Plain English Summary
Background and study aims
Severe, antineutrophil cytoplasm antibody associated vasculitis (AAV) is an uncommon disease of the immune system diagnosed in about 1430 per 100,000 people in the UK each year. It is caused by caused by abnormal antibodies that attack the body’s own cells and tissues. AAV is important because it carries a poor prognosis, with up to half of patients dying or developing kidney failure within 5 years. Two major problems hinder the treatment of AAV: a lack of treatment strategies to bring the disease under control quickly before it causes major organ damage, and a high degree of treatment-related toxicity (side effects). The aim of this study is to examine these problems in patients with severe AAV.
Who can participate?
Patients aged 15 or over with severe AAV
What does the study involve?
Participants are randomly allocated to either receive plasma exchange (a method of rapidly removing the abnormal antibodies), or to not receive plasma exchange. Participants are also randomly allocated to receive either a standard dose of steroids or a low-dose scheme which is predicted to reduce treatment-related toxicity.
What are the possible benefits and risks of participating?
By addressing these problems we hope to significantly improve patient survival and reduce the frequency of kidney failure in patients with AAV.
Where is the study run from?
Addenbrooke's Hospital (UK)
When is the study starting and how long is it expected to run for?
November 2009 to July 2018
Who is funding the study?
Health Technology Assessment Programme (UK)
Who is the main contact?
Dr David Jayne
dj106@cam.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Dr David Jayne
ORCID ID
Contact details
Addenbrooke's Hospital
Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
United Kingdom
+44 (0)1223 256 039
dj106@cam.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT00987389
Protocol/serial number
HTA 08/56/04; PEXIVASv1.0
Study information
Scientific title
Plasma exchange and glucocorticoid dosing in the treatment of antineutrophil cytoplasm antibody associated vasculitis: an international randomised controlled trial
Acronym
PEXIVAS
Study hypothesis
This is a two-by-two factorial design randomised controlled trial and has two primary hypotheses:
1. Plasma exchange in addition to immunosuppressive therapy and glucocorticoids will reduce death and end-stage renal disease (ESRD) compared to immunosuppression and glucocorticoids alone in patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis
2. A reduced dose glucocorticoids regimen will be non-inferior to a standard regimen with respect to death and ESRD in patients with ANCA associated vasculitis
More details can be found at: http://www.nets.nihr.ac.uk/projects/hta/085604
Protocol can be found at: http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0011/53012/PRO-08-56-04.pdf
Ethics approval
Ethics Board: NRES Committee London – Harrow, 30/10/2009, Ref: 09/H0709/56
Study design
Two-by-two factorial design randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Anti-neutrophil cytoplasm antibody associated vasculitis (AAV) with nephritis or lung haemorrhage
Intervention
1. Plasma exchange (seven exchanges of human albumin at a dose of 60 ml/kg over 14 days) as an adjunctive therapy to standard immunosuppression treatment and glucocorticoids
2. A reduced dose glucocorticoid tapering regimen compared to a standard dose glucocorticoid tapering regimen
Intervention type
Mixed
Phase
Drug names
Primary outcome measure
Death or end-stage renal disease. Timepoint for all analyses is the common closeout date (2 years after the last patient is enrolled).
Secondary outcome measures
Current secondary outcome measures, as of 21/03/2018:
1. Sustained remission will be analyzed by comparing the difference in proportions (and associated 95% confidence intervals) of patients that achieve a sustained remission in each treatment group.
2. Death and ESRD will be analyzed separately in an identical manner to the composite primary endpoint.
3. Safety analyses will be performed by assessing the 95% confidence interval of the rate difference of serious adverse events between treatment groups.
4. The rate of serious infections will be assessing the 95% confidence interval of the rate difference between the treatment groups both for the first year and at trial end.
5. Health-related quality of life using the SF-36 Physical Composite, Mental Composite and EQ-5D Index Score.
Patients were seen at Week 26, Week 52 and then every 6 months until study end.
