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    Clinical Trial Results:
    A Multi-center, Randomized Parallel Group, Placebo-Controlled Double-Blind Trial to Evaluate the Safety, Efficacy, and Pharmacokinetics of Belimumab, a Human Monoclonal Anti-BLyS Antibody, Plus Standard Therapy in Pediatric Patients with Systemic Lupus Erythematosus (SLE)

    Summary
    EudraCT number
    		 2011-000368-88
    Trial protocol
    		 GB   ES   PL   NL   IT   Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Aug 2018
    First version publication date
    08 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    114055
    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,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000520-PIP01-08
    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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    16 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the safety, tolerability, pharmacokinetics, efficacy of belimumab and to evaluate the effects of belimumab on the quality of life in the pediatric SLE population.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Peru: 14
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    93
    EEA total number of subjects
    21
    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)
    13
    Adolescents (12-17 years)
    80
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 93 pediatric participants with Systemic Lupus Erythematosus (SLE) were enrolled at 29 study centers in 10 different countries. This was a multi-center study to evaluate the safety, efficacy and pharmacokinetics of belimumab plus background standard therapy. The results presented are based on Part A (double blind).

    Pre-assignment
    Screening details
    		 The study consisted of three separate phases: Randomized, placebo-controlled, double-blind 52-week treatment phase (Part A), Long term belimumab open label safety follow up for participants who completed Part A (Part B) and Long term safety follow-up phase for participants who were withdrawn from Part A or Part B at any time (Part C).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received saline infusion (placebo) intravenously monthly for 48 weeks on a background of standard of care
    Arm type
    		 Placebo

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

    Arm title
    		 Belimumab 10 mg/kg
    Arm description
    		 Participants received 10 milligrams per kilograms (mg/kg) reconstituted solution intravenously monthly for 48 weeks on a background of standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benlysta (belimumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Belimumab (10 mg/kg or adjusted dose) intravenously.

    Number of subjects in period 1
    		Placebo Belimumab 10 mg/kg
    Started
    40
    53
    Completed
    31
    45
    Not completed
    9
    8
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    1
         Physician decision
    -
    3
         Adverse event, non-fatal
    4
    3
         Lack of efficacy
    1
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received saline infusion (placebo) intravenously monthly for 48 weeks on a background of standard of care

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received 10 milligrams per kilograms (mg/kg) reconstituted solution intravenously monthly for 48 weeks on a background of standard of care.

    Reporting group values
    		 Placebo Belimumab 10 mg/kg Total
    Number of subjects
    		 40 53
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.8 ( 2.17 ) 13.5 ( 2.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 49 88
        Male
    		 1 4 5
    Race/Ethnicity, Customized
    Units: Subjects
        Race White - White/Caucasian/European Heritage
    		 21 27 48
        Race Asian
    		 6 8 14
        Race African American/African Heritage
    		 2 3 5
        Race American Indian or Alaskan Native
    		 11 15 26

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received saline infusion (placebo) intravenously monthly for 48 weeks on a background of standard of care

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received 10 milligrams per kilograms (mg/kg) reconstituted solution intravenously monthly for 48 weeks on a background of standard of care.

    Primary: Percentage of participants with SLE Responder Index (SRI) response at Week 52

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    End point title
    		 Percentage of participants with SLE Responder Index (SRI) response at Week 52
    End point description
    SRI response is defined as >=4 point reduction, from Baseline in safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score, no worsening (increase of <0.30 points from Baseline) in physician's global assessment (PGA) and no new British Isles Lupus Assessment Group of SLE clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SELENA SLEDAI score (<=12 vs. >=13). Percentage of participants with SRI response at Week 52 of Part A were reported. Intent-to-Treat Population comprised of all participants who were randomized and treated with at least one dose of study agent in Part A. One participant had missing data at Baseline and therefore, could not be included in the analysis.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    39 [1]
    53 [2]
    Units: Percentage of participants
    number (not applicable)
        Percentage of participants
    43.6
    52.8
    Notes
    [1] - Intent-to-Treat Population
    [2] - Intent-to-Treat Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 3.46

    Secondary: Percentage of participants meeting Pediatric Rheumatology International Trials Organization (PRINTO)/ American College of Rheumatology (ACR) Juvenile SLE Response Evaluation criteria for improvement in juvenile SLE at Week 52 using definition 1 and 2

