RAVE
(2010)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
• 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
Inclusion Criteria
ANCA-positive Wegener's granulomatosis or microscopic polyangiitis with severe disease and BVAS/WG ≥3
Study Design
Arms: Rituximab group (n=99) vs Control/Cyclophosphamide group (n=98)
Patients per Arm: 99 rituximab, 98 control
Outcome
• Primary: Complete remission without prednisone at 6 months
• Secondary: Disease flares, adverse events, quality of life measures
• Rituximab met non-inferiority criteria and showed superiority in relapsing disease
• Secondary: Disease flares, adverse events, quality of life measures
• Rituximab met non-inferiority criteria and showed superiority in relapsing disease
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
Study Design
- Study Type
- Randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy design with patients, investigators, and outcome assessors blinded
- Sample Size
- 197
- Follow-up
- 6 months
- Centers
- 9
- Countries
- United States, Netherlands
Primary Outcome
Definition: BVAS/WG of 0 and successful completion of prednisone taper at 6 months
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 52/98 (53%) | 63/99 (64%) | - (-3.2 to 24.3 percentage points) | P<0.001 for noninferiority, P=0.09 for superiority |
Limitations & 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
Citation
N Engl J Med 2010;363:221-32