Low-dose Glucocorticoids Plus Rituximab Versus High-dose Glucocorticoids Plus Rituximab for Remission Induction in ANCA-associated Vasculitis; a Multicentre, Open Label, Randomised Control Trial
试验速览
- 阶段
- 4 期
- 入组人数
- 140
- 试验地点
- 17
- 主要终点
- Proportion of the patients achieving remission
研究概览
简要总结
Previous reports suggested conventional immunosuppressants such as cyclophosphamide could not reduce glucocorticoid dose in remission induction in ANCA-associated vasculitis because of lower remission rate and higher relapse rate. However those reports didn't include rituximab.
B cell depletion therapy by rituximab is a new strategy for remission induction in ANCA-associated vasculitis. The RAVE and RITUXVAS trial (NEJM 2010, both) showed high-dose glucocorticoid plus rituximab had roughly the same efficacy and safety as high-dose glucocorticoid plus IV-cyclophosphamide. In addition, recent retrospective observational studies reported low-dose glucocorticoid plus rituximab led to re-induction in severe relapsing ANCA-associated vasculitis.
Thus, the investigators aim to investigate whether rituximab can reduce glucocorticoid dose in induction remission in ANCA-associated vasculitis (to show non-inferiority for efficacy between low-dose and high-dose glucocorticoid plus rituximab). Participants will be randomised to the "low-dose glucocorticoid plus rituximab" or the high-dose glucocorticoid plus rituximab" groups. Primary endpoint is proportion of remission at 6 months, then data regarding relapse and long-term safety will be collected until 24 months.
The study has been designed by the principal and coordinating investigators. It will include 140 participants from 18 hospitals in Japan. It is funded by Chiba University Hospital and Chiba East Hospital.
详细描述
ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is characterised by small vessel vasculitis and presence of autoantibodies, ANCA. It can be a life-threatening disease with renal/respiratory failure. Current standard therapy in induction remission for ANCA-associated vasculitis is combination of high-dose glucocorticoid and IV-cyclophosphamide. This regimen is effective (remission rate; 80-90%), but often cause various glucocorticoid-related side effects. Especially, infection is related to death. Thus a new regimen reducing glucocorticoid dose is required.
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
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of written informed consent by a patient or a surrogate decision maker
- •Age=>20 years
- •New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis or renal limited ANCA-associated vasculitis) consistent with the 2012 Chapel Hill consensus definitions
- •Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA
排除标准
- •Prior treatment for ANCA-associated vasculitis before trial entry
- •ANCA-associated vasculitis related glomerulonephritis (eGFR<15ml/min) or alveolar hemorrhage (oxygen inhalation >2L/min)
- •Presence of another multisystem autoimmune disease
- •Known infection with HIV; a past or current history of hepatitis B virus or hepatitis C virus infection
- •Desire to bear children, pregnancy or lactating
- •History of malignancy within the past 5 years or any evidence of persistent malignancy
- •Ongoing or recent (last 1 year) evidence of active tuberculosis
- •Severe allergy or anaphylaxis to monoclonal antibody therapy
- •Any concomitant condition anticipated to likely require oral systemic glucocorticoids, immunosuppressants, biologics, plasma exchange or IVIg
- •Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months
- •Other conditions, in the investigator's opinion, inappropriate for the trial entry
研究组 & 干预措施
Low-dose glucocorticoid
Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy.
干预措施: Rituximab (Drug)
Low-dose glucocorticoid
Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy.
干预措施: Glucocorticoids (Drug)
High-dose glucocorticoid
Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering.
干预措施: Rituximab (Drug)
High-dose glucocorticoid
Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering.
干预措施: Glucocorticoids (Drug)
结局指标
主要结局
Proportion of the patients achieving remission
时间窗: 6 months
Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone \<10mg/day
次要结局
- Proportions of the patients with new onset hypertension(at 6 and 24 months)
- Proportions of patients achieving remission and discontinuance of glucocorticoids(at 6 and 24 months)
- Time to remission(assessed at 1, 2, 4 and 6 months)
- Proportions of death, relapse, end-stage renal disease and the composite of these(at 6 and 24 months)
- Proportions of major relapse(at 24 months)
- Accumulative dose of glucocorticoids(assessed at 6 and 24 months)
- Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events(at 6 and 24 months)
- Birmingham Vasculitis Activity Score (BVAS) version 3(assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months)
- Short-Form 36 (SF-36)(assessed at 0, 6, 12, 18 and 24 months)
- Patient global assessment (visualised analogue scale)(assessed at 0, 6, 12, 18 and 24 months)
- Proportions of the patients with new onset diabetes mellitus(at 6 and 24 months)
- Proportion of the patients with new onset bone fracture, bone density(at 6 and 24 months)
- Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event(0-24 months)
- Vasculitis Damage Index (VDI)(assessed at 0, 6, 12, 18 and 24 months)
- Proportion of the patients with new onset insomnia(at 6 and 24 months)
- Proportions of the patients with new onset hyperlipidemia(at 6 and 24 months)
- Number of infections, proportions of the patients with infection(at 6 and 24 months)
研究者
Shunsuke Furuta
Associate Professor
Chiba University