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    Clinical Trial Results:
    Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomised Controlled Trial

    Summary
    EudraCT number
    2009-013220-24
    Trial protocol
    GB   IT   SE   DK   CZ   ES   PL  
    Global end of trial date
    31 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jul 2018
    First version publication date
    19 Jul 2018
    Other versions
    Summary report(s)
    PEXIVAS Cumulative SAE report

    Trial information

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    Trial identification
    Sponsor protocol code
    A091637
    Additional study identifiers
    ISRCTN number
    ISRCTN07757494
    US NCT number
    NCT00987389
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Hill's Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Elizabeth Broadhurst, Cambridge University Hospitals NHS Foundation Trust, 01223 349350, elizabeth.broadhurst@addenbrookes.nhs.uk
    Scientific contact
    Prof David Jayne, Cambridge University Hospitals NHS Foundation Trust, 01223 336816, dj106@cam.ac.uk
    Sponsor organisation name
    University of Pennsylvania; Division of Rheumatology
    Sponsor organisation address
    3400 Spruce St, White Building, 5th Floor, Philadelphia, United States, 19104
    Public contact
    Carol A. McAlear, MA, University of Pennsylvania, cmcalear@pennmedicine.upenn.edu
    Scientific contact
    Peter A. Merkel, MD, MPH, University of Pennsylvania, pmerkel@upenn.edu
    Sponsor organisation name
    Okayama University
    Sponsor organisation address
    1-1-1Tsushima-naka, Kita-Ku, Okayama, Japan, 700-8530
    Public contact
    Hirofumi Makino, Okayama University, makino@okayama-u.ac.jp
    Scientific contact
    Hirofumi Makino, Okayama University, makino@okayama-u.ac.jp
    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
    02 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    There are 2 principal questions for this research: 1) Does the addition of 7 plasma exchange procedures to usual therapy early in the treatment of patients with severe ANCA associated vasculitis significantly reduce their risk of death or kidney failure? 2) Does a reduced-dose regimen of steroids compared to a standard-dose regimen in the first 6 months of treatment of patients with ANCA associated vasculitis significantly reduce their risk of death or kidney failure?
    Protection of trial subjects
    This clinical trial involved over 700 participants with systemic vasculitis. The inclusion criteria consists of an ANCA-associated vasculitis diagnosis (AAV) with at least one severe manifestation, either nephritis or lung haemorrhage. Patients with anti-glomerular basement membrane disease; other forms of vasculitis; or who are pregnant were excluded. Any participants becoming pregnant whilst are permitted to remain on study provided that consent remains valid and all tetratogenic medications are switched to safer alternatives. Informed consent was sought from all potentially eligible patients, or deferred consent from a surrogate decision maker if the patient was unable to consent. Subsequent patient consent was sought once the patient regained capacity. Strict patient confidentiality was observed throughout all aspects of the study. Medical records were reviewed by members of the local research team only. No patient identifiable data was distributed beyond the local team as all patient data was anonymised prior to transmitting to the data and coordination teams. Overall supervision of the trial is provides by a Trial Steering Committee to ensure safe conduct of the trial and compliance with GCP and the trial protocol.
    Background therapy
    Once enrolled, participants were randomised to receive either a low- or standard-dose glucocorticoid regime; and to receive adjunctive plasma exchange or not. Alongside this, patients received standard immunosuppressive therapy in the form of either Rituximab or Cyclophosphamide. All patients received between 1-3g of IV Methylprednisolone over 1 to 3 days before beginning their oral Glucocorticoid regime. The standard immunosuppressive therapy was decided by preference of the site investigator/patient. Participants may have received either intravenous (15mg/kg/pulse) or oral (2mg/kg/day) Cyclophosphamide according to local preferences. Cyclophosphamide doses were reduced according to advanced age, poor baseline renal function or cytopenias. Participants receiving Rituximab were given 4 weekly intravenous infusions (375mg/m²). The first dose was received within 14 days of participation and subsequent doses should follow 7 days later, with a 5-10 day window to allow for practical considerations. All doses of Rituximab were given within 42 days of enrolment and Rituximab was not given within 48 hours prior to receiving a PLEX treatment. Randomisation was stratified according to background immunosuppressant.
    Evidence for comparator
    Plasma exchange (PLEX), a method of rapidly removing potentially pathogenic ANCA and other mediators of inflammation and coagulation, has shown promise as an adjunctive therapy in AAV to improve early disease control and improve rates of renal recovery in severe disease. Glucocorticoids (GC) are a standard of care in the treatment of AAV. High doses of GC early in disease although undeniably reduce disease activity due to their anti-inflammatory and immunosuppressive properties also increase the risk of infection particularly in the elderly and in the presence of uremia. There are no randomized trial data to guide GC dosing. Evidence summarised in Walsh et. al., Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis 2011; 57(4) 566-574
    Actual start date of recruitment
    08 Jun 2010
    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
    Norway: 8
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 179
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Denmark: 57
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Canada: 191
    Country: Number of subjects enrolled
    Japan: 12
    Country: Number of subjects enrolled
    Australia: 94
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Belgium: 1
    Worldwide total number of subjects
    704
    EEA total number of subjects
    351
    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)
    1
    Adults (18-64 years)
    339
    From 65 to 84 years
    337
    85 years and over
    27

