RAVE
Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis
Year of Publication: 2010
Authors: John H. Stone, Peter A. Merkel, Robert Spiera, ..., Ulrich Specks
Journal: New England Journal of Medicine
Citation: N Engl J Med 2010;363:221-32
Link: https://doi.org/10.1056/NEJMoa0909905
PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true
PDF: Clinical Question
Is rituximab plus glucocorticoids non-inferior to cyclophosphamide plus glucocorticoids for remission induction in severe ANCA-associated vasculitis?
Study Overview
Objective
To compare rituximab versus cyclophosphamide for remission induction in severe ANCA-associated vasculitis
Study Summary
- Rituximab was non-inferior to cyclophosphamide for inducing remission (64% vs 53%)
- Rituximab was superior in patients with relapsing disease (67% vs 42%)
- Both treatments had similar safety profiles and effectiveness for severe renal disease and alveolar hemorrhage
Intervention
Rituximab 375 mg/m² weekly for 4 weeks vs daily cyclophosphamide 2 mg/kg
Patients per Arm
99 rituximab, 98 control
Bottom Line
Rituximab was non-inferior to cyclophosphamide for inducing remission in severe ANCA-associated vasculitis and may be superior in patients with relapsing disease.
Major Points
- Multicenter, randomized, double-blind, double-dummy, noninferiority trial comparing rituximab vs cyclophosphamide
- 197 ANCA-positive patients with Wegener's granulomatosis or microscopic polyangiitis enrolled
- Primary endpoint was complete remission (BVAS/WG=0) without prednisone at 6 months
- 64% of rituximab patients vs 53% of cyclophosphamide patients achieved primary endpoint
- Rituximab was significantly more effective in relapsing disease subgroup (67% vs 42%)
- Both treatments equally effective for major renal disease and alveolar hemorrhage
- No significant differences in overall adverse events between groups
Design
Study Type: Randomized controlled trial
Randomization: 1
Blinding: Double-blind, double-dummy design with patients, investigators, and outcome assessors blinded
Enrollment Period: December 30, 2004 to June 30, 2008
Follow-up Duration: 6 months
Centers: 9
Countries: United States, Netherlands
Sample Size: 197
Analysis: Intention-to-treat analysis, noninferiority testing with 95.1% confidence intervals, logistic regression for adjusted analyses
Inclusion Criteria
- Wegener's granulomatosis or microscopic polyangiitis diagnosis
- Positive serum proteinase 3-ANCA or myeloperoxidase-ANCA
- Manifestations of severe disease
- BVAS/WG score ≥3
- Either newly diagnosed or relapsing disease
Exclusion Criteria
- Limited Wegener's granulomatosis
- ANCA-negative patients
- Alveolar hemorrhage severe enough to require ventilatory support
- Advanced renal dysfunction (serum creatinine >4.0 mg/dL)
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age at onset | 51.5±14.1 years | 54.0±16.8 years |
| Male sex | 54% | 46% |
| Wegener's granulomatosis | 76% | 75% |
| Microscopic polyangiitis | 24% | 24% |
| Newly diagnosed | 49% | 48% |
| BVAS/WG score | 8.2±3.2 | 8.5±3.2 |
| Renal involvement | 66% | 66% |
| Pulmonary involvement | 54% | 52% |
| Alveolar hemorrhage | 24% | 27% |
| Proteinase 3-ANCA | 66% | 67% |
| Myeloperoxidase-ANCA | 34% | 32% |
Arms
| Field | Control | Rituximab Group |
|---|---|---|
| Intervention | Daily cyclophosphamide 2 mg/kg (adjusted for renal insufficiency) plus glucocorticoids with option to switch to azathioprine 2 mg/kg/day between 3-6 months if in remission | Rituximab 375 mg/m² weekly for 4 weeks plus glucocorticoids with placebo cyclophosphamide/azathioprine |
| Duration | 6 months | 6 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| BVAS/WG of 0 and successful completion of prednisone taper at 6 months | Primary | 52/98 (53%) | 63/99 (64%) | 10 | P<0.001 for noninferiority, P=0.09 for superiority |
| Complete remission with prednisone <10 mg/day | Secondary | 61/98 (62%) | 70/99 (71%) | P=0.10 | |
| Severe disease flares | Secondary | 10 patients | 6 patients | P=0.30 | |
| Limited disease flares | Secondary | 15 flares in 14 patients | 13 flares in 11 patients | P=0.81 | |
| Selected adverse events | Adverse | 32/98 (33%) | 22/99 (22%) | P=0.01 | |
| Grade 2+ leukopenia | Adverse | 10 events | 3 events | ||
| Deaths | Adverse | 2 | 1 | ||
| Hospitalizations | Adverse | 2/98 (2%) | 8/99 (8%) |
Subgroup Analysis
Among patients with relapsing disease at baseline, rituximab was significantly more efficacious: 34/51 (67%) vs 21/50 (42%) achieved primary endpoint (P=0.01). No significant differences were found for newly diagnosed patients, different ANCA types, or patients with major renal disease or alveolar hemorrhage.
Criticisms
- Only enrolled ANCA-positive patients with severe disease, limiting generalizability
- Excluded patients with very severe alveolar hemorrhage requiring ventilation
- Excluded patients with advanced renal dysfunction (creatinine >4.0 mg/dL)
- Six-month follow-up may be too short to detect long-term cyclophosphamide toxicities
- Did not address retreatment strategies with rituximab
- Lower remission rates than other vasculitis trials due to requirement for complete glucocorticoid discontinuation
Funding
National Institute of Allergy and Infectious Diseases, Genentech, and Biogen
Based on: RAVE (New England Journal of Medicine, 2010)
Authors: John H. Stone, Peter A. Merkel, Robert Spiera, ..., Ulrich Specks
Citation: N Engl J Med 2010;363:221-32
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