The RAVE Trial studied Rituxan compared with cyclophosphamide (CYC) followed by azathioprine (AZA) for the induction of remission in Granulomatosis with Polyangiitis and Microscopic Polyangiitis1
A multicenter, randomized, double-blind, double-dummy, noninferiority trial1
- Compared Rituxan (rituximab) to cyclophosphamide (CYC) followed by azathioprine (AZA) for complete remission induction.1
Primary end point: Complete Remission was defined as no disease activity (defined as BVAS/GPA of 0)* and successful tapering off of prednisone by Month 6.1
- The RAVE Trial included patients with1:
- Granulomatosis with Polyangiitis (GPA) or Microscopic Polyangiitis (MPA)
- Newly diagnosed or relapsing disease
- MPO or PR3 ANCA-positivity at baseline
Treatment arms were randomized with the objective of similar baseline demographic and disease characteristics. Notable baseline information includes1:
- Mean age of patients at onset of symptoms1
- Rituxan group 54.0 years (ranged from 16 to 92)
- CYC group 51.5 years (ranged from 15 to 80)
- A total of 197 patients completed the study1
- 99 patients received Rituxan plus glucocorticoids and CYC placebo
- 98 patients received CYC plus glucocorticoids and Rituxan placebo followed by AZA maintenance regimen at remission
The RAVE Trial was conducted by the Immune Tolerance Network and sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Genentech and Biogen Idec also provided funding and study drug.1
- The randomization was stratified by clinical study center and type of ANCA (PR3 or MPO). Patients were assigned 1:1 and balanced according to disease type, newly diagnosed or relapsing disease, disease activity, organ involvement, pre-enrollment therapy, past exposure to cyclophosphamide, and total glucocorticoids administered in the interval from 14 days before informed consent was obtained to first investigational infusion.
- The BVAS/GPA (Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis) is a validated tool that quantifies disease activity based on evidence of active disease in 8 organ systems, an "other" category, and a physician's global assessment. Disease features are scored only if they are attributed to active vasculitis, as opposed to damage. Adapted from Stone et al.2
- BVAS/GPA≥3, severe disease.
- BVAS/GPA=0, patients reaching clinical remission with no disease activity.
- Stone JH, Merkel PA, Spiera R, et al; for the RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.
- Stone JH, Hoffman GS, Merkel PA, et al; for the International Network for the Study of the Systemic Vasculitides (INSSYS). A disease-specific activity index for Granulomatosis with Polyangiitis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum. 2001;44(4):912-920.
- Rituxan® (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)
- Limitations of Use: Rituxan is not recommended for use in patients with severe, active infections
BOXED WARNINGS and Additional Important Safety Information
Infusion Reactions: Rituxan administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions.
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.
Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan. Discontinue Rituxan and concomitant medications in the event of HBV reactivation.
Progressive Multifocal Leukoencephalopathy (PML): PML, including fatal PML, can occur in patients receiving Rituxan. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Warnings and Precautions
Tumor Lysis Syndrome (TLS): Administer aggressive intravenous hydration and anti hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after Rituxan exposure). Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy.
Cardiovascular: Discontinue infusions for serious or life threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.
Immunization: The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live vaccines is not recommended. For RA patients, physicians should follow current immunization guidelines and administer non-live vaccines at least 4 weeks prior to a course of Rituxan.
Laboratory Monitoring: Obtain complete blood counts (CBC) and platelet counts at 2- to 4-month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period.
Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate in RA, GPA, and MPA: Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in RA patients exhibiting peripheral B-cell depletion following treatment with Rituxan. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituxan.
Retreatment in Patients With Granulomatosis With Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA): Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with GPA and MPA. In the active-controlled, double-blind study, subsequent courses of Rituxan were allowed for patients experiencing a relapse of disease. The safety and efficacy of retreatment with Rituxan have not been established.
Adverse reactions reported in ≥15% of Rituxan-treated patients vs cyclophosphamide-treated patients were infections (62% vs 47%), nausea (18% vs 20%), diarrhea (17% vs 12%), headache (17% vs 19%), muscle spasms (17% vs 15%), anemia (16% vs 20%), and peripheral edema (16% vs 6%), respectively.
Infusion Reactions: In the active-controlled, double-blind study, 12% vs 11% (Rituxan-treated vs cyclophosphamide), of patients experienced at least one infusion-related reaction. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituxan group, the proportion of patients experiencing an infusion-related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each Rituxan infusion and were on background oral corticosteroids which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
Infections: In the active-controlled, double-blind study, 62% vs 47% (Rituxan-treated vs cyclophosphamide, respectively) of patients experienced an infection by Month 6. The most common infections in the Rituxan group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% vs 10% (Rituxan-treated vs cyclophosphamide, respectively), with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.
Hypogammaglobulinemia: Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit or normal) has been observed in patients with GPA and MPA treated with Rituxan. At 6 months, in the Rituxan group, 27%, 58%, and 51% of patients with normal immunoglobulin levels at Baseline had low IgA, IgG, and IgM levels, respectively compared to 25%, 50%, and 46% in cyclophosphamide group.
Immunogenicity: A total of 23/99 (23%) Rituxan-treated patients with GPA or MPA tested positive for HACA by 18 months. The clinical relevance of HACA formation in Rituxan-treated patients is unclear.
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.