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    Clinical Trial Results:
    Safety and efficacy of Belimumab After B cell depletion therapy in systemic LUPUS erythematosus (BEAT LUPUS)

    Summary
    EudraCT number
    		 2015-005543-14
    Trial protocol
    		 GB  
    Global end of trial date
    03 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2021
    First version publication date
    17 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTU/2013/096
    Additional study identifiers
    ISRCTN number
    		 ISRCTN47873003
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IRAS ID: 195085
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Enquiries, The Comprehensive Clinical Trials Unit, University College London, 44 020 7907 4669, cctu-enquiries@ucl.ac.uk
    Scientific contact
    Enquiries, The Comprehensive Clinical Trials Unit, University College London, 44 020 7907 4669, cctu-enquiries@ucl.ac.uk
    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
    03 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the safety, efficacy, and immunological effects of anti-BAFF treatment Belimumab in lupus patients after B cell depletion therapy. To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the Human Tissue (Quality and Safety for Human Application) Regulations 2007, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Although Rituximab therapy is given as standard of care, the sequential combination of Belimumab soon after Rituximab, has never been given before and so this was a phase II trial assessing the safety and efficacy of this strategy. Adverse Events were collected throughout the trial and treated accordingly. Participants were reviewed every 4 weeks when treatment was administered, up until 52 weeks of treatment. The protocol included steps to take in cases of abnormal liver chemistry results. To manage hypersensitivity reactions (infusion reactions/anaphylaxis) participants were monitored for 3 hours after completing each of the first 2 infusions (when it was more frequently to occur). For subsequent infusions, participants were monitored during and for an appropriate period of time after completing the infusion as per local policies. In cases of severe reactions, study treatment was discontinued immediately and the appropriate medical therapy administered. Protocol pre-defined reasons for discontinuation of treatment were in place. As participation was voluntary, participants were free to discontinue at any given time without giving reason and without it affecting their normal standard of care.
    Background therapy
    		 All participants were permitted to receive Rituximab treatment (B cell depletion therapy) as standard of care and had to have received two cycles after being screened and consented, with the first cycle occurring 4-8 weeks prior to randomisation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 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
    United Kingdom: 52
    Worldwide total number of subjects
    52
    EEA total number of subjects
    0
    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)
    51
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started 8th November 2016 and ended 29th March 2019. Participants were recruited from 16 specialist lupus centres in England. Participants were randomised 1:1 (Belimumab or Placebo). Participants had to be due their first cycle of Rituximab therapy (standard of care) 4-8 weeks prior to randomisation.

