
    34
    30
        Depression/suicide/self-injury
    16
    11
        Deaths
    3
    4
    Notes
    [22] - Safety Population.
    [23] - Safety Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were reported from start of treatment until Week 104. All AEs are included regardless of time since last investigational product (IP) treatment.
    Adverse event reporting additional description
    AEs and SAEs were collected for Safety Population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were randomized to receive Belimumab 10 mg/kg IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (HDCS plus CYC vs. HDCS plus MMF) and race.

    Reporting group title
    Placebo
    Reporting group description
    Participants were randomized to receive matching placebo IV plus SoC on Days 0 (Baseline), 14, 28 and then every 28 days thereafter through 100 Weeks with a final evaluation for the double-blind treatment period at Week 104. The randomization was stratified by their induction regimen (high dose cortiocsteroids [HDCS] plus Cyclophosphamide [CYC] versus [vs.] HDCS plus Mycophenolate Mofetil [MMF]) and race.

    Serious adverse events
    Belimumab 10 mg/kg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 224 (29.02%)
    78 / 224 (34.82%)
         number of deaths (all causes)
    6
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 224 (0.89%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymoma
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immunosuppression
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolonged labour
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 224 (0.89%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 224 (0.89%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Head injury
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood immunoglobulin G decreased
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal biophysical profile score equivocal
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 224 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis uraemic
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 224 (0.45%)
    6 / 224 (2.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 224 (1.34%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglobulinaemia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow toxicity
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Organizing pneumonia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lupus
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Generalized tonic-clonic seizure
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 224 (0.89%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 224 (1.34%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiploic appendagitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis gastrointestinal
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    2 / 224 (0.89%)
    8 / 224 (3.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 224 (0.89%)
    5 / 224 (2.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus rash
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema annulare
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 224 (0.45%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligoarthritis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    10 / 224 (4.46%)
    10 / 224 (4.46%)
         occurrences causally related to treatment / all
    3 / 11
    5 / 11
         deaths causally related to treatment / all
    2 / 3
    0 / 1
    Herpes zoster
         subjects affected / exposed
    4 / 224 (1.79%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 224 (0.89%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 224 (1.79%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 224 (0.00%)
    5 / 224 (2.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 224 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Subcutaneous abscess
         subjects affected / exposed
    2 / 224 (0.89%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone abscess
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis viral
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteus infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary nocardiosis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rhodococcus infection
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster viral infection
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Belimumab 10 mg/kg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    186 / 224 (83.04%)
    191 / 224 (85.27%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 224 (5.36%)
    20 / 224 (8.93%)
         occurrences all number
    14
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 224 (13.39%)
    21 / 224 (9.38%)
         occurrences all number
    38
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 224 (5.80%)
    23 / 224 (10.27%)
         occurrences all number
    16
    26
    Leukopenia
         subjects affected / exposed
    15 / 224 (6.70%)
    19 / 224 (8.48%)
         occurrences all number
    28
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 224 (15.18%)
    35 / 224 (15.63%)
         occurrences all number
    51
    57
    Dizziness
         subjects affected / exposed
    13 / 224 (5.80%)
    19 / 224 (8.48%)
         occurrences all number
    18
    21
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 224 (4.91%)
    17 / 224 (7.59%)
         occurrences all number
    14
    20
    Oedema peripheral
         subjects affected / exposed
    16 / 224 (7.14%)
    13 / 224 (5.80%)
         occurrences all number
    23
    17
    Oedema
         subjects affected / exposed
    9 / 224 (4.02%)
    12 / 224 (5.36%)
         occurrences all number
    9
    15
    Fatigue
         subjects affected / exposed
    12 / 224 (5.36%)
    14 / 224 (6.25%)
         occurrences all number
    12
    15
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 224 (4.46%)
    18 / 224 (8.04%)
         occurrences all number
    10
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    45 / 224 (20.09%)
    48 / 224 (21.43%)
         occurrences all number
    59
    56
    Nausea
         subjects affected / exposed
    21 / 224 (9.38%)
    24 / 224 (10.71%)
         occurrences all number
    28
    33
    Vomiting
         subjects affected / exposed
    16 / 224 (7.14%)
    16 / 224 (7.14%)
         occurrences all number
    25
    21
    Abdominal pain
         subjects affected / exposed
    12 / 224 (5.36%)
    13 / 224 (5.80%)
         occurrences all number
    15
    13
    Dyspepsia
         subjects affected / exposed
    9 / 224 (4.02%)
    15 / 224 (6.70%)
         occurrences all number
    10
    18
    Abdominal pain upper
         subjects affected / exposed
    16 / 224 (7.14%)
    6 / 224 (2.68%)
         occurrences all number
    16
    7
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    23 / 224 (10.27%)
    17 / 224 (7.59%)
         occurrences all number
    31
    18
    Acne
         subjects affected / exposed
    12 / 224 (5.36%)
    9 / 224 (4.02%)
         occurrences all number
    13
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 224 (11.61%)
    32 / 224 (14.29%)
         occurrences all number
    44
    52
    Back pain
         subjects affected / exposed
    17 / 224 (7.59%)
    17 / 224 (7.59%)
         occurrences all number
    24
    17
    Muscle spasms