    Subject disposition

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    Recruitment
    Recruitment details
    704 patients were recruited. The first patient was recruited on 8th June 2010 and the last patient recruited on 30th September 2016.

    Pre-assignment
    Screening details
    During screening, patient's eligibility was assessed based on a diagnosis of new or relapsing severe ANCA-associated vasculitis (AAV). Any previous vasculitis treatment was also considered and patients would not have been eligible to participate if they had recently received Cyclophosphamide; Rituximab; dialysis or a prior renal transplant.

    Period 1
    Period 1 title
    Recruitment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not blinded.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Plasma Exchange
    Arm description
    7 x Plasma Exchange procedures within 14 days of randomisation.
    Arm type
    Experimental

    Investigational medicinal product name
    Glucocorticoids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.

    Arm title
    No Plasma Exchange
    Arm description
    No Plasma Exchange received.
    Arm type
    No Intervention

    Investigational medicinal product name
    Glucocorticoids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.

    Arm title
    Reduced Glucocorticoids
    Arm description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Week 1, 25mg at Week 2, 20mg at Weeks 3-4, 15mg at Weeks 5-6, 12.5mg at Weeks 7-8, 10mg at Weeks 9-10, 7.5mg at Weeks 11-12, 6mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 60mg at Week 1, 30mg at Week 2, 25mg at Weeks 3-4, 20mg at Weeks 5-6, 15mg at Weeks 7-8, 12.5mg at Weeks 9-10, 10mg at Weeks 11-12, 7.5mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 75mg at Week 1, 40mg at Week 2, 30mg at Weeks 3-4, 25mg at Weeks 5-6, 20mg at Weeks 7-8, 15mg at Weeks 9-10, 12.5mg at Weeks 11-12, 10mg at Weeks 13-14, 7.5mg at Weeks 15–18, 5mg from Week 19-52.
    Arm type
    Experimental

    Investigational medicinal product name
    Glucocorticoids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.

    Arm title
    Standard Glucocorticoids
    Arm description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Weeks 1-2, 40mg at Weeks 3-4, 30mg at Weeks 5-6, 25mg at Weeks 7-8, 20mg at Weeks 9-10, 15mg at Weeks 11-12, 12.5mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing between 50-75kg will receive the following: 60mg at Weeks 1-2, 50mg at Weeks 3-4, 40mg at Weeks 5-6, 30mg at Weeks 7-8, 25mg at Weeks 9-10, 20mg at Weeks 11-12, 15mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing over 75kg will receive the following: 75mg at Weeks 1-2, 60mg at Weeks 3-4, 50mg at Weeks 5-6, 40mg at Weeks 7-8, 30mg at Weeks 9-10, 25mg at Weeks 11-12, 20mg at Weeks 13-14, 15mg at Weeks 15-18, 10mg from Week 19-20, 7.5mg at Week 21-22 and 5mg from Week 23-52.
    Arm type
    Active comparator

    Investigational medicinal product name
    Glucocorticoids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.

