An international, randomised, open label trial comparing a rituximab-based regimen with a standard cyclophosphamide/azathioprine based regimen in the treatment of active, generalised anti-neutrophilic cytoplasmic antibodies associated vasculitis

ISRCTN	ISRCTN28528813
DOI	https://doi.org/10.1186/ISRCTN28528813
Secondary identifying numbers	N/A

Submission date: 21/09/2005
Registration date: 13/03/2006
Last edited: 06/03/2015

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Circulatory System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Not provided at time of registration

Study website

Contact information

Dr Jayne David
Scientific

Box 118
Department of Renal Medicine
Addenbrooke's Hospital
Hills Road
Cambridge
CB2 2QQ
United Kingdom

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Not specified
Study type	Treatment
Scientific title	An international, randomised, open label trial comparing a rituximab-based regimen with a standard cyclophosphamide/azathioprine based regimen in the treatment of active, generalised anti-neutrophilic cytoplasmic antibodies associated vasculitis
Study acronym	RITUXVAS
Study hypothesis	Rituximab leads to a higher rate of sustained remission compared to standard therapies (cyclophosphamide/azathioprine) with a lower rate of severe adverse events and reduced cyclophosphamide exposure
Ethics approval(s)	Not provided at time of registration
Condition	ANCA-associated vasculitis
Intervention	Drug regimens: 1. Rituximab regimen: rituximab, 375 mg/m2 IV once a week for four weeks (i.e. four doses total), with two doses of cyclophosphamide 15 mg/kg, two weeks apart given with the first and third rituximab dose 2. Control (cyclophosphamide/azathioprine) regimen: cyclophosphamide 15 mg/kg for 3-6 months (6-10 doses total) to be given intravenously according to protocol for remission induction. Cyclophosphamide should be converted to azathioprine for remission maintenance. 3. Steroids: all patients will receive 1 g IV methylprednisolone, then same daily oral corticosteroid regimen 4. Plasma exchange or IV methylprednisolone will be allowed according to local practice for patients with organ threatening disease. Randomisation should not occur until completion of plasma exchange to avoid loss of rituximab during plasma exchange. The first dose of cyclophosphamide can be given prior to completion of plasma exchange.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Rituximab, cyclophosphamide, azathioprine
Primary outcome measure	1. Sustained remission (Birmingham Vasculitis Assessment Score [BVAS] = 0 at six months and sustained for six months) 2. Severe adverse events (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥3) at two years
Secondary outcome measures	1. Efficacy 1.1. Response rate at six weeks (BVAS <50% baseline) 1.2. Remission at six months (BVAS = 0 for 2 months by 6 months) 1.3. Time to remission (BVAS = 0) 1.4. Relapses (all relapses and major or minor) 1.5. BVAS area under the curve 1.6. Change in Glomerular Filtration Rate (GFR) 1.7. Change in SF-36 1.8. Change in Venous Distensibility Index (VDI) 2. Safety 2.1. Severe adverse events (CTCAE grade ≥3) at six weeks and six months 2.2. All adverse events 2.3. Death 2.4. Prednisolone cumulative dose 2.5. Cyclophosphamide cumulative dose
Overall study start date	01/11/2005
Overall study end date	01/11/2008

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	40
Participant inclusion criteria	1. A new diagnosis of Wegener's Granulomatosis (WG), Microscopic Polyangiitis (MP) or Renal-Limited Vasculitis (RLV) 2. Renal involvement attributable to active WG, MP or RLV with at least one of the following: 2.1. Biopsy demonstrating necrotizing glomerulonephritis 2.2. Red cell casts on urine microscopy or ≥++ haematuria 3. Anti-Neutrophilic Cytoplasmic Antibodies (ANCA) positivity; ANCA positivity requires either: 3.1. Proteinase 3 anti-neutrophilic cytoplasmic antibody (PR3-ANCA) by Enzyme-Linked Immunosorbent Assay (ELISA) or a typical antineutrophil cytoplasmic antibody (cANCA) pattern by indirect immunofluorescence (IIF), or both 3.2. Myeloperoxidase- anti-neutrophilic cytoplasmic antibody (MPO-ANCA) by ELISA. A positive perinuclear anti-neutrophilic cytoplasmic antibody (pANCA) by IIF requires confirmation by MPO-ANCA ELISA 4. Written informed consent
Participant exclusion criteria	1. Previous cyclophosphamide, (greater than two weeks of an oral or intravenous [IV] pulse cyclophosphamide regimen) 2. Co-existence of another multisystem autoimmune disease, e.g. SLE, Churg Strauss syndrome, Henoch Schonlein purpura, rheumatoid vasculitis, essential mixed cryoglobulinaemia, anti-glomerular basement membrane antibody positivity 3. Hepatitis B antigen positive or hepatitis C antibody positive 4. Known HIV positive (HIV testing will not be a requirement for this trial) 5. Previous malignancy (usually exclude unless agreed with trial co-ordinator) 6. Pregnancy, breast feeding or inadequate contraception if female 7. Allergy to a study medication 8. Live vaccine within last four weeks
Recruitment start date	01/11/2005
Recruitment end date	01/11/2008

Locations

Countries of recruitment

Australia
Czech Republic
England
Germany
Mexico
Netherlands
Sweden
Switzerland
United Kingdom

Study participating centre

Addenbrooke's Hospital

Cambridge
CB2 2QQ
United Kingdom

Sponsor information

Cambridge University Hospitals NHS Foundation Trust (UK)
Hospital/treatment centre

Box 146
Addenbrooke's Hospital
Hills Road
Cambridge
CB2 2QQ
England
United Kingdom

"ROR"	https://ror.org/04v54gj93

Funders

Funder type

Industry

Research grant provided by Hoffman La Roche to investigator own account - vasculitis research account

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	15/07/2010		Yes	No
Results article	results	01/06/2015		Yes	No