    Pre-assignment
    Screening details
    		 Systemic Lupus Erythematosus (SLE) patients with active lupus resistant to conventional therapy and receiving B cell depletion therapy (Rituximab) as standard of care. Participants with anti-dsDNA antibodies detectable in the past 5 years. Written informed consent obtained prior to any trial activities commencing. Standard of care bloods assessed.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Participants were randomised 1:1 ratio to receive either Belimumab or Placebo treatment using a secure online randomisation service provider, Sealed Envelope (SE). Randomisation was performed using minimisation, incorporating a random element to maximise balance in the stratifying variables. The unblinded trial statistician produced a unique list of infusion codes and this was incorporated into SE and provided to the unblinded pharmacists at sites.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Belimumab
    Arm description
    		 IV infusion administered according to the standard dosage regime. 10mg/kg at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Benlysta
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400mg single use vial of Belimumab reconstituted and diluted prior to administration. 10mg/kg administered over a period of 1 hour at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Arm title
    		 Placebo (Saline)
    Arm description
    		 Sodium Chloride (0.9% solution) 10mg/kg IV infusions at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Sodium Chloride 0.9% solution
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/kg IV infusions at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Number of subjects in period 1
    		Belimumab Placebo (Saline)
    Started
    26
    26
    Completed
    16
    16
    Not completed
    10
    10
         Consent withdrawn by subject
    5
    2
         Adverse event, non-fatal
    5
    7
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Belimumab
    Reporting group description
    		 IV infusion administered according to the standard dosage regime. 10mg/kg at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Sodium Chloride (0.9% solution) 10mg/kg IV infusions at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Reporting group values
    		 Belimumab Placebo (Saline) Total
    Number of subjects
    		 26 26 52
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38 ( 11.4 ) 41 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 23 44
        Male
    		 5 3 8
    Ethnicity
    Units: Subjects
        White
    		 13 17 30
        Black
    		 3 3 6
        South Asian
    		 4 2 6
        Chinese
    		 2 1 3
        Other
    		 4 3 7
    Previous rituximab
    Units: Subjects
        Yes
    		 6 8 14
        No
    		 20 18 38
    Previous rituximab within 2 years from screening
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 22 23 45
    Concomitant Mycophenolate at screening and randomization
    Units: Subjects
        Yes
    		 19 15 34
        No
    		 7 11 18
    Concomitant Azathioprine at screening and randomization
    Units: Subjects
        Yes
    		 2 2 4
        No
    		 24 24 48
    Concomitant Methotrexate at screening and randomization
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 23 24 47
    Concomitant Prednisolone at screening and randomization
    Units: Subjects
        Yes
    		 22 24 46
        No
    		 4 2 6
    Any concomitant immunosuppressant at screening and randomization
    Units: Subjects
        Yes
    		 24 19 43
        No
    		 2 7 9
    Receiving concomitant immunosuppressant or prednisolone at screening or randomization
    Units: Subjects
        Yes
    		 24 26 50
        No
    		 2 0 2
    Concomitant hydroxychloroquine at screening and randomization
    Units: Subjects
        Yes
    		 17 20 37
        No
    		 9 6 15
    Patients taking ≥7.5 mg of prednisolone per day at screening
    Units: Subjects
        Yes
    		 14 18 32
        No
    		 12 8 20
    Patients taking ≥7.5 mg of prednisolone per day at randomization
    Units: Subjects
        Yes
    		 15 18 33
        No
    		 11 8 19
    Patients taking ≥10 mg of prednisolone per day at screening and randomization
    Units: Subjects
        Yes
    		 13 16 29
        No
    		 13 10 23
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Constitutional
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 23 24 47
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Cardiorespiratory
    Units: Subjects
        Yes
    		 4 6 10
        No
    		 22 20 42
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Mucocutaneous
    Units: Subjects
        Yes
    		 13 14 27
        No
    		 13 12 25
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Musculoskeletal
    Units: Subjects
        Yes
    		 11 9 20
        No
    		 15 17 32
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Neuropsychiatric
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 26 25 51
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Ophthalmic
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 25 26 51
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Gastrointestinal
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 26 26 52
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Renal
    Units: Subjects
        Yes
    		 10 10 20
        No
    		 16 16 32
    Organ involvement (BILAG-2004 A or B score) at screening or randomization - Hematologic
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 25 26 51
    BILAG-2004 score at randomization - ≥1 A score
    Units: Subjects
        Yes
    		 6 8 14
        No
    		 20 18 38
    BILAG-2004 score at randomization - ≥1 A score or 2 B scores
    Units: Subjects
        Yes
    		 13 9 22
        No
    		 13 17 30
    BILAG-2004 score at randomization - ≥1 A score, 2 B scores, or 1 B score
    Units: Subjects
        Yes
    		 23 20 43
        No
    		 3 6 9
    Positive anti-dsDNA IgG antibody result at screening
    Units: Subjects
        Yes
    		 24 23 47
        No
    		 2 3 5
    Low complement C3 level at screening
    Units: Subjects
        Yes
    		 11 13 24
        No
    		 15 13 28
    Patients with CD19 count <0.01 x 10^9/L at randomization
    Units: Subjects
        Yes
    		 22 22 44
        No
    		 4 4 8
    Disease duration at screening
    Units: Years
        arithmetic mean (standard deviation)
    		 11.8 ( 8.8 ) 9.2 ( 7.4 ) -
    Time between screening and randomization
    Units: Days
        arithmetic mean (standard deviation)
    		 44.7 ( 9.4 ) 41.8 ( 9.3 ) -
    Daily prednisolone dose at screening
    Units: mg/day
        arithmetic mean (standard deviation)
    		 13.3 ( 9.0 ) 14.9 ( 9.8 ) -
    Daily prednisolone dose at randomization
    Units: mg/day
        arithmetic mean (standard deviation)
    		 12.9 ( 7.7 ) 12.5 ( 6.7 ) -
    IgG anti-dsDNA level at screening
    Units: IU/mL
        arithmetic mean (standard deviation)
    		 282 ( 281 ) 229 ( 238 ) -

