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    Clinical Trial Results:
    A randomized, double blind (sponsor open), comparative, multicenter study to evaluate the safety and efficacy of subcutaneous belimumab (GSK1550188) and intravenous rituximab coadministration in subjects with primary Sjögren’s syndrome

    Summary
    EudraCT number
    2015-000400-26
    Trial protocol
    SE   NO   DE   ES   NL   GB   FR   IT  
    Global end of trial date
    23 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2021
    First version publication date
    29 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    201842
    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 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety and tolerability of anti- B lymphocyte stimulator (anti-BLyS)/ anti-cluster of differentiation 20 (anti-CD 20) co-administration therapy and anti-BLyS and anti-CD 20 monotherapies.
    Protection of trial subjects
    Not Applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Feb 2016
    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
    Canada: 8
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    86
    EEA total number of subjects
    66
    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)
    71
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 10 countries across 31 centers. Participants were randomized to receive one of the four treatments; Placebo, Belimumab + Rituximab Co-administration therapy, Belimumab Monotherapy or Rituximab Monotherapy.

    Pre-assignment
    Screening details
    A total of 162 participants were screened of which 76 were screen failures. A total of 86 participants were enrolled in this study.

    Period 1
    Period 1 title
    Treatment Period (Up to Week 52)
    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 belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.
    Arm type
    Placebo

    Investigational medicinal product name
    Rituximab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab placebo infusions at Weeks 8 and 10.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Arm title
    Belimumab + Rituximab Co-administration therapy
    Arm description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 1000 mg intravenous (IV) infusions at Weeks 8 and 10.

    Arm title
    Belimumab Monotherapy
    Arm description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Rituximab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab placebo infusions at Weeks 8 and 10.

    Arm title
    Rituximab Monotherapy
    Arm description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 1000 mg intravenous (IV) infusions at Weeks 8 and 10.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Number of subjects in period 1
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Started
    13
    24
    24
    25
    Completed
    9
    17
    19
    17
    Not completed
    4
    7
    5
    8
         Physician decision
    1
    -
    -
    1
         Reached stopping criteria
    -
    -
    1
    -
         Lack of efficacy
    1
    1
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    4
    2
    2
         Consent withdrawn by subject
    1
    1
    2
    5
    Period 2
    Period 2 title
    General follow-up (GFU) (Up to Week 68)
    Is this the baseline period?
    No
    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 belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.
    Arm type
    Placebo

    Investigational medicinal product name
    Rituximab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab placebo infusions at Weeks 8 and 10.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Arm title
    Belimumab + Rituximab Co-administration therapy
    Arm description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 1000 mg intravenous (IV) infusions at Weeks 8 and 10.

    Arm title
    Belimumab Monotherapy
    Arm description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections up to Week 52.

    Investigational medicinal product name
    Rituximab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab placebo infusions at Weeks 8 and 10.

    Arm title
    Rituximab Monotherapy
    Arm description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received rituximab 1000 mg intravenous (IV) infusions at Weeks 8 and 10.

    Investigational medicinal product name
    Belimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received belimumab placebo weekly subcutaneous injections up to Week 52.

    Number of subjects in period 2
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Started
    9
    17
    19
    17
    Completed
    8
    17
    19
    16
    Not completed
    1
    0
    0
    1
         Lost to follow-up
    1
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.

    Reporting group title
    Belimumab + Rituximab Co-administration therapy
    Reporting group description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Belimumab Monotherapy
    Reporting group description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Rituximab Monotherapy
    Reporting group description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy Total
    Number of subjects
    13 24 24 25 86
    Age categorical
    Units: Subjects
        All participants
    13 24 24 25 86
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    52.7 ± 12.67 45.1 ± 10.93 52.0 ± 11.49 55.2 ± 15.07 -
    Sex: Female, Male
    Units: Participants
        Female
    13 22 22 23 80
        Male
    0 2 2 2 6
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    1 2 2 1 6
        American Indian or Alaskan Native
    0 0 0 1 1
        Asian - East Asian Heritage
    0 1 1 2 4
        White - Arabic/North African Heritage
    0 2 3 0 5
        White-White/Caucasian/European Heritage
    12 18 18 21 69
        African American/African and Asian Heritage
    0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.

    Reporting group title
    Belimumab + Rituximab Co-administration therapy
    Reporting group description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Belimumab Monotherapy
    Reporting group description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Rituximab Monotherapy
    Reporting group description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.
    Reporting group title
    Placebo
    Reporting group description
    Participants received belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.

