MAINtenance of Remission With RITuximab Versus Azathioprine for Patients With Newly-diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis. A Prospective, Randomized, Controlled, Double-blind Study: the MAINRITSEG Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 98
- 试验地点
- 1
- 主要终点
- Duration of remission in weeks
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •patients with a diagnosis of EGPA according to Lanham and/or ACR 1990 criteria and/or Revised Chapel Hill Nomenclature and/or MIRRA study inclusion criteria
- •18 years of age or more
- •with newly-diagnosed EGPA or after a vasculitis flare and remission achieved within the past year
- •independently of ANCA status
- •within 30-360 days following achievement of vasculitis remission (corresponding to a Birmingham Vasculitis Activity Score (BVAS)=0) achieved with an induction regimen including the one used in the REOVAS trial: either CS alone or in association with CYC (total dose ranging from 4.5-10 g for patients <65 years old and from 3-10g for patients ≥65 years old) or RTX (2 x 1g (D1, D15) or 4 weekly 375 mg/m2).
- •with a stable prednisone dose for 30 days or no more prednisone
- •after oral immunosuppressive drug cessation if started at remission.
- •Patients included in the REOVAS trial and achieving remission can be included at month 12 visit if they fulfil the other criteria
- •Patients able to give written informed consent prior to participation in the study.
- •Affiliation with a mode of social security (profit or being entitled).
排除标准
- •patients with GPA, MPA or other vasculitides
- •patients with vasculitis not in remission defined as a BVAS >0
- •acute or chronic active infections (including HIV, HBV or HCV)
- •active or recent cancer ( <5 years), except basocellular carcinoma and low activity prostatic cancer controlled by hormonal treatment
- •severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease
- •pregnant women and lactation
- •patients with childbearing potential will have reliable contraception for all the duration of the study and another 12 months after. Women are considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
- •men who refuse to use effective method of contraception (condom) from the date of consent through the end of the study
- •patients who had already been treated with rituximab before the last relapse/flare
- •patients who have been treated with rituximab with a different induction regimen than 2 x 1g (D1, D14) or 4 weekly 375 mg/m2 infusions
- •hypersensitivity to a monoclonal antibody or biologics
- •contraindication to rituximab or azathioprine
- •other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation
- •patients included in other investigational therapeutic study within the previous 3 months except in the REOVAS trial, after which patients achieving remission can be included if they fulfil the other criteria
- •patients suspected not to be observant to the proposed treatments
- •white blood cell count ≤4,000/mm3
- •platelet count ≤100,000/mm3
- •ALT or AST level >3 times the upper limit of normal
- •patients not able to stop allopurinol and febuxostat which may enhance azathioprine toxicity
- •patients unable to give written informed consent prior to participation in the study.
研究组 & 干预措施
Rituximab
- pre-emptive 500-mg fixed-dose of IV rituximab every 6 months (total duration of 18 months = 4 infusions)
- plus orally placebo-azathioprine for 24 months
干预措施: Rituximab (Drug)
Rituximab
- pre-emptive 500-mg fixed-dose of IV rituximab every 6 months (total duration of 18 months = 4 infusions)
- plus orally placebo-azathioprine for 24 months
干预措施: Placebo-azathioprine (Drug)
Azathioprine
- standard maintenance oral azathioprine therapy (2 mg/kg/day) for 24 months
- plus 4 placebo-rituximab infusions given every 6 months for 18 months
干预措施: Azathioprine (Drug)
Azathioprine
- standard maintenance oral azathioprine therapy (2 mg/kg/day) for 24 months
- plus 4 placebo-rituximab infusions given every 6 months for 18 months
干预措施: Placebo-rituximab (Drug)
结局指标
主要结局
Duration of remission in weeks
时间窗: 28 months
accrued number of weeks where a patient remains in remission with BVAS=0 and prednisone dose ≤7.5 mg/day
次要结局
- proportion of patients with serious adverse events(28 months)
- proportion of patients with selected severe adverse events including grade 3 or 4 adverse effects (Common Terminology Criteria for Adverse Events)(28 months)
- number and causes of deaths over the 28 month study period(28 months)
- damage assessed by the mean variation of the Vasculitis Damage Index (VDI)(28 months)
- proportion of patients with adverse events(28 months)
- proportion of patients remaining in remission with a BVAS=0 and prednisone dose ≤7.5 mg/day(28 months)
- Accrued number of weeks where a patient remains in remission with BVAS=0 and prednisone dose ≤4 mg/day(28 months)
- proportion of patients remaining in remission with a BVAS=0 over the 28 months study period(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(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(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(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(28 months)
- proportion of patients with at least one vasculitis relapse (major, minor, either)(28 months)
- proportion of patients with at least one clinically significant asthma/rhino-sinusal exacerbation(28 months)
- time to first vasculitis relapse(28 months)
- time to first clinically significant asthma/rhino-sinusal exacerbation(28 months)
- variation of the obstructive pulmonary disease(28 months)
- prednisone dose at months 6, 12, 18, 24 and 28, and area under the curve over the 28 month study period(28 months)
- quality of life assessed by the mean variation of the SF-36(28 months)
- disability assessed by the mean variation of the Health Assessment Questionnaire (HAQ)(28 months)
- number of days of hospitalization(28 months)