    End points

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    End points reporting groups
    Reporting group title
    Belimumab
    Reporting group description
    		 IV infusion administered according to the standard dosage regime. 10mg/kg at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Sodium Chloride (0.9% solution) 10mg/kg IV infusions at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Primary: IgG anti-dsDNA antibody levels

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    End point title
    		 IgG anti-dsDNA antibody levels
    End point description
    Serum total IgG anti-dsDNA antibody levels (normal value <20 IU/mL) were analyzed by a commercially available enzyme-linked immunosorbent assay (Abnova) in a central laboratory at University College London.
    End point type
    Primary
    End point timeframe
    Randomization to week 52
    End point values
    		 Belimumab Placebo (Saline)
    Number of subjects analysed
    20
    23
    Units: UI/mL
        geometric mean (confidence interval 95%)
    47 (25 to 88)
    103 (49 to 213)
    Attachments
    		 Serum IgG anti-dsDNA antibody levels
    Statistical analysis title
    		 ANCOVA at 52 weeks
    Statistical analysis description
    Linear regression analysis of covariance (ANCOVA) models were used to evaluate the difference in IgG anti-dsDNA antibody levels (log-transformed) between treatment groups at week 52. This model adjusted for CD19 count at randomization (<0.01 or ≥0.01 x 10^9/L), renal involvement at screening, and log anti-dsDNA levels at screening and randomization. The intention-to-treat analysis included all participants who were randomly assigned and contributed the relevant data at the timepoint analyzed.
    Comparison groups
    Belimumab v Placebo (Saline)
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Percentage change
    Point estimate
    70
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46
         upper limit
    		 84

    Secondary: Time to first severe flare

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    End point title
    		 Time to first severe flare
    End point description
    Defined as ≥1 BILAG-2004 A score
    End point type
    Secondary
    End point timeframe
    Over the 52 weeks of the trial
    End point values
    		 Belimumab Placebo (Saline)
    Number of subjects analysed
    26
    26
    Units: Severe flares
        number (not applicable)
    26
    26
    Statistical analysis title
    		 Survival analysis
    Comparison groups
    Belimumab v Placebo (Saline)
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.98

    Secondary: Time to first severe flare or moderate flare

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    End point title
    		 Time to first severe flare or moderate flare
    End point description
    Defined as ≥1 BILAG-2004 A score or ≥2 BILAG-2004 B scores
    End point type
    Secondary
    End point timeframe
    Over the 52 weeks of the trial
    End point values
    		 Belimumab Placebo (Saline)
    Number of subjects analysed
    26
    26
    Units: Severe/moderate flares
        number (not applicable)
    26
    26
    Statistical analysis title
    		 Survival analysis
    Comparison groups
    Belimumab v Placebo (Saline)
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.124
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All safety events (adverse event, adverse reaction, serious adverse event, serious adverse reaction) were to be reported from the time of randomisation until 30 days after the last treatment administration (end of study visit).
    Adverse event reporting additional description
    Adverse events did not include: - Medical or surgical procedures - Pre-existing disease or condition present before treatment that does not worsen - Hospitalisation where no untoward or unintended response has occurred e.g. elective cosmetic surgery - Any new symptoms recorded on the BILAG 2004 Index which is related to SLE
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Belimumab
    Reporting group description
    		 IV infusion administered according to the standard dosage regime. 10mg/kg at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Sodium Chloride (0.9% solution) infusions at 2-week intervals for the first 3 infusions (Day 0, week 2 and week 4), and 4-weekly intervals thereafter for a total of 52 weeks (weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).

