Plasma exchange and glucocorticoid dosing in the treatment of antineutrophil cytoplasm antibody associated vasculitis

ISRCTN	ISRCTN07757494
DOI	https://doi.org/10.1186/ISRCTN07757494
ClinicalTrials.gov (NCT)	NCT00987389
Clinical Trials Information System (CTIS)	2009-013220-24
Protocol serial number	HTA 08/56/04; PEXIVASv1.0
Sponsor	Cambridge University Hospitals NHS Foundation Trust (UK)
Funders	Health Technology Assessment Programme, Medical Research Council (MRC) (UK) (ref: 86772), Food and Drug Administration (USA) and National Institutes of Health (USA) (ref: 1 R01 FD003516-01)

Submission date: 01/06/2009
Registration date: 22/06/2009
Last edited: 27/09/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Mental and Behavioural Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

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

Contact information

Dr David Jayne
Scientific

Addenbrooke's Hospital
Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Phone	+44 (0)1223 256 039
Email	dj106@cam.ac.uk

Study information

Primary study design	Interventional
Study design	Two-by-two factorial design randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Plasma exchange and glucocorticoid dosing in the treatment of antineutrophil cytoplasm antibody associated vasculitis: an international randomised controlled trial
Study acronym	PEXIVAS
Study objectives	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(s)	Ethics Board: NRES Committee London – Harrow, 30/10/2009, Ref: 09/H0709/56
Health condition(s) or problem(s) studied	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
Primary outcome measure(s)	Death or end-stage renal disease. Timepoint for all analyses is the common closeout date (2 years after the last patient is enrolled).
Key secondary outcome measure(s)	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).
Completion date	31/07/2018

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Target sample size at registration	700
Total final enrolment	704
Key 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
Key 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
Date of first enrolment	30/09/2016
Date of final enrolment	31/07/2017

Locations

Countries of recruitment

United Kingdom
England
Australia
Canada
Czech Republic
Denmark
France
Germany
Italy
Mexico
Netherlands
New Zealand
Spain
Sweden
Switzerland
United States of America

Study participating centre

Addenbrooke's Hospital

Cambridge
CB2 0QQ
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	13/02/2020	14/02/2020	Yes	No
Results article		01/09/2022	27/09/2022	Yes	No
Protocol article	protocol	14/03/2013		Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

27/09/2022: Publication reference added.
14/02/2020: Publication reference added.
13/11/2019: The intention to publish date was changed from 01/12/2017 to 31/05/2020.
30/10/2019: The exclusion criteria were updated.
14/05/2019: Publication reference and total final enrolment added.
21/03/2018: Secondary outcome measures were updated.
15/03/2018: The following changes were made:
1. The target number was changed from 500 to 700
2. The recruitment end date was updated from 30/09/2016 to 31/07/2017.
3. Telephone number for primary contact was updated.
4. Sponsor email address was changed from julie.uttridge@addenbrookes.nhs.uk to louise.stockley@addenbrookes.nhs.uk
13/11/2017: The recruitment end date has been updated from 01/11/2016 to 30/09/2016. The overall trial end date has been updated from 01/11/2016 to 31/07/2018. The participant level data sharing statement has been added.
07/07/2016: Plain English summary added.