    Number of subjects in period 1
    Plasma Exchange No Plasma Exchange Reduced Glucocorticoids Standard Glucocorticoids
    Started
    352
    352
    353
    351
    Completed
    352
    352
    353
    351

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Plasma Exchange
    Reporting group description
    7 x Plasma Exchange procedures within 14 days of randomisation.

    Reporting group title
    No Plasma Exchange
    Reporting group description
    No Plasma Exchange received.

    Reporting group title
    Reduced Glucocorticoids
    Reporting group description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Week 1, 25mg at Week 2, 20mg at Weeks 3-4, 15mg at Weeks 5-6, 12.5mg at Weeks 7-8, 10mg at Weeks 9-10, 7.5mg at Weeks 11-12, 6mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 60mg at Week 1, 30mg at Week 2, 25mg at Weeks 3-4, 20mg at Weeks 5-6, 15mg at Weeks 7-8, 12.5mg at Weeks 9-10, 10mg at Weeks 11-12, 7.5mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 75mg at Week 1, 40mg at Week 2, 30mg at Weeks 3-4, 25mg at Weeks 5-6, 20mg at Weeks 7-8, 15mg at Weeks 9-10, 12.5mg at Weeks 11-12, 10mg at Weeks 13-14, 7.5mg at Weeks 15–18, 5mg from Week 19-52.

    Reporting group title
    Standard Glucocorticoids
    Reporting group description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Weeks 1-2, 40mg at Weeks 3-4, 30mg at Weeks 5-6, 25mg at Weeks 7-8, 20mg at Weeks 9-10, 15mg at Weeks 11-12, 12.5mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing between 50-75kg will receive the following: 60mg at Weeks 1-2, 50mg at Weeks 3-4, 40mg at Weeks 5-6, 30mg at Weeks 7-8, 25mg at Weeks 9-10, 20mg at Weeks 11-12, 15mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing over 75kg will receive the following: 75mg at Weeks 1-2, 60mg at Weeks 3-4, 50mg at Weeks 5-6, 40mg at Weeks 7-8, 30mg at Weeks 9-10, 25mg at Weeks 11-12, 20mg at Weeks 13-14, 15mg at Weeks 15-18, 10mg from Week 19-20, 7.5mg at Week 21-22 and 5mg from Week 23-52.

    Reporting group values
    Plasma Exchange No Plasma Exchange Reduced Glucocorticoids Standard Glucocorticoids Total
    Number of subjects
    352 352 353 351 704
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    1 0 0 1 1
        Adults (18-64 years)
    171 168 164 175 339
        From 65-84 years
    169 168 173 164 337
        85 years and over
    11 16 16 11 27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.8 ± 14.4 63.5 ± 13.7 63.3 ± 14.2 63.1 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    149 158 156 151 307
        Male
    203 194 197 200 397
    Prior history of AAV
    Units: Subjects
        Yes
    35 28 34 29 63
        No
    317 324 319 322 641
    ANCA
    Units: Subjects
        PR3+
    143 143 143 143 286
        MPO+
    209 209 210 208 418
    Lung Haemorrhage
    Units: Subjects
        No haemorrhage
    257 256 257 256 513
        Not severe
    64 66 65 65 130
        Severe
    31 30 31 30 61
    Creatinine at randomisation
    Units: µmol/L
        median (inter-quartile range (Q1-Q3))
    327 (206 to 491) 335.9 (209 to 495) 320 (190 to 480) 335 (219 to 502) -

    End points

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    End points reporting groups
    Reporting group title
    Plasma Exchange
    Reporting group description
    7 x Plasma Exchange procedures within 14 days of randomisation.

    Reporting group title
    No Plasma Exchange
    Reporting group description
    No Plasma Exchange received.

