Clinical Trial Results:
Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomised Controlled Trial
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Summary
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EudraCT number |
2009-013220-24 |
Trial protocol |
GB IT SE DK CZ ES PL |
Global end of trial date |
31 Jul 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jul 2018
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First version publication date |
19 Jul 2018
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Other versions |
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Summary report(s) |
PEXIVAS Cumulative SAE report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
A091637
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Additional study identifiers
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ISRCTN number |
ISRCTN07757494 | ||
US NCT number |
NCT00987389 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Cambridge University Hospitals NHS Foundation Trust
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Sponsor organisation address |
Hill's Road, Cambridge, United Kingdom, CB2 0QQ
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Public contact |
Elizabeth Broadhurst, Cambridge University Hospitals NHS Foundation Trust, 01223 349350, elizabeth.broadhurst@addenbrookes.nhs.uk
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Scientific contact |
Prof David Jayne, Cambridge University Hospitals NHS Foundation Trust, 01223 336816, dj106@cam.ac.uk
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Sponsor organisation name |
University of Pennsylvania; Division of Rheumatology
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Sponsor organisation address |
3400 Spruce St, White Building, 5th Floor, Philadelphia, United States, 19104
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Public contact |
Carol A. McAlear, MA, University of Pennsylvania, cmcalear@pennmedicine.upenn.edu
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Scientific contact |
Peter A. Merkel, MD, MPH, University of Pennsylvania, pmerkel@upenn.edu
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Sponsor organisation name |
Okayama University
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Sponsor organisation address |
1-1-1Tsushima-naka, Kita-Ku, Okayama, Japan, 700-8530
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Public contact |
Hirofumi Makino, Okayama University, makino@okayama-u.ac.jp
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Scientific contact |
Hirofumi Makino, Okayama University, makino@okayama-u.ac.jp
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 May 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jul 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jul 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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?
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 8
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Country: Number of subjects enrolled |
Poland: 7
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
Sweden: 9
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Country: Number of subjects enrolled |
United Kingdom: 179
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Country: Number of subjects enrolled |
Czech Republic: 10
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Country: Number of subjects enrolled |
Denmark: 57
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Country: Number of subjects enrolled |
France: 52
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Country: Number of subjects enrolled |
Italy: 26
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Country: Number of subjects enrolled |
Mexico: 7
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Country: Number of subjects enrolled |
United States: 39
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Country: Number of subjects enrolled |
Canada: 191
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Country: Number of subjects enrolled |
Japan: 12
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Country: Number of subjects enrolled |
Australia: 94
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Country: Number of subjects enrolled |
New Zealand: 10
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Country: Number of subjects enrolled |
Belgium: 1
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Worldwide total number of subjects |
704
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EEA total number of subjects |
351
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
339
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From 65 to 84 years |
337
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85 years and over |
27
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Recruitment
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Recruitment details |
704 patients were recruited. The first patient was recruited on 8th June 2010 and the last patient recruited on 30th September 2016. | |||||||||||||||
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Pre-assignment
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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. | |||||||||||||||
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Period 1
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Period 1 title |
Recruitment (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||
Blinding implementation details |
Not blinded.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Plasma Exchange | |||||||||||||||
Arm description |
7 x Plasma Exchange procedures within 14 days of randomisation. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Glucocorticoids
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.
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Arm title
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No Plasma Exchange | |||||||||||||||
Arm description |
No Plasma Exchange received. | |||||||||||||||
Arm type |
No Intervention | |||||||||||||||
Investigational medicinal product name |
Glucocorticoids
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Glucocorticoids administered as per randomisation allocation: low or standard dose Glucocorticoids.
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Baseline characteristics reporting groups
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Reporting group title |
Plasma Exchange
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Reporting group description |
7 x Plasma Exchange procedures within 14 days of randomisation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
No Plasma Exchange
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Reporting group description |
No Plasma Exchange received. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Reduced Glucocorticoids
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Plasma Exchange
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Reporting group description |
7 x Plasma Exchange procedures within 14 days of randomisation. | ||
Reporting group title |
No Plasma Exchange
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Reporting group description |
No Plasma Exchange received. | ||
Reporting group title |
Reduced Glucocorticoids
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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
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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. | ||
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End point title |
Composite of time to death and/or ESRD | |||||||||||||||||||||||||
End point description |
Time to event (ESRD and Death)
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End point type |
Primary
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End point timeframe |
Whole trial
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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.
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Comparison groups |
Plasma Exchange v No Plasma Exchange
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Number of subjects included in analysis |
704
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||||||||||||
P-value |
= 0.422 | |||||||||||||||||||||||||
Method |
Regression, Cox | |||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||||||||||||
Point estimate |
0.89
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.68 | |||||||||||||||||||||||||
upper limit |
1.17 | |||||||||||||||||||||||||
| Notes [1] - Adjusted for treatment arm as part of the factorial design. |
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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
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Comparison groups |
Plasma Exchange v No Plasma Exchange
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Number of subjects included in analysis |
704
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||||||||||||||||||
P-value |
= 0.268 | |||||||||||||||||||||||||
Method |
Regression, Cox | |||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||||||||||||
Point estimate |
0.86
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.65 | |||||||||||||||||||||||||
upper limit |
1.13 | |||||||||||||||||||||||||
| Notes [2] - Adjusted for all minimisation variables. |
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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.
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Comparison groups |
Reduced Glucocorticoids v Standard Glucocorticoids
|
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Number of subjects included in analysis |
704
|
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Analysis specification |
Pre-specified
|
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Analysis type |
non-inferiority [3] | |||||||||||||||||||||||||
P-value |
= 0.863 | |||||||||||||||||||||||||
Method |
Regression, Cox | |||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||||||||||||
Point estimate |
1.02
|
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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. |
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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. |
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End point title |
Per-Protocol Analysis | |||||||||||||||||||||||||
End point description |
||||||||||||||||||||||||||
End point type |
Primary
|
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End point timeframe |
Whole trial
|
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|
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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.
|
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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. |
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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.
|
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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 |
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|
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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. |
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|
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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. |
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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. |
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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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