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    End point title
    		 Percentage of participants meeting Pediatric Rheumatology International Trials Organization (PRINTO)/ American College of Rheumatology (ACR) Juvenile SLE Response Evaluation criteria for improvement in juvenile SLE at Week 52 using definition 1 and 2
    End point description
    Percentage of participants meeting PRINTO/ACR Juvenile SLE Response Evaluation criteria for improvement in juvenile SLE using two different PRINTO/ACR Juvenile SLE Response Evaluation definitions of improvement that is Definition 1: At least 50% improvement in any 2 of 5 endpoints below and no more than 1 of the remaining worsening by more than 30% and Definition 2: At least 30% improvement in 3 of 5 endpoints below and no more than 1 of the remaining worsening more than 30%. Endpoints were: 1. Percent change in Parent’s Global Assessment (ParentGA) at Week 52, 2. Percent change in PGA at Week 52, 3. Percent change in SELENA SLEDAI score at Week 52, 4. Percent change in Pediatric Quality of Life Inventory (PedsQL) physical functioning domain at Week 52, 5. Percent change in 24 hour proteinuria at Week 52 (gram/24hour equivalent by spot urine protein to creatinine ratio).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    40 [3]
    53 [4]
    Units: Percentage of participants
    number (not applicable)
        Definition 1
    35.0
    60.4
        Definition 2
    27.5
    52.8
    Notes
    [3] - Intent-to-Treat Population
    [4] - Intent-to-Treat Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Definition 1
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 6.54
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Definition 2
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 7.17

    Secondary: Percent change from Baseline in ParentGA at Week 52

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    End point title
    		 Percent change from Baseline in ParentGA at Week 52
    End point description
    ParentGA assesses the participant’s overall well-being at the moment rated on a 21-numbered circle visual analog scale (VAS; 0 - very well, 10 - very poorly). Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. Last Observation Carried Forward (LOCF) was used. Eight participants had a score of zero at Baseline and therefore, could not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    38 [5]
    47 [6]
    Units: Percent change
    median (full range (min-max))
        Percent change
    -23.61 (-95.0 to 600.0)
    -53.85 (-100.0 to 900.0)
    Notes
    [5] - Intent-to-Treat Population
    [6] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percent change from Baseline in PGA at Week 52

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    End point title
    		 Percent change from Baseline in PGA at Week 52
    End point description
    The PGA is a 10 centimeter (cm) visual analogue scale (VAS), anchored at 0 (none) and 3 (severe), designed for the physician to indicate the participant's overall disease activity at a particular visit as part of the validated SELENA SLEDAI index. Primary investigator or a subinvestigator scored the PGA for the participant, and same person evaluated the participant each time. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    40 [7]
    53 [8]
    Units: Percent change
    arithmetic mean (standard deviation)
        Percent change
    -48.802 ( 42.0423 )
    -56.525 ( 43.7939 )
    Notes
    [7] - Intent-to-Treat Population
    [8] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percent change from Baseline in SELENA SLEDAI at Week 52

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    End point title
    		 Percent change from Baseline in SELENA SLEDAI at Week 52
    End point description
    The SELENA SLEDAI score is a weighted index for assessing SLE disease activity in which signs and symptoms, laboratory tests and physician's assessment for each of 9 organ system were given a weighted score and summed if present at the time of the visit or in the preceding 10 days. A SELENA SLEDAI score of 0 would suggest no lupus activity; while a score of 105 is the maximum calculable if all items were scored as being present from active lupus. A decrease of 4 points or more equates to a clinically meaningful improvement. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. One participant had missing data at Baseline and therefore, could not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    39 [9]
    53 [10]
    Units: Percent change
    arithmetic mean (standard deviation)
        Percent change
    -38.0 ( 39.50 )
    -43.3 ( 43.73 )
    Notes
    [9] - Intent-to-Treat Population
    [10] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percent change from Baseline in PedsQL Physical Functioning Domain Score at Week 52

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    End point title
    		 Percent change from Baseline in PedsQL Physical Functioning Domain Score at Week 52
    End point description
    The PedsQL is a generic quality of life scale validated for the pediatric population which consists of 23 items, encompassing 4 health domains: Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items). From the raw scores of the 23 items, a total summary score and individual domain scores can be calculated. The total and domain scores are each transformed on a 0 to 100 score with higher scores indicating higher quality of life. For Physical Functioning Domain scale, score was from 0 to 100 where, 0 indicates lower quality of life and 100 indicates greater quality of life. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline Value X 100. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    40 [11]
    53 [12]
    Units: Percent change
    median (full range (min-max))
        Percent change
    12.5 (-53 to 575)
    10.5 (-100 to 280)
    Notes
    [11] - Intent-to-Treat Population
    [12] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percent change from Baseline in proteinuria at Week 52

