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    Clinical Trial Results:
    A Phase 3, Multi-Centre, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis.

    Summary
    EudraCT number
    2011-004569-33
    Trial protocol
    GB   DE   CZ   BE   ES   IE   SE   HU   IT   PL  
    Global end of trial date
    06 Feb 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    21 Mar 2018
    First version publication date
    14 Feb 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    115466
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    18 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To evaluate the efficacy of belimumab in the maintenance of remission following a standard induction regimen in subjects with Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA). -To evaluate the safety of belimumab in subjects with WG or MPA
    Protection of trial subjects
    N/A
    Background therapy
    N/A
    Evidence for comparator
    N/A
    Actual start date of recruitment
    20 Mar 2013
    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
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Peru: 10
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 31
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    106
    EEA total number of subjects
    46
    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)
    79
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants with diagnosis of Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were randomized in this study. The study was conducted at 37 centers in 15 countries in North America, Central America, South America, Western Europe, Eastern Europe, and Australia during 20 March 2013 - 06 February 2017.

    Pre-assignment
    Screening details
    A total of 164 participants were screened and 106 were enrolled and randomized in a 1:1 ratio to receive placebo or belimumab 10 milligram per kilogram (mg/kg). Of which, 105 received at least 1 dose of study agent and one participant was randomized in error.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered intravenously over 1 hour, at Day 0, 14, 28 and every 28 days

    Arm title
    Belimumab 10 mg/kg
    Arm description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    Belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Belimumab was administered intravenously over 1 hour, at Day 0, 14, 28 and every 28 days

    Number of subjects in period 1 [1]
    Placebo Belimumab 10 mg/kg
    Started
    52
    53
    Completed
    40
    33
    Not completed
    12
    20
         Protocol deviation
    -
    1
         Other-Study closed/terminated
    1
    1
         Physician decision
    1
    4
         Lack of efficacy
    5
    6
         Adverse event, non-fatal
    3
    7
         Consent withdrawn by subject
    2
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 164 participants were screened and 106 were enrolled and randomized in a 1:1 ratio to receive placebo or belimumab 10 mg/kg. Of which, 105 received at least 1 dose of study agent and one participant was randomized in error.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.

    Reporting group values
    Placebo Belimumab 10 mg/kg Total
    Number of subjects
    52 53
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.5 ± 13.56 56.2 ± 13.59 -
    Gender categorical
    Units: Subjects
        Female
    25 26 51
        Male
    27 27 54
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    1 1 2
        American Indian or Alaskan Native
    5 6 11
        Central/South Asian Heritage
    2 0 2
        White
    44 46 90

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 mg/kg intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.

    Primary: Time to First Relapse

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    End point title
    Time to First Relapse
    End point description
    Time to relapse is defined as the number of days from Day 0 until the participant experienced a relapse (relapse date – treatment start date +1). Only post-baseline relapses were considered in these analyses. Only relapses occurring up to and including the last visit date in the double-blind treatment period were considered in these analyses. Intent-to-treat population comprised of all randomized participants who received at least one dose of study agent (belimumab or placebo). “99999” indicates that the data was not available as Kaplan Meier statistics could not be estimated where the number of events is too low to estimate the value. Median and Inter-quartile range were presented and were based on Kaplan Meier estimates.
    End point type
    Primary
    End point timeframe
    Approximately up to 4 years
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    52 [1]
    53 [2]
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    99999 (789.0 to 99999)
    99999 (99999 to 99999)
    Notes
    [1] - Intent-to-treat population
    [2] - Intent-to-treat population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards model with covariates treatment group, Actual ANCA type, Actual disease stage at induction and Actual induction regimen.
    Comparison groups
    Placebo v Belimumab 10 mg/kg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.884 [4]
    Method
    Cox Proportional Hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    2.59
    Notes
    [3] - Analysis was adjusted for ANCA type, disease stage at induction and induction regimen
    [4] - Cox proportional Hazards (Wald Chi Square)

    Secondary: Number of participants with major relapse during the double-bind phase of the study

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    End point title
    Number of participants with major relapse during the double-bind phase of the study
    End point description
    Data for number of participants with major relapse [defined as experiencing at least 1 major Birmingham Vasculitis Activity Score (BVAS) item] during the double-bind phase of the study was reported. Analysis was performed using a Cox proportional hazard model.
    End point type
    Secondary
    End point timeframe
    Approximately up to 4 years
    End point values
    Placebo Belimumab 10 mg/kg
    Number of subjects analysed
    52 [5]
    53 [6]
    Units: Participants
        Participants
    0
    1
    Notes
    [5] - Intent-to-treat population
    [6] - Intent-to-treat population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) were collected from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent (approximately up to 4 years).
    Adverse event reporting additional description
    Intent to treat population. Participants who discontinued treatment, all AE were collected through 8 weeks following the last dose of study agent. All SAEs were collected until relapse or the study was analyzed for the primary endpoint and study sites are informed that SAE data collection can cease, whichever occurs first.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered matching placebo intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 milligram per kilogram per day (mg/kg/day). In Belgium-only open-label extension, all participants received belimumab 10mg/day every 28 days until Week 24, with a final evaluation at Week 28.