    Reporting group title
    Reduced Glucocorticoids
    Reporting group description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Week 1, 25mg at Week 2, 20mg at Weeks 3-4, 15mg at Weeks 5-6, 12.5mg at Weeks 7-8, 10mg at Weeks 9-10, 7.5mg at Weeks 11-12, 6mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 60mg at Week 1, 30mg at Week 2, 25mg at Weeks 3-4, 20mg at Weeks 5-6, 15mg at Weeks 7-8, 12.5mg at Weeks 9-10, 10mg at Weeks 11-12, 7.5mg at Weeks 13-14, 5mg from Week 15-52. Patients weighing between 50-75kg will receive the following: 75mg at Week 1, 40mg at Week 2, 30mg at Weeks 3-4, 25mg at Weeks 5-6, 20mg at Weeks 7-8, 15mg at Weeks 9-10, 12.5mg at Weeks 11-12, 10mg at Weeks 13-14, 7.5mg at Weeks 15–18, 5mg from Week 19-52.

    Reporting group title
    Standard Glucocorticoids
    Reporting group description
    Glucocorticoid dose according to patient weight. Patients weighing less than 50kg will receive the following: 50mg at Weeks 1-2, 40mg at Weeks 3-4, 30mg at Weeks 5-6, 25mg at Weeks 7-8, 20mg at Weeks 9-10, 15mg at Weeks 11-12, 12.5mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing between 50-75kg will receive the following: 60mg at Weeks 1-2, 50mg at Weeks 3-4, 40mg at Weeks 5-6, 30mg at Weeks 7-8, 25mg at Weeks 9-10, 20mg at Weeks 11-12, 15mg at Weeks 13-14, 10mg at Weeks 15-18, 7.5mg from Week 19-22, 5mg from Week 23-52. Patients weighing over 75kg will receive the following: 75mg at Weeks 1-2, 60mg at Weeks 3-4, 50mg at Weeks 5-6, 40mg at Weeks 7-8, 30mg at Weeks 9-10, 25mg at Weeks 11-12, 20mg at Weeks 13-14, 15mg at Weeks 15-18, 10mg from Week 19-20, 7.5mg at Week 21-22 and 5mg from Week 23-52.

    Primary: Composite of time to death and/or ESRD

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    End point title
    Composite of time to death and/or ESRD
    End point description
    Time to event (ESRD and Death)
    End point type
    Primary
    End point timeframe
    Whole trial
    End point values
    Plasma Exchange No Plasma Exchange Reduced Glucocorticoids Standard Glucocorticoids
    Number of subjects analysed
    352
    352
    353
    351
    Units: Events
        No
    252
    243
    246
    249
        Yes
    100
    109
    107
    102
    Statistical analysis title
    PLEX ITT (Partially Adjusted)
    Statistical analysis description
    The primary outcome is a composite of all-cause mortality or ESRD. The comparison of PLEX vs. no PLEX is based on the ITT analysis population using a time to event analysis (time from randomisation to death or ESRD). A Cox proportional hazards model was fitted to obtain an adjusted hazard ratio and 95% confidence interval. No PLEX and Standard GC were used as the reference groups in the Cox regression model.
    Comparison groups
    Plasma Exchange v No Plasma Exchange
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.422
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.17
    Notes
    [1] - Adjusted for treatment arm as part of the factorial design.
    Statistical analysis title
    PLEX ITT (Adjusted)
    Statistical analysis description
    The primary outcome is a composite of all-cause mortality or ESRD. The comparison of PLEX vs. no PLEX is based on the ITT analysis population using a time to event analysis (time from randomisation to death or ESRD). A Cox proportional hazards model was fitted to obtain an adjusted hazard ratio and 95% confidence interval. No PLEX and Standard GC were used as the reference groups in the Cox regression model. No PLEX and Standard GC were used as the reference groups in the Cox regression mo
    Comparison groups
    Plasma Exchange v No Plasma Exchange
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.268
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.13
    Notes
    [2] - Adjusted for all minimisation variables.
    Statistical analysis title
    Glucocorticoids ITT (Partially Adjusted)
    Statistical analysis description
    The primary outcome is a composite of all-cause mortality or ESRD. The comparison of PLEX vs. no PLEX is based on the ITT analysis population using a time to event analysis (time from randomisation to death or ESRD). A Cox proportional hazards model was fitted to obtain an adjusted hazard ratio and 95% confidence interval. No PLEX and Standard GC were used as the reference groups in the Cox regression model.
    Comparison groups
    Reduced Glucocorticoids v Standard Glucocorticoids
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.863
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.34
    Notes
    [3] - Adjusted for treatment arm as part of factorial design.
    Statistical analysis title
    Glucocorticoids ITT (Adjusted)
    Statistical analysis description
    The primary outcome is a composite of all-cause mortality or ESRD. The comparison of PLEX vs. no PLEX is based on the ITT analysis population using a time to event analysis (time from randomisation to death or ESRD). A Cox proportional hazards model was fitted to obtain an adjusted hazard ratio and 95% confidence interval. No PLEX and Standard GC were used as the reference groups in the Cox regression model. No PLEX and Standard GC were used as the reference groups in the Cox regression mod
    Comparison groups
    Reduced Glucocorticoids v Standard Glucocorticoids
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    = 0.998
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.31
    Notes
    [4] - Adjusted for all minimisation variables.