Previous secondary outcome measures:
1. Disease activity (measured with the Birmingham Vasculitis Activity Score 2003)
2. Health related quality of life (measured with the EuroQoL EQ5D index score and 36-item Short Form Health Survey)
3. Serious adverse events
Timepoint for all analyses is the common closeout date (2 years after the last patient is enrolled).
Overall trial start date
01/11/2009
Overall trial end date
31/07/2018
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. New or previous clinical diagnosis of Wegener's granulomatosis, or microscopic polyangiitis consistent with the Chapel-Hill consensus definitions
2. Positive test for proteinase 3-ANCA or myeloperoxidase-ANCA
3. Severe vasculitis defined by at least one of the following:
3.1. Renal involvement, characterised by:
3.1.1. Renal biopsy demonstrating focal necrotising glomerulonephritis or active urine sediment demonstrating glomerular haematuria/red cell casts and proteinuria, and
3.1.2. Estimated glomerular filtration rate (eGFR) less than 50 ml/min/1.73 m2), or
3.2. Pulmonary haemorrhage due to active vasculitis (defined by a compatible chest x-ray or computed tomography [CT] scan (diffuse pulmonary infiltrates), and
3.3. The absence of an alternative explanation for all pulmonary infiltrates (i.e. volume overload or pulmonary infection), and
3.4. At least one of the following:
3.4.1. Evidence of alveolar haemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage
3.4.2. Observed haemoptysis
3.4.3. Unexplained anaemia (less than 10 g/dl) or documented drop in haemoglobin (greater than 1 g/dl)
3.4.4. An increased diffusing capacity of carbon dioxide
4. Provision of informed consent by patient or a surrogate decision maker
5. Aged greater than or equal to 15 years, either sex
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
700
Total final enrolment
704
Participant exclusion criteria
1. A diagnosis of vasculitis other than Wegener's granulomatosis or microscopic polyangiitis
2. Positive anti-glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition
3. Receipt of dialysis for greater than 21 days immediately prior to randomisation or prior renal transplant
4. Aged less than 15 years (aged less than 18 years at centres that do not treat paediatric patients)
5. Pregnancy
6. Treatment with greater than 1 intravenous (IV) dose of cyclophosphamide and/or greater than 14 days of oral cyclophosphamide and/or greater than 14 days of prednisone/prednisolone (greater than 30 mg/day) and/or greater than 1 dose of rituximab within the 28 days immediately prior to randomisation
7. A comorbidity that, in the opinion of the investigator, precludes the use of cyclophosphamide, glucocorticoids, or plasma exchange or absolutely mandates the use of plasma exchange
Added 30/10/2019:
8. Plasma exchange in 3 months prior to randomization
Recruitment start date
30/09/2016
Recruitment end date
31/07/2017
Locations
Countries of recruitment
Australia, Canada, Czech Republic, Denmark, France, Germany, Italy, Mexico, Netherlands, New Zealand, Spain, Sweden, Switzerland, United Kingdom, United States of America
Trial participating centre
Addenbrooke's Hospital
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Organisation
Cambridge University Hospitals NHS Foundation Trust (UK)
Sponsor details
Box 277
Hills Road
Cambridge
CB2 0QQ
United Kingdom
+44 (0)1223 596377
louise.stockley@addenbrookes.nhs.uk
Sponsor type
Government
Website
Funders
Funder type
Government
Funder name
Health Technology Assessment Programme
Alternative name(s)
NIHR Health Technology Assessment Programme, HTA
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Medical Research Council (MRC) (UK) (ref: 86772)
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Food and Drug Administration (USA) and National Institutes of Health (USA) (ref: 1 R01 FD003516-01)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
2018 results presented at 2018 ACR/ARHP Annual Meeting: https://acrabstracts.org/abstract/the-effects-of-plasma-exchange-and-reduced-dose-glucocorticoids-during-remission-induction-for-treatment-of-severe-anca-associated-vasculitis/ [added 14/05/2019]
IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
31/05/2020
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list
2013 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/23497590
Publication citations
-
Protocol
Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, De Zoysa J, Ives N, Clark WF, Quillen K, Winters JL, Wheatley K, Jayne D, , Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial., Trials, 2013, 14, 73, doi: 10.1186/1745-6215-14-73.