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    End point title
    		 Percent change from Baseline in proteinuria at Week 52
    End point description
    Percent change from Baseline in proteinuria was calculated. The percent change from baseline to Week 52 in 24 hour proteinuria was analyzed using summary statistics and 95% confidence intervals, without any adjustment for covariates. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline Value X 100. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 52
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    40 [13]
    53 [14]
    Units: Percent Change
    median (full range (min-max))
        Percent Change
    7.0920 (-90.568 to 570.149)
    -2.1277 (-85.073 to 1681.884)
    Notes
    [13] - Intent-to-Treat Population
    [14] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with a sustained SRI response

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    End point title
    		 Percentage of participants with a sustained SRI response
    End point description
    Sustained SRI response was defined as having a response on the primary efficacy endpoint at Weeks 44, 48, and 52. Data for percentage of participants with a sustained SRI response was presented. Drop Outs and Treatment Failures were considered Non-Responders. Only those participants with data available at specific time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    39 [15]
    53 [16]
    Units: Percentage of participants
    number (not applicable)
        Percentage of participants
    41.0
    43.4
    Notes
    [15] - Intent-to-Treat Population
    [16] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with a sustained ParentGA response

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    End point title
    		 Percentage of participants with a sustained ParentGA response
    End point description
    Sustained ParentGA response was defined as having >0.7 improvement at Weeks 44, 48, and 52 compared at Baseline. Data for percentage of participants with a sustained ParentGA response was presented. Thirteen participants had a score of <=0.7 at Baseline and therefore, could not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    36 [17]
    44 [18]
    Units: Percentage of Participants
    number (not applicable)
        Percentage of Participants
    33.3
    59.1
    Notes
    [17] - Intent-to-Treat Population
    [18] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, 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 AEs and SAEs have been reported.
    End point type
    Secondary
    End point timeframe
    Up to 60 weeks
    End point values
    		 Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    40 [19]
    53 [20]
    Units: Participants
        AEs
    33
    42
        SAEs
    14
    9
    Notes
    [19] - Intent-to-Treat Population
    [20] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Maximum concentration at steady state (Cmax, ss) and minimum concentration at steady state (Cmin, ss)

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    End point title
    		 Maximum concentration at steady state (Cmax, ss) and minimum concentration at steady state (Cmin, ss) [21]
    End point description
    The pharmacokinetic (PK) population comprised all participants included in the As- Treated population for whom at least one post belimumab treatment PK sample was obtained and analyzed. The PK model was fitted to the observed serum concentration-time data. The maximum (Cmax) and minimum (Cmin) concentrations reported in this table are model derived values at ss, assuming a 10 mg/kg dose administered once every 28 days.
    End point type
    Secondary
    End point timeframe
    28-days dosing interval at steady state
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Belimumab 10 mg/kg
    Number of subjects analysed
    53 [22]
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Cmax, ss
    315 ( 31.2 )
        Cmin, ss
    50 ( 68.3 )
    Notes
    [22] - PK Population
    No statistical analyses for this end point

    Secondary: Area under curve of Belimumab at steady state (AUC, ss)

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    End point title
    		 Area under curve of Belimumab at steady state (AUC, ss) [23]
    End point description
    The PK model was fitted to the observed serum concentration-time data. The AUC values reported in this table are model derived values at ss, assuming a 10 mg/kg dose administered once every 28 days.
    End point type
    Secondary
    End point timeframe
    28-days dosing interval at steady state
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Belimumab 10 mg/kg
    Number of subjects analysed
    53 [24]
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Micrograms per milliliter
    3012 ( 43.2 )
    Notes
    [24] - PK Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from start of the study to the follow up visit (Up to 60 weeks).
    Adverse event reporting additional description
    Intent-to-Treat Population was used to collect adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    		 Participants received 10 milligrams per kilograms (mg/kg) reconstituted solution intravenously monthly for 48 weeks on a background of standard of care.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received saline infusion (placebo) intravenously monthly for 48 weeks on a background of standard of care