    Serious adverse events
    		 Belimumab Placebo (Saline)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 26 (23.08%)
    6 / 26 (23.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Pulmonary embolism and deep venous thrombosis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Tonic-clonic seizure
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial numbness
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Lupus flare
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleurisy
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (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
    Acute kidney injury
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis/arthralgia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft-tissue infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (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
    Hypoglycemia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         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 Placebo (Saline)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 26 (92.31%)
    24 / 26 (92.31%)
    Gastrointestinal disorders
    Diarrhea and constipation
         subjects affected / exposed
    7 / 26 (26.92%)
    4 / 26 (15.38%)
         occurrences all number
    20
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    8 / 26 (30.77%)
    6 / 26 (23.08%)
         occurrences all number
    15
    8
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Depression-like illness
         subjects affected / exposed
    4 / 26 (15.38%)
    5 / 26 (19.23%)
         occurrences all number
    4
    5
    Musculoskeletal and connective tissue disorders
    Arthritis/arthralgia
         subjects affected / exposed
    11 / 26 (42.31%)
    12 / 26 (46.15%)
         occurrences all number
    27
    29
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 26 (61.54%)
    15 / 26 (57.69%)
         occurrences all number
    32
    30
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 26 (19.23%)
    9 / 26 (34.62%)
         occurrences all number
    6
    12
    Urinary tract infection
         subjects affected / exposed
    7 / 26 (26.92%)
    5 / 26 (19.23%)
         occurrences all number
    12
    9
    Herpes zoster/shingles
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 26 (11.54%)
         occurrences all number
    3
    6
    Other
         subjects affected / exposed
    13 / 26 (50.00%)
    10 / 26 (38.46%)
         occurrences all number
    17
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2016
    Protocol updated to v2.0 - first protocol version approved for global use.
    25 Apr 2017
    Protocol updated to v3.0 - Reduction to the frequency of some routine blood collection. Changes to secondary outcome with additional exploratory outcomes added. Extended time from 1st SOC infusion to 1st day of trial treatment. Additional exclusion criteria. Updated liver stopping criteria (as per funders requests). Treatment windows added.
    15 May 2018
    Protocol updated to v4.0 - Changes to inclusion #3 and clarification to inclusion #4. Additional text to address contraception use for male participants. Inclusion of Pregnancy monitoring PIS/ICF for participants and their partners. Length of trial shortened; follow up visits 60 and 64 removed.
    13 Mar 2019
    Protocol updated to v5.0 - Changes to Secondary Outcomes: - Specific times of follow-up at which secondary outcomes will be analysed have been added where these were previously missing. - Additional outcome; ‘Proportion of participants’ with any serious adverse events by week 52 has been added (secondary outcome #3). - Distinction made between ‘severe’ (2 BILAG B or 1 A) and ‘moderate’ flare (1 BILAG B with increase in any concomitant medication). - Additional outcome; the proportion of patients who have any ‘severe or moderate’ flare by 52 weeks (secondary outcome #6). - Steroids and immunosuppressant’s allowed post-randomisation, added to secondary outcome #6 to capture all steroid changes and any potential moderate flares as per the trial Statistical Analysis Plan. - The analysis of EQ5D changed from analysis of the value at 52 weeks to analysis of the average value from randomisation as per the trial Statistical Analysis Plan. The statistical analysis plan has been amended to change the primary analysis to intention to treat, and added to two supportive analysis of the primary outcome; an analysis of whether trial treatment effects are mediated by changes in concomitant medication following randomisation, and an additional analysis of 52-week anti-dsDNA which excludes measurements taken after any increase in a concomitant medication due to flare (using instead the last anti-dsDNA measurement taken prior to this point). A secondary per-protocol analysis of the primary outcome will be also be done. Further clarification on the dose reduction of prednisolone following randomisation. Removal of anti-dsDNA collected and processed locally by sites at visit 17 (Participant Timeline section 6.6.). Further clarification added to Participant Timeline to address the trial assessments performed at withdrawal and patient reported severe flares. Updates to the roles/responsibilities of sponsor trial team and general admin changes throughout protocol.
    02 Sep 2019
    Protocol updated to v6.0 - To include information provided by GlaxoSmithKline (GSK) in regards to the risks of serious depression and/or suicidal Ideation or behaviour or self-Injury during treatment with belimumab. Update to contact details of the Sponsor’s trial team at UCL CCTU.
    25 Feb 2020
    Protocol updated to v7.0 - The statistical analysis plan changed, following discussion about the analysis strategy and production of the BEAT-LUPUS statistical analysis plan (SAP) document in Autumn 2019. The following sections regarding the analysis have been changed in the protocol to match the new SAP: - The structured trial summary outcomes list has been updated - In Section 6.5 Outcomes, the outcomes list has been updated - Section 6.10 Data Collection, Management and Analysis has been changed to reflect changes to the SAP.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34698499
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