The purpose of this study is to investigate, after achievement of remission, the efficacy of rituximab compared with azathioprine maintenance therapy on duration of remission, in patients with relapsing or newly-diagnosed Eosinophilic granulomatosis with polyangiitis EPGA receiving standard of care therapy including glucocorticoid therapy reduction/withdrawal.
Rituximab, an anti-CD20 monoclonal antibody, has been shown to be as effective as cyclophosphamide to induce GPA and MPA remission, with an acceptable safety profile, leading to its registration by the FDA and EMA as remission-induction therapy in these patients. In addition, the MAINRITSAN trial has demonstrated that 500 mg rituximab given every 6 months for 18 months was significantly more effective than azathioprine standard of care to maintain remission in patients with GPA or MPA, with a similar profile of tolerance. EGPA patients were excluded from these trials. Long-term studies have shown that only 29% of EGPA patients achieved long-term remission and that relapses occurred in more than 40% of them, leading to high cumulative morbidity and damage. Moreover, most patients cannot be weaned off corticosteroids due to asthma and rhino-sinusal manifestations, even after vasculitis remission. However, recent retrospective series indicated that rituximab may also be an effective remission induction and maintenance agent in refractory or relapsing EGPA. REOVAS, the first randomized controlled trial with rituximab as induction therapy in EGPA, has started within the French Vasculitis Study Group network. The MAINRITSEG trial is a phase III, comparative, multicenter, randomized, double-blind, double-dummy and superiority trial, comparing pre-emptive low-dose rituximab-based regimen with azathioprine standard therapy, for the remission maintenance in newly-diagnosed or relapsing EGPA. Patients, with newly diagnosed or relapsing EGPA, after achievement of remission, will be randomized in a 1:1 ratio to receive: * Standard regimen: maintenance oral azathioprine (2 mg/kg/day) for 24 months. This control group will receive conventional therapy plus 4 infusions of placebo-rituximab (every 6 months for 18 months) * Experimental regimen: pre-emptive 500-mg fixed-dose of rituximab every 6 months for 18 months (4 infusions). This group will receive intravenous rituximab plus orally placebo-azathioprine for 24 months. All patients will receive standard of care therapy including glucocorticoid therapy reduction/withdrawal.
Study Type
INTERVENTIONAL
Allocation
pre-emptive 500-mg fixed-dose of IV rituximab every 6 months (total duration of 18 months = 4 infusions)
oral tablets : 2 mg/kg/day for 24 months
4 infusions for 18 months
Hôpital Cochin
Paris, Paris, France
Duration of remission in weeks
accrued number of weeks where a patient remains in remission with BVAS=0 and prednisone dose ≤7.5 mg/day
Time frame: 28 months
proportion of patients remaining in remission with a BVAS=0 and prednisone dose ≤7.5 mg/day
Time frame: 28 months
Accrued number of weeks where a patient remains in remission with BVAS=0 and prednisone dose ≤4 mg/day
Time frame: 28 months
proportion of patients remaining in remission with a BVAS=0 over the 28 months study period
Time frame: 28 months
proportion of participants who achieved remission of vasculitis (BVAS = 0) while receiving prednisone at a dose of 4.0 mg or less per day at month 6
Time frame: 6 months
proportion of participants who achieved remission of vasculitis (BVAS = 0) while receiving prednisone at a dose of 4.0 mg or less per day at month 12
Time frame: 12 months
proportion of participants who achieved remission of vasculitis (BVAS = 0) while receiving prednisone at a dose of 4.0 mg or less per day at month 18
Time frame: 18 months
proportion of participants who achieved remission of vasculitis (BVAS = 0) while receiving prednisone at a dose of 4.0 mg or less per day at month 28
Time frame: 28 months
proportion of patients with at least one vasculitis relapse (major, minor, either)
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RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
98
oral tablets for 24 months
Time frame: 28 months
proportion of patients with at least one clinically significant asthma/rhino-sinusal exacerbation
defined as a worsening of asthma/rhino-sinusal disease leading to the doubling (or more) of the existing maintenance dose of corticosteroids for 3 or more days or hospital admission or an emergency department visit.
Time frame: 28 months
time to first vasculitis relapse
Time frame: 28 months
time to first clinically significant asthma/rhino-sinusal exacerbation
defined as a worsening of asthma/rhino-sinusal disease leading to the doubling (or more) of the existing maintenance dose of corticosteroids for 3 or more days or hospital admission or an emergency department visit.
Time frame: 28 months
variation of the obstructive pulmonary disease
assessed by change of FEV1 at pulmonary function tests after use of a bronchodilator
Time frame: 28 months
prednisone dose at months 6, 12, 18, 24 and 28, and area under the curve over the 28 month study period
Time frame: 28 months
proportion of patients with adverse events
Time frame: 28 months
proportion of patients with serious adverse events
Time frame: 28 months
proportion of patients with selected severe adverse events including grade 3 or 4 adverse effects (Common Terminology Criteria for Adverse Events)
necessitating hospitalization, all cause deaths, cancers or infusion reactions (within 24 hours of infusion) that contraindicated further infusions
Time frame: 28 months
number and causes of deaths over the 28 month study period
Time frame: 28 months
damage assessed by the mean variation of the Vasculitis Damage Index (VDI)
Time frame: 28 months
quality of life assessed by the mean variation of the SF-36
Time frame: 28 months
disability assessed by the mean variation of the Health Assessment Questionnaire (HAQ)
Time frame: 28 months
number of days of hospitalization
Time frame: 28 months