    Reporting group title
    Belimumab + Rituximab Co-administration therapy
    Reporting group description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Belimumab Monotherapy
    Reporting group description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Rituximab Monotherapy
    Reporting group description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Primary: Number of participants with serious adverse events (SAE) and non-serious AEs (non-SAE)

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    End point title
    Number of participants with serious adverse events (SAE) and non-serious AEs (non-SAE) [1]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations based on medical or scientific judgment and is associated with liver injury and impaired liver function. Data for number of participants with SAE and non-SAE has been summarized. Safety Population comprised of all participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 68
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    13 [2]
    24 [3]
    24 [4]
    25 [5]
    Units: Participants
        Any SAE
    0
    3
    2
    4
        Any non-SAE
    12
    24
    23
    17
    Notes
    [2] - Safety Population
    [3] - Safety Population
    [4] - Safety Population
    [5] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with adverse event of special interests (AESIs)

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    End point title
    Number of participants with adverse event of special interests (AESIs) [6]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AESIs were Malignant Neoplasms, Post-Administration Systemic Reactions (PASR), All Infections of Special Interest (opportunistic infections, herpes zoster, tuberculosis and sepsis), Depression/suicide/self-injury, Deaths and study specific AESI which includes: severe skin reaction per GlaxoSmithKline (GSK) Adjudication, cardiac disorders, Posterior Reversible Encephalopathy Syndrome (PRES) and Progressive multifocal leukoencephalopathy (PML). Data for number of participants with AESI has been summarized.
    End point type
    Primary
    End point timeframe
    Up to Week 68
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    13 [7]
    24 [8]
    24 [9]
    25 [10]
    Units: Participants
        Malignant Neoplasms
    0
    0
    0
    1
        PASR
    4
    2
    3
    5
        All Infections of Special Interest
    2
    1
    3
    2
        Depression/Suicide/Self-injury
    0
    3
    5
    1
        Deaths
    0
    1
    0
    0
        Severe Skin Reactions
    0
    0
    0
    0
        Cardiac Disorders
    0
    1
    0
    1
        PRES
    0
    0
    0
    0
        PML
    0
    0
    0
    0
    Notes
    [7] - Safety Population
    [8] - Safety Population
    [9] - Safety Population
    [10] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) Total scores over time