    Primary: Per-Protocol Analysis

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    End point title
    Per-Protocol Analysis
    End point description
    End point type
    Primary
    End point timeframe
    Whole trial
    End point values
    Plasma Exchange No Plasma Exchange Reduced Glucocorticoids Standard Glucocorticoids
    Number of subjects analysed
    338
    322
    330
    325
    Units: Events
        No
    243
    223
    238
    242
        Yes
    95
    99
    92
    83
    Statistical analysis title
    Glucocorticoids (Partially Adjusted)
    Statistical analysis description
    The comparison of Reduced GC to Standard dose GC is a non-inferiority hypothesis with a non-inferiority margin of an 11% absolute risk increase expressed as the reduced dose GC group relative to the standard dose GC group. Since an intention to treat analysis can increase the risk of falsely claiming non-inferiority, this analysis was conducted for participant’s adherent to the assigned GC regimen (the per-protocol population). Standard GC was used as the reference groups in the Binomial model.
    Comparison groups
    Reduced Glucocorticoids v Standard Glucocorticoids
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.507
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.023
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.034
         upper limit
    0.08
    Notes
    [5] - The GC dose per-protocol analysis population will consist of: • Participants randomised to reduced dose GC who receive ≤130% of the cumulative oral dose of the reduced dose regimen in the first 6 months of therapy. • Participants randomised to standard dose GC who receive ≥70% of the cumulative oral dose of the standard regimen in the first 6 months of therapy.
    Statistical analysis title
    PLEX (Partially Adjusted)
    Statistical analysis description
    As part of the sensitivity analysis, we have also analysed the primary outcome for the PLEX arm as per-protocol. Per-Protocol set for the PLEX arms was defined as any patients randomised in the PLEX arm to have received at least one PLEX treatment within 14 days of randomisation or any patients randomised to PLEX arm to not have received any PLEX but died within 14 days of randomisation. No PLEX was used as the reference groups in the Cox regression model.
    Comparison groups
    Plasma Exchange v No Plasma Exchange
    Number of subjects included in analysis
    660
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.352
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.16
    Notes
    [6] - T

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious Adverse Events (SAEs) were required to be reported to the Sponsor within 24 hours of site awareness. SAEs continued to be reported until completion of all patient follow-up on 31 July 2017. The only non-SAEs collected were infections.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: All SAEs are captured in the attached cumulative SAE report.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2012
    Protocol Version 2, patient medication diary and patient card were introduced. The patient medication diary enabled better drug accountability. The exclusion criteria were updated to clarify any patients that had received plasma exchange within 3 months prior to randomisation would not be eligible. The Patient Information Sheet/ Informed Consent Form were also updated to clarify which staff member was taking consent.
    12 Dec 2014
    Amendment 7 introduced Protocol Version 3.0 and included an increase in target recruitment from 500 to 700 participants due to a lower than expected event rate. The increased sample size allowed us to address the primary outcome measure: death and end stage renal disease.

    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.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/23497590
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