Avacopan With Short-term Reduced-dose Glucocorticoids vs Reduced-dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-associated Vasculitis
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 22
- 主要终点
- Proportions of patients achieving remission
研究概览
简要总结
The goal of this clinical trial is to learn if avacopan in combination with short-term (4 weeks) reduced-dose glucocorticoid and rituximab works to treat patients with newly-onset ANCA-associated vasculitis. It will also learn about the long-term safety of avacopan. The main questions it aims to answer are:
Is avacopan in combination with short-term reduced-dose glucocorticoid and rituximab as effective as the combination of 20 week reduced-dose glucocorticoid and rituximab in the proportion of the patients achieving remission? Does avacopan lower the relapse rate compared to the 6 monthly rituximab maintenance therapy? What medical problems do participants have when taking long-term avacopan?
Participants will:
Be treated with avacopan in combination with short-term (until 4 weeks) reduced-dose glucocorticoid and rituximab (at 0 week) or reduced-dose glucocorticoid (until 20 weeks) and rituximab (at 0, 26, 52 and 78 weeks).
Be assessed at 0, 4, 8, 16, 26, 52, 78 and 104 weeks regarding disease status (remission/relapse), disease activity by Birmingham Vasculitis Activity Score ver3, disease damage by Vasculitis Damage Index and adverse events.
The primary endpoint is remission rates at 26 weeks.
详细描述
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is characterized by a small to medium-size vasculitis and the presence of ANCA. ANCA-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. ANCA-associated vasculitis can be a life-threatening disease and the mortality is 80% at 1 year in untreated patients. In 2010s, standard therapies for remission induction of ANCA-associated vasculitis were the combination of high-dose glucocorticoids and either cyclophosphamide or rituximab. Although those therapies have high remission rates of 80-90%, mortality at 5 years is still high at 10-20% mainly due to treatments-related adverse events.
In the LoVAS trial (2021, JAMA), the combination of reduced-dose glucocorticoid and rituximab showed non-inferiority to high-dose glucocorticoid and rituximab in remission rates at 6 months. In addition, adverse events were dramatically less in the reduced-dose group than in the high-dose group.
In the ADVOCATE trial (2021, NEJM), the combination of avacopan, newly developed complement C5a inhibitor, and rituximab or cyclophosphamide showed non-inferiority to high-dose glucocorticoid and rituximab or cyclophosphamide in remission rates at 6 months. The avacopan group was allowed to use glucocorticoid within 1 month from the trial entry, and over 80% of patients used glucocorticoid indeed. Regarding adverse events, they were less in the avacopan group than in the glucocorticoid group.
Although both the reduced-dose glucocorticoid regimen in the LoVAS trial and the avacopan regimen in the ADVOCATE trial are effective and safe for patients with ANCA-associated vasculitis, there is no trial directly comparing both regimens at the moment. Thus, in this multicenter, open-label, randomized, non-ineriority, phase 4 trial, we aim to investigate if the combination of avacoapn, short-term (4 weeks) reduced-dose glucocorticoid and rituximab is non-inferior to the combination of reduced-dose glucocorticoid (20 weeks) and rituximab. We also compare safety profiles and disease relapse between the two groups. A total of 160 patients with new-onset ANCA-associated vasculitis (microscopic polyangiitis and granulomatosis with polyangiitis) will be recruited and randomized to the two treatments groups. The primary end point is remission rate at 26 weeks, and the patients will be followed until 104 weeks for assessing disease relapse and long-term safety.
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
- 18 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=>18 years
- •New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) consistent with the 2012 Chapel Hill consensus definitions and 2022 EULAR/ACR classification criteria
- •Positive test by ELISA, CLEIA or FEIA 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 less than 15ml/min) or alveolar hemorrhage (oxygen inhalation more than 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
- •History of 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)-use within the past 6 months
- •Past history of medication of avacopan
- •Patients can not take avacopan and prednisolone orally
- •Other conditions, in the investigator's opinion, inappropriate for the trial entry
研究组 & 干预措施
Glucocorticoid group
Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 5 months. If a patient fails to achieve BVAS=0 or normalization of CRP levels or normalization of ANCA levels, an investigator can keep 5mg/day of prednisolone and postpone the procedure of stopping prednisolone. Patients will also receive rituximab (375mg/m2/w x4).
During remission maintenance phase (6-24 months),, patients will receive rituximab (500mg/body) every 6 months as remission maintenance therapy.
In the case of inadequate response to the combination therapy of prednisolone and rituximab, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy.
During remission maintenance phase, in the case of minor relapse, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. Minor relapse is defined as relapse with no major BVAS item.
干预措施: Prednisolone and rituximab (Drug)
Avacopan group
Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 1 months. Patients will also receive avacopan (60mg/day) and rituximab (375mg/m2/w x4).
During remission maintenance phase (6-24 months), patients will receive avacopan (60mg/day) as remission maintenance therapy until the trial end.
In the case of inadequate response to the combination therapy of avacopan, prednisolone and rituximab, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy.
During remission maintenance phase, in the case of minor relapse, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. Minor relapse is defined as relapse with no major BVAS item.
干预措施: Avacopan, prednisolone and rituximab (Drug)
结局指标
主要结局
Proportions of patients achieving remission
时间窗: 26 weeks
Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone.
次要结局
- Sustained remission without taking prednisolone at 104 weeks(104 weeks)
- Survival, relapse and end-stage renal disease(26 and 104 weeks)
- Accumulative dose of glucocorticoids(26 and 104 weeks)
- Birmingham Vasculitis Activity Score (BVAS) version 3(26 and 104 weeks)
- Short-Form 36 (SF-36)(26 and 104 weeks)
- Proportions of the patients with new onset hypertension(26 and 104 weeks)
- Vasculitis Damage Index (VDI)(104 weeks)
- Serious adverse event (SAE)(26 and 104 weeks)
- Proportions of the patients with new onset hyperlipidemia(26 and 104 weeks)
- Proportion of the patients with new onset bone fracture, bone density(104 weeks)
- Proportions of patients achieving remission without the rescue therapy(26 weeks)
- Sustained remission without taking prednisolone at 104 weeks and the rescue therapy during the trial period(104 weeks)
- Proportions of the patients with new onset diabetes mellitus(26 and 104 weeks)
- Number of infections, proportions of the patients with infection(26 and 104 weeks)
- Number of serious infections, proportions of the patients with serious infection(26 and 104 weeks)
- Proportions of the patients with liver dysfunction(26 and 104 weeks)
- Proportions of the patients with new onset malignancies(26 and 104 weeks)
- Proportions of patients treated with the rescue therapy(26 and 104 weeks)
研究者
Shunsuke Furuta
Associate Professor, Department of Allergy and Clinical Immunology
Chiba University