Obinutuzumab for Remission Induction in Patients With Relapsing PR3-ANCA Granulomatosis With Polyangiitis (Wegener's). Phase 2 Prospective, Open-label Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- the percentage of patients who achieved clinical and serological remission at week 24 (month 6)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of obinutuzumab to induce clinical and serological remission in patients with relapsing PR3-ANCA granulomatosis with polyangiitis.
详细描述
Systemic vasculitides are rare inflammatory diseases of blood vessels, among which anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are one of the most severe forms with life-threatening manifestations. In patients with AAV, the most important questions are how to achieve a long-term remission and prevent a relapse most effectively.
The pivotal RAVE trial showed that rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in AAV; and could be superior than cyclophoshamide in proteinase 3 (PR3)-ANCA patients. The MAINRITSAN trial, conducted by our group (Groupe Français d'Etude des Vascularites), has then demonstrated that more AAV patients had sustained remission with rituximab than with azathioprine.
However, despite its ability to induce and maintain remission, rituximab is associated with the occurrence of relapse after discontinuation in up to 50% of patients at 5-years in PR3-ANCA patients. Data strongly suggest that achieving clinical and serological remission (i.e. a BVAS (Birmingham Vasculitis Activity Score) of 0 and a negativation of ANCA) and longer B-cell depletion could be major goals to achieve in PR3-ANCA granulomatosis with polyangiitis to decrease the risk of relapse.
Obinutuzumab is a humanized type 2 antibody targeted against CD20. In preclinical studies, obinutuzumab showed superior efficacy, as compared with rituximab. In clinical studies, obinutuzumab was shown to be superior to rituximab in patients with chronic lymphocytic leukemia and follicular lymphoma, and met its primary and secondary endpoints in lupus nephritis.
The OBI-WAN study aims to evaluate the efficacy and safety of obinutuzumab to induce clinical and serological remission in patients with relapsing PR3-ANCA granulomatosis with polyangiitis. We hypothesize that obinutuzumab would induce higher remission rates and subsequent longer B-cell depletion compared to what is described for rituximab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patient aged of 18 years or older,
- •Patients with relapsing granulomatosis with polyangiitis positive for PR3-ANCA at inclusion according to the ACR/EULAR 2022 classification criteria, and/or the 2012 revised Chapel Hill Consensus Conference definition.
- •Patients with an active disease defined as a Birmingham Vasculitis Activity Score (BVAS) ≥ 3,
- •Patients within the first 21 days following initiation/increase of glucocorticoids at a dose ≤1 mg/kg/day (pulses of methylprednisolone before oral glucocorticoid therapy are authorized)
- •Patient 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 MPO-positive AAV, or other vasculitis, defined by the ACR criteria and/or the Chapel Hill Consensus Conference,
- •Patients with vasculitis in remission of the disease defined as a BVAS < 3,
- •Patients with a newly-diagnosis of GPA
- •Patients treated with rituximab within the last 6 months before inclusion
- •Patients treated with cyclophosphamide within the last 6 months before inclusion
- •Patients with severe cardiac failure defined as class IV in New York Heart Association
- •Subject known to be seropositive for human immunodeficiency virus (HIV), hepatitis B (included history of previous infection) or hepatitis C
- •Patients with active cancer or recent cancer (< 5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment,
- •Patients with hypersensitivity to a monoclonal antibody or biologic agent,
- •Patients with hypersensitivity to obinutuzumab or to its excipients
- •Contra-indications to auxiliary medicinal products (methylprednisolone, paracetamol, prednisone, dexchlorpheniramine)
- •Patients with other uncontrolled diseases, including drug or alcohol abuse, active infections or antecedents of chronic or recurrent infections, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
- •Patients suspected not to be observant to the proposed treatments,
- •Pregnant women and lactation. All women of childbearing potential (WOCBP) are required to have a negative pregnancy test (blood or urine) before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using an effective method of birth control from the date of consent through the end of the study, and at least 18 months after stopping obinutuzumab such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (Oral, Intravaginal, Transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (Oral, Injectable, Implantable); Intrauterine device (IUD); Intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomised partner,
- •Men who refuse to use effective method of contraception (condom) from the date of consent through the end of the study and at least 18 months after stopping obinutuzumab (unless permanently sterile by bilateral orchidectomy or vasectomy),
- •Patient participating in another investigational therapeutic study
- •Protected adults (including individual under legal guardianship by court order or curatorship) or adults deprived of liberty
- •Patients unable to give written informed consent prior to participation in the study.
- •Patients with severe liver insufficiency (prothrombin time <50% and total bilirubin >50 micrmol/L)) or pulmonary insufficiency requiring nasal oxygen,
- •Patients with an active infection or a history of chronic or recurrent infections
- •Vaccination with live virus vaccines in the 4 weeks before study enrolment
研究组 & 干预措施
Single Arm: Obinutuzumab
All participants receive obinutuzumab for remission induction
干预措施: Obinutuzumab (Drug)
结局指标
主要结局
the percentage of patients who achieved clinical and serological remission at week 24 (month 6)
时间窗: week 24
The percentage of patients who achieved clinical and serological remission at week 24 (month 6), defined by: * a BVAS of 0, * a negativation of PR3-ANCA, * and successful completion of the prednisone taper
次要结局
- Proportion of participants experiencing adverse events and severe adverse events(Week 24 and 52)
- Number and causes of deaths(Week 52)
- Proportion of disease flares, including minor and major relapses(Week 52)
- Proportion of participants who remain with a BVAS of 0 during the treatment period with prednisone at a dose of less than 10 mg per day(Treatment period)
- The time to B-cell repopulation defined by detectable CD19+ B cells in peripheral blood over the 12 months study period(Week 24 and 52)
- The patient-reported outcomes (PRO) including HAQ and SF-36, patient-reported disease activity at week 24 and 52(Week 24 and 52)
- The Vasculitis Damage Index at week 24 and 52(Week 24 and 52)