• The RAVE Trial was a multicenter, randomized, double-blind, double-dummy, noninferiority trial to compare Rituxan (n=99) with CYC (n=98) for the induction of complete remission at 6 months in patients with severe GPA or MPA. Each arm included treatment with glucocorticoids1
  • Primary end point of noninferiority was complete remission, which was defined as a BVAS/GPA* of 0 and a complete taper of steroids, at 6 months1,2
 
The RAVE Trial was conducted by the Immune Tolerance Network and sponsored by the National Institute of Allergic and Infectious Diseases, part of the National Institutes of Health. Genentech and Biogen also provided funding and study medication.1

Trial design

RAVE Trial design: Multicenter, randomized, double-blind, double-dummy1,2

RAVE Trial design
Study Design
Primary end point was complete remission (defined as BVAS/GPA* of 0 and prednisone dose of 0 by Month 6).1,2
  • The Rituxan group received IV Rituxan (at a dose of 375 mg/m2/wk for 4 weeks) plus daily placebo-CYC1
  • The control group received placebo-Rituxan infusions plus daily CYC (2 mg/kg, adjusted for renal insufficiency)1
  • Patients in the control group who had a remission between 3 and 6 months were eligible to switch from CYC to AZA1
  • Maintenance therapy continued unless patient experienced relapse
  • The two treatment groups received the same glucocorticoid regimen: 1–3 pulses of methylprednisolone (1000 mg each), followed by prednisone1
  • The dose was tapered so that by 5 months, all patients who had a remission without disease flares had discontinued GCC1
  • The crossover design allowed patients with certain types of treatment failure (severe flare or limited flare that would normally require CYC between Week 5 and the Month 6 visit) to switch to the opposite treatment regimen1
  • AZA, azathioprine; CYC, cyclophosphamide; GCC, glucocorticoids.
  • Adapted from Stone N Engl J Med 2010.
*
The BVAS/GPA 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.4
The crossover design allowed patients who had severe flares during the first 6 months to cross over to the other treatment group in a blinded fashion.
CYC dose was adjusted for patients with renal insufficiency.
§
Patients who had a remission between 3 and 6 months were eligible to switch from CYC to AZA.
||
Maintenance therapy continued unless patient experienced relapse.
  • AZA, azathioprine; CYC, cyclophosphamide; BVAS/GPA, Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis; GCC, glucocorticoids.
*
The BVAS/GPA 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.4

 

RAVE Trial population

Key inclusion and exclusion criteria from the RAVE Trial1,3

INCLUSION CRITERIA EXCLUSION CRITERIA
  • Diagnosis of GPA or MPA (Chapel Hill criteria)
  • Newly diagnosed or relapsing disease
  • Active disease: BVAS/GPA* ≥3
  • Severe disease: ≥1 major BVAS/GPA item or disease severe enough to require treatment with CYC
  • Positive serum assay for PR3-ANCA or MPO-ANCA
  • Limited disease not requiring CYC
  • Mechanical ventilation for alveolar hemorrhage
  • Serum creatinine >4.0 mg/dL
  • CYC use within 4 months before enrollment
  • CYC toxicity
  • Any previous Rituxan use
INCLUSION CRITERIA
  • Diagnosis of GPA or MPA (Chapel Hill criteria)
  • Newly diagnosed or relapsing disease
  • Active disease: BVAS/GPA* ≥3
  • Severe disease: ≥1 major BVAS/GPA item or disease severe enough to require treatment with CYC
  • Positive serum assay for PR3-ANCA or MPO-ANCA
EXCLUSION CRITERIA
  • Limited disease not requiring CYC
  • Mechanical ventilation for alveolar hemorrhage
  • Serum creatinine >4.0 mg/dL
  • CYC use within 4 months before enrollment
  • CYC toxicity
  • Any previous Rituxan use
ANCA, antineutrophil cytoplasmic antibody; CYC, cyclophosphamide; MPO, myeloperoxidase; PR3, proteinase 3.
*
The Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA). For new or worse disease ranges from 0 to 68, with higher scores indicating more active disease. A BVAS/GPA of 0 indicates remission.4

 

RAVE Trial: Study enrollment, randomization and completion to 18 months4

RAVE Trial: Study enrollment, randomization and completion to 18 months RAVE Trial: Study enrollment, randomization and completion to 18 months
  • AZA, azathioprine; CYC, cyclophosphamide.

RAVE Trial inclusion criteria: BVAS/GPA ≥3 with any organ involvement

  • Vital-organ involvement in the Rituxan-treated group at Baseline included2:
  • 52% Major Renal Disease
  • 61% Ears, Nose, and Throat
  • 27% Alveolar Hemorrhage

RAVE Trial was not powered to determine whether results were consistent across subgroups