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    End point title
    Change from Baseline in European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) Total scores over time
    End point description
    ESSDAI is a disease activity index developed by EULAR consortium consisting of twelve clinically relevant organ specific domains. Each domain has 3 or 4 possible activity levels (i.e., no, low, moderate, high [if available]) using a 4-point scale, ranging from 0 (No activity) to 3 (High activity). Higher score indicates high disease activity. Each domain is assigned a weight between 1 and 6. Total ESSDAI Scores are obtained by multiplying level of activity (domain score) by domain weights, ranges between 0 (no activity) and 123 (highest activity). Higher score indicates more disease activity. Baseline value is screening visit value. Change from Baseline was defined as post-dose visit value minus Baseline value. Completer Population comprised of participants who completed 52 Week treatment visits and general follow up phase of study including visit at Week 68. Only those participants with data available at specified data points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    8 [11]
    17 [12]
    19 [13]
    16 [14]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 12; n=8, 17, 19 ,15
    -2.00 ± 1.449
    -4.85 ± 0.996
    -3.87 ± 0.949
    -4.22 ± 1.048
        Week 24; n=8, 17, 19 ,16
    -2.87 ± 1.324
    -5.32 ± 0.911
    -3.87 ± 0.869
    -5.25 ± 0.940
        Week 36; n=8, 17, 19 ,16
    -3.12 ± 1.520
    -4.09 ± 1.045
    -4.23 ± 0.995
    -4.94 ± 1.079
        Week 52;n=8, 17, 19 ,16
    -2.87 ± 1.294
    -5.67 ± 0.890
    -4.76 ± 0.850
    -4.32 ± 0.919
        Week 68;n=8, 17, 19 ,16
    -1.75 ± 1.400
    -5.73 ± 0.962
    -3.87 ± 0.918
    -4.38 ± 0.994
    Notes
    [11] - Completer Population
    [12] - Completer Population
    [13] - Completer Population
    [14] - Completer Population
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 12. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab + Rituximab Co-administration therapy
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -2.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.38
         upper limit
    0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.758
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 12. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Belimumab Monotherapy
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.75
         upper limit
    1.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.382
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Week 12. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Rituximab Monotherapy
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.52
         upper limit
    2.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.442
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Week 12. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab Monotherapy
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.34
         upper limit
    1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.732
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Week 12. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab Monotherapy v Rituximab Monotherapy
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    3.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.422
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Week 24. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab + Rituximab Co-administration therapy
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -2.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.67
         upper limit
    0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.607
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Week 24. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Belimumab Monotherapy
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.99
         upper limit
    1.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.265
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Week 24. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Rituximab Monotherapy
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.68
         upper limit
    2.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.305
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Week 24. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab Monotherapy
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.17
         upper limit
    2.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.584
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Week 24. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab Monotherapy v Rituximab Monotherapy
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    3.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Week 36. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab + Rituximab Co-administration therapy
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.66
         upper limit
    2.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.845
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Week 36. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Belimumab Monotherapy
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.76
         upper limit
    3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.449
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Week 36. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Rituximab Monotherapy
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.15
         upper limit
    3.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.498
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Week 36. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab Monotherapy
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.76
         upper limit
    2.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.817
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Week 36. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab Monotherapy v Rituximab Monotherapy
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.25
         upper limit
    3.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.476
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Week 52. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab + Rituximab Co-administration therapy
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.95
         upper limit
    0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.57
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Week 52. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Belimumab Monotherapy
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.39
         upper limit
    1.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.237
    Statistical analysis title
    Statistical Analysis 18
    Statistical analysis description
    Week 52. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Rituximab Monotherapy
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.91
         upper limit
    1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.275
    Statistical analysis title
    Statistical Analysis 19
    Statistical analysis description
    Week 52. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab Monotherapy
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.99
         upper limit
    1.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.548
    Statistical analysis title
    Statistical Analysis 20
    Statistical analysis description
    Week 52. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab Monotherapy v Rituximab Monotherapy
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.97
         upper limit
    2.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.261
    Statistical analysis title
    Statistical Analysis 21
    Statistical analysis description
    Week 68. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab + Rituximab Co-administration therapy
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -3.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.39
         upper limit
    -0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.699
    Statistical analysis title
    Statistical Analysis 22
    Statistical analysis description
    Week 68. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Belimumab Monotherapy
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.54
         upper limit
    0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.336
    Statistical analysis title
    Statistical Analysis 23
    Statistical analysis description
    Week 68. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab + Rituximab Co-administration therapy v Rituximab Monotherapy
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.12
         upper limit
    1.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.379
    Statistical analysis title
    Statistical Analysis 24
    Statistical analysis description
    Week 68. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Placebo v Belimumab Monotherapy
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    LS mean difference
    Point estimate
    -2.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.47
         upper limit
    1.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.674
    Statistical analysis title
    Statistical Analysis 25
    Statistical analysis description
    Week 68. Analysis was performed using mixed effects repeated measures model, with Baseline, treatment, visit and interactions of visit with treatment as fixed effects and participant as a random effect.
    Comparison groups
    Belimumab Monotherapy v Rituximab Monotherapy
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.21
         upper limit
    3.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.362

    Secondary: Stimulated salivary flow rate over time

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    End point title
    Stimulated salivary flow rate over time
    End point description
    Participants were instructed to chew a piece of paraffin wax for a period of 5 minutes and saliva was collected. The volume of saliva (milliliter) was divided by the duration of the test (minutes) to calculate the stimulated salivary flow rate (milliliter per minute). Baseline value is the screening visit value (within 35 days prior to Day 0). Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    8 [15]
    17 [16]
    19 [17]
    16 [18]
    Units: Milliliter per minute
    arithmetic mean (standard deviation)
        Baseline (Screening); n=8, 17, 19 ,16
    0.470 ± 0.2470
    0.714 ± 0.6294
    0.425 ± 0.3292
    0.618 ± 0.6211
        Week 12; n=8, 17, 19 ,16
    0.486 ± 0.2045
    0.754 ± 0.8342
    0.493 ± 0.3733
    0.581 ± 0.5265
        Week 24; n=8, 17, 19 ,16
    0.554 ± 0.3054
    0.784 ± 0.7900
    0.454 ± 0.4105
    0.724 ± 0.8901
        Week 36; n=8, 17, 19 ,15
    0.404 ± 0.2497
    1.039 ± 1.1027
    0.506 ± 0.4261
    0.689 ± 0.5907
        Week 52; n=8, 17, 19 ,16
    0.531 ± 0.3782
    0.999 ± 1.1457
    0.582 ± 0.6084
    0.693 ± 0.7813
        Week 68; n=8, 17, 19 ,15
    0.361 ± 0.1628
    0.879 ± 0.8167
    0.517 ± 0.4499
    0.733 ± 0.7850
    Notes
    [15] - Completer Population
    [16] - Completer Population
    [17] - Completer Population
    [18] - Completer Population
    No statistical analyses for this end point

