Rituxan, in combination with glucocorticoids, was proven non-inferior to induce remission compared with cyclophosphamide

RAVE TRIAL DESIGN

Objective

The RAVE Trial studied Rituxan compared with cyclophosphamide (CYC) followed by azathioprine (AZA) for the induction of remission in Granulomatosis with Polyangiitis and Microscopic Polyangiitis.1

  • This study was a multicenter, randomized, double-blind, double-dummy, noninferiority trial to compare Rituxan (rituximab) with CYC followed by AZA for complete remission induction1
  • Treatment arms were randomized with the objective of similar Baseline demographic and disease characteristics1
  • Participants: 197 antineutrophil cytoplasmic antibody (ANCA)-positive patients diagnosed with Granulomatosis with Polyangiitis (GPA) or Microscopic Polyangiitis (MPA)1
 
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 Idec 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 defined as 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-cyclophosphamide (CYC)1
  • 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 azathioprine (AZA)1
  • 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 glucoconicoids1
  • 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.
  • Adapted from Stone N Engl J Med 2010.
*
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 regimen.
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.
||
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.
  • BVAS/GPA ≥3, severe disease.
  • BVAS/GPA=0, patients reaching clinical remission with no disease activity.3

 

 
Primary end point was defined as complete remission (defined as BVAS/GPA of 0* and prednisone dose of 0 by Month 6).1,2
*
GPA or MPA.

RAVE Trial: Key Inclusion/Exclusion Criteria

INCLUSION1 EXCLUSION1
  • Active severe ANCA-associated GPA or MPA
    • BVAS/GPA* and MPA ≥ 3
    • At least 1 major BVAS/GPA item or deemed severe enough to require CYC
  • Chapel Hill criteria: Newly diagnosed or relapsing disease patients eligible
  • 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 prior to enrollment
  • CYC toxicity or unresponsiveness
  • Any previous Rituxan use
INCLUSION1
  • Active severe ANCA-associated GPA or MPA
    • BVAS/GPA* and MPA ≥ 3
    • At least 1 major BVAS/GPA item or deemed severe enough to require CYC
  • Chapel Hill criteria: Newly diagnosed or relapsing disease patients eligible
  • Positive serum assay for PR3-ANCA or MPO-ANCA
EXCLUSION1
  • Limited disease not requiring CYC
  • Mechanical ventilation for alveolar hemorrhage
  • Serum creatinine >4.0 mg/dL
  • CYC use within 4 months prior to enrollment
  • CYC toxicity or unresponsiveness
  • Any previous Rituxan use
ANCA, anti-neutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide; eGFR, estimated Glomerular Filtration Rate; MPO, myeloperoxidase; PR3, proteinase 3.
*
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.
BVAS/GPA ≥3, severe disease.
BVAS/GPA=0, patients reaching clinical remission with no disease activity.3

 

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.

Baseline Demographics and Clinical Characteristics of Patients

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
Inderminate 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 ± 3.2
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; CYC, cyclophosphamide; ELISA, enzyme-linked immunosorbent assay.
  • 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. ANCA denotes antineutrophil cytoplasmic antibody, C-ANCA cytoplasmic ANCA-labeling pattern, ELISA enzyme-linked immunosorbent assay, and P-ANCA perinuclear ANCA-labeling pattern.
American College of Rheumatology Criteria were used for the classification of Granulomatosis with Polyangiitis.
The Birmingham Vasculitis Score for Granulomatosis with Polyangiitis (BVAS/GPA). For new or worse disease ranges from 0 to 67, with higher scores indicating more active disease. A BVAS/GPA of 0 indicates remission.
§
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 U.S. 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 STATEMENT

  • 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

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.

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.

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. 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

Granulomatosis With Polyangiitis and Microscopic Polyangiitis

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 (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 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 Idec Inc. and Genentech Inc.; September 2013.
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.