Baseline Patient Information1*

VARIABLE RITUXAN
(n=99)
CYC FOLLOWED BY AZA
(n=98)
Age at onset of symptoms, years 54.0 ± 16.8 51.5 ± 14.1
Sex, %    
Male 46 54
Female 54 46
Race or ethnic group, %    
White 92 95
Black 3 3
Asian 1 0
Other 4 2
Ethnic group, %    
Not Hispanic or Latino 92 95
Hispanic or Latino 6 3
Unknown 2 2
ANCA-associated vasculitis, %    
Granulomatosis with polyangiitis 75 76
Microscopic polyangiitis 24 24
Indeterminate 1 0
Newly diagnosed at enrollment, % 48 49
Pre-enrollment disease duration in patients with relapse disease, years 6.5 ± 6.7 5.3 ± 7.4
Pre-enrollment exposure to cyclophosphamide in patients with relapsed disease, % 82 74
Disease-assessment scores    
BVAS/GPA 8.5 ± 3.2 8.2 ± 3.2
Physician’s global assessment 5.7 ± 2.4 5.6 ± 2.4
Vasculitis Damage Index 1.4 ± 1.8 1.0 ± 1.4
SF-36§    
Physical component 37.2 ± 9.8 38.6 ± 11.9
Mental component 41.7 ± 13.2 44.0 ± 11.4
Organ involvement    
Constitutional signs or symptoms, % 56 66
Cutaneous involvement, % 20 16
Mucous membranes and eyes, % 27 26
Ear, nose and throat, % 61 56
Pericarditis, % 0 1
Mesenteric ischemia, % 2 0
Pulmonary involvement, % 52 54
Alveolar hemorrhage 27 24
Endobronchial lesions 4 9
Nodules or cavities 18 28
Other lung infiltrate 25 21
Pleurisy 8 9
Respiratory failure 2 0
Renal Involvement, %|| 66 66
Hematuria, % 28 29
Red cell casts, % 37 36
Creatinine clearance, mL/min 54 ± 3 69 ± 4
Neurologic involvement, % 25 15
Cranial-nerve palsy 0 1
Meningitis 1 0
Motor mononeuritis multiplex 11 9
Sensory peripheral neuropathy 22 13
ANCA-positive at diagnosis, %    
By immunofluorescence    
All 98 96
C-ANCA 66 62
P-ANCA 33 34
By ELISA    
All 98 100
Proteinase 3 ANCA 67 66
Myeloperoxidase-ANCA 32 34
Mean dose of glucocorticoids from 14 days before consent provided to first infusion of study drug    
Methylprednisolone, g 0.8 ± 1.28 0.7 ± 1.10
Prednisone, mg 253.6 ± 236.5 296.1 ± 266.2
  • ANCA, antineutrophil cytoplasmic antibody; AZA, azathioprine; C-ANCA, cytoplasmic ANCA-labeling pattern; CYC, cyclophosphamide; ELISA, enzyme-linked immunosorbent assay; MPO, myeloperoxidase; P-ANCA, perinuclear ANCA-labeling pattern; PR3, proteinase 3.
  • Adapted from Stone N Engl J Med 2010.
*
Plus–minus values are means ±SD, except for the values for creatinine clearance, which are means ±SE. Race and ethnic group were self-reported. The chi-square test or Fisher’s exact test was used for the comparison of categorical data, and Student’s t-test or the Wilcoxon rank-sum test was used for the analysis of continuous data.
American College of Rheumatology Criteria were used for the classification of Granulomatosis with Polyangiitis.
The Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA). For new or worse disease ranges from 0 to 68, with higher scores indicating more active disease. A BVAS/GPA of 0 indicates remission.3
§
Scores on the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), version 2, range from 0 to 100, with higher scores indicating better health. A score of 50 represents the mean score for the US population.
Constitutional signs or symptoms of disease activity included arthritis, arthralgias, and fever (temperature ≥38.0°C).
||
On the BVAS/GPA instrument, hematuria is not scored if red cell casts are present or a renal-biopsy specimen shows active glomerulonephritis at the same time.

INDICATION

  • 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)

BOXED WARNINGS and Additional Important Safety Information

BOXED WARNINGS

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. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

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), 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): Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan in patients with Non–Hodgkin’s Lymphoma (NHL). 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. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections.

Cardiovascular Adverse Reactions: 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.

Renal Toxicity: Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with Non–Hodgkin’s Lymphoma (NHL). Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria.

Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

Immunization: The safety of immunization with live viral vaccines following Rituxan therapy has not been studied, and vaccination with live vaccines is not recommended before or during treatment.

Embryo-Fetal Toxicity: Rituxan can cause fetal harm due to B-cell lymphocytopenia in infants exposed to Rituxan in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving Rituxan and for 12 months following the last dose of Rituxan.

Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate: 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) and Microscopic Polyangiitis (MPA): Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with GPA and MPA. The safety and efficacy of retreatment with Rituxan have not been established.

Adverse Reactions

Clinical Trials Experience in GPA and MPA

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 premedicated 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-treated, 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 of 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 anti-rituximab antibodies by 18 months. The clinical relevance of anti-rituximab antibody formation in Rituxan-treated patients is unclear.

You may report side effects to the FDA at (800) FDA-1088 (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555(888) 835-2555.

For additional Important Safety Information, please see the Rituxan full Prescribing Information, including BOXED WARNINGS.

Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion.

REFERENCES
1.
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. Download Article
2.
Rituxan [package insert]. South San Francisco, CA: Biogen and Genentech Inc.; April 2016.
3.
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 Wegener’s Granulomatosis: Modification of the Birmingham Vasculitis Activity Score. Arth Rheum. 2001;44(4):912-920.
4.
Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417-427.
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