    Secondary: Oral dryness numeric response scale (NRS) over time

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    End point title
    Oral dryness numeric response scale (NRS) over time
    End point description
    Oral dryness was reported by participants on a numeric response scale, ranging from 0 (no dryness) to 10 (maximal dryness), higher score indicates worst imaginable dryness. Baseline value is the screening visit value (within 35 days prior to Day 0). Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    8 [19]
    17 [20]
    19 [21]
    16 [22]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (Screening); n= 8, 17, 19, 16
    7.6 ± 1.51
    7.4 ± 1.46
    7.2 ± 2.14
    7.3 ± 1.91
        Week 12; n=8, 17, 19, 16
    6.1 ± 2.59
    5.7 ± 1.96
    6.9 ± 2.32
    5.1 ± 2.77
        Week 24; n=8, 17, 19, 15
    5.8 ± 2.38
    5.3 ± 1.83
    6.8 ± 2.51
    5.6 ± 2.72
        Week 36; n=8, 17, 19, 16
    5.8 ± 2.76
    5.9 ± 2.26
    6.6 ± 2.19
    6.2 ± 2.51
        Week 52; n=8, 17, 19, 16
    5.6 ± 2.13
    5.7 ± 1.92
    7.0 ± 2.40
    6.3 ± 2.32
        Week 68; n=8, 17, 19, 16
    6.6 ± 2.26
    6.1 ± 2.63
    6.9 ± 2.34
    6.1 ± 2.62
    Notes
    [19] - Completer Population
    [20] - Completer Population
    [21] - Completer Population
    [22] - Completer Population
    No statistical analyses for this end point

    Secondary: Absolute values for B-cells (cluster of differentiation 20 [CD20]) within salivary gland biopsy at Week 24

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    End point title
    Absolute values for B-cells (cluster of differentiation 20 [CD20]) within salivary gland biopsy at Week 24
    End point description
    Minor salivary gland biopsies were taken for histological analysis to quantify CD20 B Cells. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Number of subjects analysed
    8 [23]
    10 [24]
    15 [25]
    12 [26]
    Units: Cells per millimeter square
        arithmetic mean (standard deviation)
    380.21719 ± 569.908102
    8.65550 ± 20.199794
    396.86058 ± 781.245844
    650.76069 ± 1311.360352
    Notes
    [23] - Completer Population
    [24] - Completer Population
    [25] - Completer Population
    [26] - Completer 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-SAEs were collected up to Week 68.
    Adverse event reporting additional description
    Safety Population was used to assess SAEs and non-SAEs which comprised of all participants who received at least one dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period.

    Reporting group title
    Belimumab + Rituximab Co-administration therapy
    Reporting group description
    Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Belimumab Monotherapy
    Reporting group description
    Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Reporting group title
    Rituximab Monotherapy
    Reporting group description
    Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period.