    Reporting group title
    Belimumab 10 mg/kg
    Reporting group description
    Participants were administered induction therapy (corticosteroids and either cyclophosphamide or rituximab) in the 6 months leading up to randomization. After randomization, participants were administered belimumab 10 milligram per kilogram (mg/kg) intravenously over 1 hour, at Day 0, 14, 28 and every 28 days thereafter until 12 months after the last subject was randomized. All participants received oral azathioprine at a target dose of 2 mg/kg/day. In Belgium-only open-label extension, all participants received belimumab 10 mg/kg every 28 days until Week 24, with a final evaluation at Week 28.

    Serious adverse events
    Placebo Belimumab 10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 52 (30.77%)
    18 / 53 (33.96%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Vasculitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal cancer
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural discharge
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Idiopathic orbital inflammation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic gastritis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (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 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle contracture
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (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
    Hypercalcaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Belimumab 10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 52 (63.46%)
    32 / 53 (60.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 52 (15.38%)
    10 / 53 (18.87%)
         occurrences all number
    10
    14
    Epistaxis
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 53 (9.43%)
         occurrences all number
    3
    20
    Oropharyngeal pain
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 53 (7.55%)
         occurrences all number
    2
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 52 (13.46%)
    5 / 53 (9.43%)
         occurrences all number
    7
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 52 (13.46%)
    7 / 53 (13.21%)
         occurrences all number
    9
    8
    Pyrexia
         subjects affected / exposed
    2 / 52 (3.85%)
    6 / 53 (11.32%)
         occurrences all number
    4
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 52 (3.85%)
    7 / 53 (13.21%)
         occurrences all number
    2
    9
    Diarrhoea
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 53 (9.43%)
         occurrences all number
    4
    6
    Vomiting
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 53 (9.43%)
         occurrences all number
    1
    5
    Abdominal pain upper
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3
    Abdominal pain
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 53 (1.89%)
         occurrences all number
    6
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 53 (9.43%)
         occurrences all number
    3
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 52 (11.54%)
    6 / 53 (11.32%)
         occurrences all number
    6
    6
    Back pain
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 53 (5.66%)
         occurrences all number
    6
    4
    Bursitis
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 52 (19.23%)
    6 / 53 (11.32%)
         occurrences all number
    15
    9
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 52 (15.38%)
    7 / 53 (13.21%)
         occurrences all number
    10
    11
    Urinary tract infection
         subjects affected / exposed
    4 / 52 (7.69%)
    5 / 53 (9.43%)
         occurrences all number
    7
    5
    Bronchitis
         subjects affected / exposed
    6 / 52 (11.54%)
    1 / 53 (1.89%)
         occurrences all number
    6
    1
    Influenza
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 53 (9.43%)
         occurrences all number
    1
    5
    Gastroenteritis
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2012
    Amendment 01: The protocol was modified to further define allowable or prohibited doses of corticosteroids that could be given for vasculitis and for reasons other than vasculitis, A statement was added to clarify that the protocol-defined induction regimens for cyclophosphamide were given as treatment targets but that they could be adjusted to account for renal insufficiency or reduced white blood cell counts as dictated by local standard of care practices, A subgroup analysis by duration of Intravenous (IV) corticosteroid pulse used for induction (1 day versus. >1 day) was added, The language regarding the recommended High dose corticosteroids (HDCS) tapering to reach the entry criteria of <10 mg/day was corrected from the previously written <10 mg/kg, The dose of Methotrexate (MTX) to be used in case of Azathioprine (AZA) toxicity was clarified to be a target dose, to allow for flexibility in individual practice. A minimum dose of MTX (no less than 10 mg/week) was also specified, to ensure participants were receiving a sufficient and relatively consistent therapy. This change also ensured the guidance given for MTX was consistent with that given for AZA
    25 Apr 2013