         subjects affected / exposed
    18 / 224 (8.04%)
    15 / 224 (6.70%)
         occurrences all number
    25
    18
    Pain in extremity
         subjects affected / exposed
    12 / 224 (5.36%)
    8 / 224 (3.57%)
         occurrences all number
    14
    9
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    24 / 224 (10.71%)
    20 / 224 (8.93%)
         occurrences all number
    36
    23
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    81 / 224 (36.16%)
    74 / 224 (33.04%)
         occurrences all number
    159
    134
    Urinary tract infection
         subjects affected / exposed
    43 / 224 (19.20%)
    37 / 224 (16.52%)
         occurrences all number
    73
    72
    Nasopharyngitis
         subjects affected / exposed
    35 / 224 (15.63%)
    31 / 224 (13.84%)
         occurrences all number
    60
    50
    Gastroenteritis
         subjects affected / exposed
    21 / 224 (9.38%)
    23 / 224 (10.27%)
         occurrences all number
    24
    28
    Bronchitis
         subjects affected / exposed
    18 / 224 (8.04%)
    19 / 224 (8.48%)
         occurrences all number
    24
    26
    Herpes zoster
         subjects affected / exposed
    17 / 224 (7.59%)
    19 / 224 (8.48%)
         occurrences all number
    17
    20
    Conjunctivitis
         subjects affected / exposed
    13 / 224 (5.80%)
    5 / 224 (2.23%)
         occurrences all number
    13
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2012
    Amendment 01: Applied to all countries and sites. The protocol was modified to clarify exclusion criteria, concurrent medications and standard of care, addition of anti-malarials, and use of corticosteroids. There were also changes to prohibited medications and non-drug therapies, live vaccines, screening procedures, and the double-blind treatment period and study calendar. An open-label extension replaced the continuation phase. An exploratory analysis of urinary biomarkers related to lupus nephritis was added. Clarifications were made to the withdrawal of study treatment and adverse event reporting sections. The endpoints and statistical analysis sections were updated to reflect changes made in other sections of the protocol.
    08 Mar 2012
    Amendment 02: Applied to all countries and sites. The protocol was modified to require participants to remain under clinical supervision for 3 hours after completion of the first 2 infusions. Results for biological markers measured by florescence activated cell sorting (FACS) were added to the list of laboratory results not provided to study sites. Language describing participant un-blinding in the protocol was amended. Language regarding the body weight used for dose calculation was corrected.
    11 Feb 2014
    Amendment 03: Applied to all countries and sites. In this amendment the protocol was modified to expand Hepatitis B serology testing, to exclude participants who tested positive according to the criteria specified, and to specify hepatitis C screening. Screening and induction initiation windows were extended and details were added for eligibility criteria pertaining to various laboratory parameters. Clarification was added for screening for active or latent infections. A belimumab Benefit and Risk Assessment, and a preliminary assessment specific to the lupus nephritis participant population were added. Information on non-acute delayed type hypersensitivity reaction and symptoms was added. Instructions for monitoring and managing cases of Grade 4 immunoglobulin G (IgG) were clarified. The concurrent medication section was modified. Steroid rescue for non-renal systemic lupus erythematosus (SLE) disease activity and non-SLE disease activity was revised. Timing of pharmacokinetic sampling in participants who withdrew from the study was clarified. A new section was added to clarify management of participants with liver chemistry events during the study. Reason for treatment withdrawal was modified. Participant un-blinding information was updated. The adverse events section was modified for consistency. Progressive multifocal leukoencephalopathy (PML) text was updated. The Independent Data Monitoring Committee (IDMC) was also to monitor all serious adverse events (SAEs). New appendices were added to provide the questionnaires for the possible suicidality-related history questionnaire (PSRHQ), the possible suicidality-related questionnaire (PSRQ), and the Country-specific Requirements for Thailand.
    16 Mar 2015
    Amendment 05: Applied in all countries and sites, except for those with a local version amendment. Eligibility criteria, exclusion criteria, and relevant sections were modified to allow patients who initiated an induction recently to be considered for enrollment. The Risk-Benefit and concomitant medications sections were updated. A urine pregnancy test was added at the 8-week follow-up visit, and any pregnancy that occurred through 16 weeks following the last dose of IP was to be reported. The section on liver safety evaluation was replaced for consistency with GlaxoSmithKline (GSK) standards. Additional Hepatitis B monitoring was added.
    25 Apr 2017
    Amendment 06: Applied in all countries and sites, except for those with a local version amendment. The renal response definition used for key efficacy endpoints evaluation was modified. Calculated glomerular filtration rate (GFR) was changed to estimated GFR to be used for all renal function evaluations. Time to first renal flare was added as a major secondary efficacy endpoint. Clarification was added regarding timing of the renal biopsy. Clarifications regarding the target sample size and sample size calculations were added. Contraception requirements were updated. The Benefit-Risk section text was updated in line with current belimumab safety information. The concomitant medications section was updated to clarify concurrent medication rules applicable to the double-blind period. At the request of the IDMC the requirement to review Grade 4 IgG reductions on an expedited basis was removed. The Van Elteren test was replaced with a Rank analysis of covariance (ANCOVA) for the primary and major secondary endpoints analysis. Updates were also made to how missing values will be handled, how the sensitivity analyses will be performed, and additional other efficacy endpoints were defined. The rate of renal flare from Week 24, time to first renal flare from Week 52, and the rate of renal flare from Week 52 were also added as other efficacy endpoints and for some of the other efficacy endpoints, clarification text has been added.
    24 Jan 2019
    Amendment 07: Applied in all countries and sites, except for those with a local version amendment. In this amendment the primary endpoint and the time to renal flare at Week 24 endpoint were changed. The testing hierarchy and the analysis methodology of the major secondary endpoints was revised accordingly. Power calculations were added to the sample size section. A subgroup for Baseline renal biopsy class was added. Other efficacy endpoints were updated to be consistent with and supportive of the revised testing hierarchy. Endpoints inadvertently omitted were added to other efficacy endpoints. The timeframe for pregnancy reporting was updated to sponsor requirements.

    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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