    Serious adverse events
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 24 (12.50%)
    2 / 24 (8.33%)
    4 / 25 (16.00%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Sjogren's syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    1 / 24 (4.17%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    1 / 24 (4.17%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Belimumab + Rituximab Co-administration therapy Belimumab Monotherapy Rituximab Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    24 / 24 (100.00%)
    23 / 24 (95.83%)
    17 / 25 (68.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    2 / 24 (8.33%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 24 (4.17%)
    2 / 24 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 24 (0.00%)
    4 / 24 (16.67%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    4
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 24 (20.83%)
    4 / 24 (16.67%)
    6 / 25 (24.00%)
         occurrences all number
    3
    7
    5
    7
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 24 (8.33%)
    6 / 24 (25.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    9
    2
    Migraine
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 24 (4.17%)
    2 / 24 (8.33%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 13 (23.08%)
    6 / 24 (25.00%)
    2 / 24 (8.33%)
    2 / 25 (8.00%)
         occurrences all number
    5
    6
    2
    2
    Pyrexia
         subjects affected / exposed
    4 / 13 (30.77%)
    3 / 24 (12.50%)
    2 / 24 (8.33%)
    2 / 25 (8.00%)
         occurrences all number
    4
    3
    2
    2
    Asthenia
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
    1 / 25 (4.00%)
         occurrences all number
    4
    2
    1
    1
    Influenza like illness
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    2 / 24 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Injection site pain
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    2 / 24 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 24 (12.50%)
    3 / 24 (12.50%)
    1 / 25 (4.00%)
         occurrences all number
    3
    5
    3
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 24 (4.17%)
    3 / 24 (12.50%)
    3 / 25 (12.00%)
         occurrences all number
    2
    1
    3
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 24 (4.17%)
    3 / 24 (12.50%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
    1 / 25 (4.00%)
         occurrences all number
    2
    2
    2
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 24 (12.50%)
    1 / 24 (4.17%)
    1 / 25 (4.00%)
         occurrences all number
    4
    3
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 13 (15.38%)
    7 / 24 (29.17%)
    7 / 24 (29.17%)
    5 / 25 (20.00%)
         occurrences all number
    2
    10
    12
    5
    Back pain
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    5 / 24 (20.83%)
    2 / 25 (8.00%)
         occurrences all number
    3
    2
    5
    3
    Pain in extremity
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 24 (12.50%)
    1 / 24 (4.17%)
    1 / 25 (4.00%)
         occurrences all number
    2
    3
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 24 (8.33%)
    2 / 24 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 13 (30.77%)
    8 / 24 (33.33%)
    6 / 24 (25.00%)
    3 / 25 (12.00%)
         occurrences all number
    10
    11
    9
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 13 (23.08%)
    5 / 24 (20.83%)
    3 / 24 (12.50%)
    2 / 25 (8.00%)
         occurrences all number
    4
    7
    9
    6
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 24 (12.50%)
    2 / 24 (8.33%)
    5 / 25 (20.00%)
         occurrences all number
    3
    4
    3
    6
    Bronchitis
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    3 / 24 (12.50%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    3
    2
    Influenza
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 24 (0.00%)
    4 / 24 (16.67%)
    1 / 25 (4.00%)
         occurrences all number
    4
    0
    4
    2
    Oral herpes
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 24 (8.33%)
    2 / 24 (8.33%)
    3 / 25 (12.00%)
         occurrences all number
    1
    2
    2
    4
    Pneumonia
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
    1 / 25 (4.00%)
         occurrences all number
    2
    3
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2015
    Amendment 1: Protocol amended in response to comments received from Swedish regulatory authority. This was country-specific and applied to sites in Sweden. Information about the interim analysis was updated to provide clarity on the timing and number of the analysis. A modification to the withdrawal/stopping criteria language was made to specify that participants will be withdrawn from investigational product (IP) in the event of a life-threatening infection. A statement was also added to clarify that regulatory agency approval is required for the protocol and for substantial amendments to the protocol.
    20 Nov 2015
    Amendment 2: Protocol amended in response to comments received from Norwegian regulatory authority. This was country-specific and applied to all sites in Norway. The protocol was amended to clarify the number of participants required for the interim analysis and the basis for the sample size recalculation following that analysis. Language was also added to provide guidance regarding tuberculosis assessment during screening.
    04 Jan 2016
    Amendment 3: Protocol amended in response to comments received from Italian regulatory authority. This was country-specific and applied to sites in Italy. The protocol was amended to update the list of highly effective methods of contraception and to correct a typographical error regarding the permitted dose of hydroxychloroquine.
    13 Jun 2016
    Amendment 4: The primary reason for this amendment was to modify the participant selection criteria (specifically exclusion criterion number 30 pertaining to exclusionary laboratory thresholds) to better align with the intended population characteristics. Other amendments included the following: Greater clarity was provided regarding the committees involved in monitoring participant safety and review of study data as well as the governance of the study. It has been made clear that a single formal interim analysis is planned. The participant withdrawal and study stopping criteria have been modified. Greater detail was provided regarding prohibited and permitted medications. Additional guidance was provided regarding vaccination. Guidance has been provided for tuberculosis assessment during the screening period. The pregnancy section has been modified to clarify the duration of follow up required.
    11 May 2018
    Amendment 5: The primary reason for this amendment was to clarify the definition of “sponsor open” in Section 6.3, with respect to study blinding. Additional minor clarifications have been made throughout the protocol.
    25 Jun 2019
    Amendment 6: The primary reason for this amendment was to clarify the timing of unblinding for GlaxoSmithKline (GSK) staff and site staff. Additional minor updates have been made in several sections of the protocol.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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