    Amendment 02: The protocol was modified to include testing at Screening for human immunodeficiency virus (HIV) antibody, to expand Hepatitis B serology testing, and to exclude participants who tested positive according to the criteria specified, an alternative test, Hepatitis C virus (HCV) ribonucleic acid (RNA)-polymerase chain reaction (PCR) assay, was used to detect the presence of viral RNA, and hence confirm a current infection, The protocol was modified to exclude participants at baseline with abnormal liver function according to the criteria specified, A new section was added to clarify how participants care should be managed if a patient had a liver chemistry event during the study, Measurement of vital signs (temperature, sitting blood pressure [systolic and diastolic], and heart rate) were added to the procedures for all scheduled study visits and a 12 lead electrocardiogram (ECG) was added to the procedures for the Day 0 visit, Text was added to clarify that study agents were to be provided by the sponsor during the double-blind treatment phase, Within the definition of postmenopausal in Inclusion Criterion, “1 year without menses” was changed to “12 consecutive months with no menses without an alternative medical cause, Steroid use for vasculitis was modified to restrict the use of corticosteroids up to a maximum of 20 mg/day of prednisone (or equivalent) for a maximum of 1 week within the first 2 months of the double-blind treatment period, and at other times, to <10 mg/day, The investigator evaluation of Adverse events regarding causality was modified from a multi-choice assessment, Two new appendices were added to provide the questionnaires for the possible suicidality related history questionnaire (PSRHQ), The protocol was modified to include a Benefit and Risk Assessment, The Chapel Hill Consensus Conference (CHCC) definitions for Wegener’s granulomatosis and microscopic polyangiitis were updated.
    04 Feb 2014
    Amendment 03: The protocol was modified to provide flexibility in timing of initiation of AZA maintenance therapy.The protocol was modified to allow alternative unlicensed RTX dose for induction (1 g every 2 weeks) in addition to the licensed dosing regimen (375 mg/m2/wk for 4 doses, The protocol was modified to provide flexibility in timing of baseline Birmingham Vasculitis Activity Score (BVAS) assessments – allowing 2 baseline assessments separated by at least 14 days, The absolute requirement to randomize within 14 days of confirmation of remission was removed and clarification was added that subjects could not be randomized until at least 6 weeks after initiation of induction therapy, Clarification was added regarding HDCS for induction and text provided guidance but allowed locally accepted practice. No subject should have received <10 mg for induction, The protocol was modified to allow some flexibility to Cyclophosphamide dosing regimens, The protocol was modified to allow the option to use MTX from the outset, as an alternative to AZA, if subject was a priori known to be AZA intolerant or had low/absent thiopurine methyltransferase (TPMT) activity. Exclusion of subjects with intolerance or contraindications to MTX (where this was being considered as an alternative to AZA), The protocol was modified to allow equal to/less than 10 mg prednisone daily during maintenance, Progressive multifocal leukoencephalopathy (PML) text was updated based on new information, The Benefit and Risk Assessment section was updated to reflect new and/or amended information in the protocol body.
    26 Feb 2015
    Amendment 04: Protocol was modified to reflect a change by the sponsor to the strategic objectives for the evaluation of belimumab in ANCA-associated vasculitis (AAV). It was proposed that trial be changed from a Phase 3 to allow for an exploratory evaluation of belimumab in AAV only. The study design and schedule was modified in to clarify that the study would no longer be driven by the requirement to achieve at least 66 relapse events. The study was to complete and the primary analysis to be undertaken once 12 months had elapsed following enrolment of the last subject. The protocol was modified throughout such that (with exception of Belgium) participants completing the study no longer had the option to participate in a 6-month open-label extension following completion of the double-blind treatment phase, In the statistical sections of the protocol, the sample size considerations were modified to reflect the fact that approximately 100 participants were to be recruited, In the section “Dose, route of administration and schedule”, it was clarified that administration of belimumab or placebo should be over 1 hour, but not less than 1 hour for reasons of safety, The section on liver chemistry stopping and follow-up criteria, which described how participant care should be managed if a liver event occurred during the study, was updated with the most recent GSK-specified protocol for managing these events, The text on Progressive multifocal PML was updated to provide further guidance, The section “Reporting a pregnancy” was modified to provide scope for following up outcomes of a pregnancy as well as the status of mother and child, The section “Randomization procedure and assignment to treatment requirements” was modified to remove the requirement for participants to be randomized within 2 weeks of achieving remission, Protocol Appendix 12 was updated to reflect the change in study status to an exploratory trial and to reflect the changes in the main 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.
    The sample size was small as it was truncated from approximately 300 to 100 participants, largely owing to a change in standard of care.
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