    Serious adverse events
    		 Belimumab 10 mg/kg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 53 (16.98%)
    14 / 40 (35.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         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
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic intracranial hypertension
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vasculitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vasculitis gastrointestinal
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (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
    Rash
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (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 / 53 (3.77%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SLE arthritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 40 (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
    Fluid overload
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 40 (2.50%)
         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
    36 / 53 (67.92%)
    27 / 40 (67.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 53 (7.55%)
    4 / 40 (10.00%)
         occurrences all number
    4
    5
    Pyrexia
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 40 (7.50%)
         occurrences all number
    2
    10
    Fatigue
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 40 (5.00%)
         occurrences all number
    2
    4
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Dysmenorrhoea
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Cough
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Oropharyngeal pain
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Dyspnoea
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Suicidal ideation
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Investigations
    Transaminases increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Blood immunoglobulin G decreased
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 53 (13.21%)
    10 / 40 (25.00%)
         occurrences all number
    9
    17
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Neutropenia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Anaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 53 (13.21%)
    3 / 40 (7.50%)
         occurrences all number
    9
    5
    Nausea
         subjects affected / exposed
    5 / 53 (9.43%)
    3 / 40 (7.50%)
         occurrences all number
    6
    4
    Abdominal pain
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Vomiting
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 40 (7.50%)
         occurrences all number
    2
    4
    Dyspepsia
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 40 (7.50%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    4 / 40 (10.00%)
         occurrences all number
    4
    10
    Back pain
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 40 (7.50%)
         occurrences all number
    3
    4
    Pain in extremity
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Joint swelling
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 53 (16.98%)
    8 / 40 (20.00%)
         occurrences all number
    14
    11
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 53 (11.32%)
    8 / 40 (20.00%)
         occurrences all number
    8
    8
    Herpes zoster
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 40 (5.00%)
         occurrences all number
    6
    2
    Pharyngitis
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Gastroenteritis
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 40 (10.00%)
         occurrences all number
    2
    8
    Bronchitis
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    4
    Influenza
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2012
    Amendment No. 1: Updated Medical Monitor information. Additional pharmacokinetic samples were taken for children not in Cohort 1 or 2. Addition of three hours observation post infusion was done. Time and Events Table including immunogenicity, vaccine titer procedure and physical assessments was updated. Other Secondary Endpoints were updated. Study Conclusion criteria was added. Minor typographical errors corrected.
    31 Jan 2013
    Amendment No. 2: Included the following changes: Exclusion Criterion #1 excludes if B cell targeted therapy is within 1 year of Day 0 and Exclusion #23 omitting HCV confirmation RIBA assay. Extra visits for collection of large blood sample collection were Allowed. Addition of 3 hours observation post infusion for first 3 infusions in Part B. The investigational product may be delivered in either 100 mL or 250mL of saline. Minor typographical errors corrected.
    18 Feb 2014
    Amendment No. 3: Included the following changes: Updated safety information on PML and Delayed Hypersensitivity Reaction. Changed the exclusion for high dose steroid use from 90 days to 60 days prior to Baseline. Clarification of treatment failure and study withdrawal criteria and Clarification of procedure for destruction of investigational product and used vials was updated. Added a home pregnancy test and follow up phone call at 16 Week post last dose. Extended visit window in Part B and Part C. Minor typographical and formatting errors corrected.
    03 Nov 2014
    Amendment No. 4: Changed the Screening inclusion criterion SELENA SLEDAI to >= 6. Changed randomization strata for Cohort 3 to stratification by age and SELENA SLEDAI 6-12 and >=13. Added requirement that 50% of participants were recruited with SS score of >= 8. Changed exclusion #4 intravenous (IV) cyclophosphamide within 60 days of Day 0. Added allowance for stable Grade 3 lymphopenia with exclusion #24. Updated GSK liver chemistry stopping criteria and added of study drug restart criteria. Clarification of laboratory tests needed to complete SS and BILAG assessments. Added immunogenicity testing in Part C. Clarification of NSAIDs use in Part A. Minor typographical errors corrected.
    22 Apr 2015
    Amendment No. 5: Country Specific Amendment for Russian Federation: Restart of study treatment after liver event is not applicable to Investigator sites in Russia. Updated phone number of back-up Medical Monitor.
    12 Dec 2016
    Amendment No. 6: Updated Author information, Medical Monitor information and site address. Total study target amended to ‘at least 70’ from 100 participants. Estimates for sample size re-estimation add to the protocol. Target for participants less than 13 years old amended to at least 14 from 20. Target for Cohort 2 amended from 12 to “at least 10”. PedsQL amended in time and events table such that it is instructed to be taken at Day 0. Anti-dsDNA; C3/C4 added to time and events table for 6 month visits in Part B. Deleted immunogenicity sample collection once a subject has left the study. Collect additional PK samples in the participants in Japan at the first 12 week and 6 month visit in Part B. Minor typographical errors corrected. Clarification of reporting of AEs, SAEs, and AESI. Change in Part C from “non-belimumab phase” to “safety follow up phase”.

    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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