An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 188
- 试验地点
- 38
- 主要终点
- Relapse-free Survival
研究概览
简要总结
Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its effect wears off and the disease can return. This occurs in at least half of patients within 2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating rituximab every six months stops the disease returning and is safe.
The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and whether it works better than the older treatments, azathioprine or methotrexate. It will also tell us how long patients remain well after the repeated rituximab treatments are stopped, and if repeated rituximab is safe. We should also learn useful information about the effects of rituximab on quality of life and economic measures. The trial results will help decide the best treatment for future patients who have their vasculitis initially treated with rituximab.
RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we anticipate that most will respond well. If their disease is under reasonable control after four months, further treatment with either rituximab (a single dose ever four months for two years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and azathioprine groups will then be compared. Patients will be in the trial for four years.
The study has been designed by members of the European Vasculitis Study group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30 hospitals in Europe, the USA, Australia and Mexico.
RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health and by Roche/Genentech.
详细描述
Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week x 4 and glucocorticoids.
Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 will be randomised to the rituximab or control remission maintenance groups.
Treatment is protocolised for the entire duration of the study, until the common close date, when the final patient recruited has completed 36 months within the study or until the patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm will receive treatment until month 20, and those in the azathioprine arm until month 27.
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
- None
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis], according to the definitions of the Chapel Hill Consensus Conference
- •Current or historical PR3/MPO ANCA positivity by ELISA
- •Disease relapse defined by one major or three minor disease activity items on the Birmingham Vasculitis Activity Score for Wegeners (BVAS/WG), in patients that have previously achieved remission following at least 3 months of induction therapy, with a combination of glucocorticoids and an immunosuppressive agent (cyclophosphamide or methotrexate or rituximab or mycophenolate mofetil)
- •Written informed consent
排除标准
- •Age < 15 years (age < 18 years at centres that do not treat paediatric patients)
- •Exclusions related to medication:
- •Previous therapy with:
- •Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months
- •Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months
- •IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months
- •Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer)
- •Exclusions related to general health:
- •Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation
- •Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic vasculitis,
- •Any concomitant condition anticipated to likely require greater than 4 weeks per year of oral or systemic glucocorticoid use and which would preclude compliance with the glucocorticoid protocol (e.g. poorly-controlled asthma, COPD, psoriasis, or inflammatory bowel disease).
- •History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies
- •Known infection with HIV (HIV testing will not be a requirement for trial entry); a past or current history of hepatitis B virus or hepatitis C virus infection.
- •Ongoing or recent (last 12 months) evidence of active tuberculosis or known active infection (screening for tuberculosis is part of "standard of care" in patients with established AAV) or evidence of untreated latent tuberculosis. Screening for tuberculosis is as per local practice.
- •History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure.
- •Pregnancy or inadequate contraception in pre-menopausal women
- •Breast feeding or lactating
- •Exclusion criteria related to laboratory parameters:
- •Bone marrow suppression as evidenced by a total white count < 4 x109/l, haemoglobin < 7 gm/dl or platelet count < 100,000/μl
- •Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the upper limit of normal, unless attributed to vasculitis
研究组 & 干预措施
Azathioprine Maintenance
Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.
干预措施: Azathioprine (Drug)
Rituximab Maintenance
Rituximab maintenance: 1g at 4, 8, 12, 16 & 20 months with standardised steroid taper
干预措施: Rituximab (Biological)
结局指标
主要结局
Relapse-free Survival
时间窗: Any patients who have not relapsed at up to a maximum of 4 years will be censored.
The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).
次要结局
- Number of Participants in Remission at 24 and 48 Months(24 and 48 months)
- Severe Adverse Event Rate(Up to 48 months)
- Combined Damage Assessment Score (Disease Related Damage Assessment)(data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.)
- Cumulative GC Exposure(Up to 48 months)
- Infection Rates(Up to 4 years)
- Health-related Quality of Life Using the SF-36 Physical Composite(48 months)
- Health-related Quality of Life Using the SF-36 Mental Composite(48 months)
研究者
David Jayne
Director, Vasculitis and Lupus Clinic
Cambridge University Hospitals NHS Foundation Trust