RITUXAN + GCC WAS STUDIED IN GPA & MPA PATIENTS IN THE RAVE AND MAINRITSAN TRIALS

RAVE Trial study design

  • 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 glucocorticoids[21]
  • 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 months[18,21]

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.[21]

Trial design

RAVE Trial design: Multicenter, randomized, double-blind, double dummy[18,21]

AZA, azathioprine; CYC, cyclophosphamide; GCC, glucocorticoids; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis.
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.[19]
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.
||Follow-up treatment continued unless patient experienced relapse.

RAVE Trial population

Key inclusion and exclusion criteria from the RAVE Trial[20,21]

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

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.[19]

RAVE Trial: Study enrollment, randomization and completion to 18 months[19]

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 included[18]:

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

Baseline Patient Information[21]*

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 withrelapsed 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.


MAINRITSAN TRIAL STUDY DESIGN

  • 28-month, multicenter, randomized, controlled, open-label study of the rituximab regimen versus AZA for follow‑up treatment in 115 patients (86 with GPA, 24 with MPA, and 5 with renal‑limited ANCA‑associated vasculitis)[18]
  • Disease control was achieved using a combination of GCC and CYC. Within a maximum of 1 month after the last CYC dose, eligible patients (based on BVAS of 0), were randomized in a 1:1 ratio to receive either EU‑approved rituximab or AZA[18]
  • Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatment after Month 18 were left to the investigator’s discretion[18]

Rituximab regimen=Roche-manufactured, EU-approved rituximab + GCC.
AZA, azathioprine; CYC, cyclophosphamide; EU, European Union; GCC, glucocorticoids.

Dosing schedule

  • 500 mg of EU-approved rituximab + GCC administered at Days 1 and 15; Months 6, 12, and 18[18]*
  • 2 mg/kg/d of AZA + GCC administered at Months 0-12; 1.5 mg/kg/d at Months 12-18; 1 mg/kg/d through Month 22[18]*

AZA, azathioprine; CYC, cyclophosphamide; GCC, glucocorticoids
*GCC tapered to a low dose for ≥18 months postrandomization. Tapering and discontinuation after Month 18 at investigator's discretion.
Major relapse was defined by the reappearance of clinical and/or laboratory signs of vasculitis activity (BVAS>0) that could lead to organ failure or damage, or could be life-threatening.

MAINRITSAN Trial population data

INCLUSION CRITERIA EXCLUSION CRITERIA

18 to 75 years of age

Newly diagnosed or relapsing GPA, MPA, or renal-limited ANCA-associated vasculitis in disease control (BVAS score of 0) after GCC and pulse CYC treatment

ANCA-positive at diagnosis or during disease course and/or histologically confirmed to have necrotizing small-vessel vasculitis

Previous treatment with Rituxan or other biologic

  • Vital-organ involvement in the rituximab-regimen treated group at diagnosis or last flare included:[18]

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

ANCA, antineutrophil cytoplasmic antibody; CYC, cyclophosphamide; GCC, glucocorticoids.

MAINRITSAN Trial baseline patient characteristics[18]

ANCA, antineutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide.
*Follow-up treatment with Rituxan may be used in patients who have achieved disease control with Rituxan or with other immunosuppressants.[18]
Plus-minus values are means ±SD. Categorical data were compared with the use of two-by-two tables or Fisher’s exact test; continuous data were analyzed with Student’s t-test or the Wilcoxon rank-sum test. ANCA denotes antineutrophil cytoplasm antibody, ELISA enzyme-linked immunosorbent assay, and GFR glomerular filtration rate (calculated according to the Modification of the Diet in Renal Disease equation).[14]
Data were missing for one patient.[14]
§Indirect immunofluorescence data were missing for 5 patients, and ELISA data were missing for 8 patients.[14]