Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome : a Double-blind Multicenter Randomized Controlled Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 88
- 试验地点
- 1
- 主要终点
- Occurrence of a relapse within 12 months following the initiation of treatment
研究概览
简要总结
B-cell depletion with rituximab induces sustained remission in children with Steroid-Dependent or Frequent Relapsing Nephrotic Syndrome (SD/FRNS). However, most patients relapse after B-cell recovery and some do not achieve B-cell depletion. Obinutuzumab is a 2nd generation humanized monoclonal antiCD20 antibody, with enhanced B cell-depleting potential. It has been reported safe and efficient in different renal autoimmune diseases including childhood nephrotic syndrome. This double-blind, randomized multicenter study is designed to assess the efficacy and safety of a single infusion of low-dose obinutuzumab compared to a single infusion of rituximab in children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS).
详细描述
Idiopathic nephrotic syndrome (INS) is the most frequent acquired glomerulopathy in children. The initial treatment relies on steroids, which enables remission of proteinuria in 90% of children. However, 80 % of steroid-sensitive patients will relapse, and 2/3 will become steroid-dependant with a long lasting disease over years. In this situation, immunosuppressive drugs are added as steroid-sparing agents. There is no international consensus on the second line treatment strategy after initial steroid therapy. RCT have demonstrated the efficacy of rituximab (RTX) to maintain remission in FR/SDNS after oral treatments withdrawal, however most patients relapse within 2 years, and some patients are resistant or allergic to Rituximab. Obinutuzumab (OBI) is a second generation antiCD20 mAb, that has been designed to overcome rituximab resistance in B-cell malignancies. Additional mechanisms of rituximab failure support the hypothesis that B-cell depletion could be optimized with OBI in autoimmune diseases. OBI has met its primary endpoint in lupus nephritis and a few randomized controlled trials are currently ongoing in nephrology for lupus nephritis and membranous nephropathy. We believe that a single infusion of OBI could reduce the risk of subsequent relapse in FR/SDNS and the cumulative exposure to immunosuppressive drugs.
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
- 3 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 3 and 18 years
- •Steroid dependant Nephrotic Syndrome defined as:
- •2 or more relapses during steroids or within 2 weeks following discontinuation.
- •2 or more relapses including one under steroid-sparing agent (MMF, Calcineurin inhibitors, cyclophosphamide, levamisole) or within 6 months following treatment withdrawal
- •OR Frequent Relapsing Nephrotic Syndrome defined as:
- •2 or more relapses within 6 months following first remission
- •3 or more relapses within any 12-month period
- •Last relapse within 3 months prior to inclusion
- •In remission, defined as 3 consecutive urinary dipsticks without proteinuria, at the time of randomization
- •Vaccination schedule in accordance with the current recommendations in France
- •Informed consent from parents
排除标准
- •Secondary cause of nephrotic syndrome (such as membranous nephropathy, IgA nephropathy, lupus nephritis)
- •Primary or secondary steroid resistance nephrotic syndrome
- •Prior treatment with Rituximab within 6 months
- •Prior treatment with obinutuzumab at any time
- •CD20+ B-cell count < 2.5%
- •Patient with neutrophils < 1.5 G/L and/or platelets < 75 G/L
- •GFR < 80 ml/min/1.73m2
- •Weight <16kg
- •History of severe infection such as tuberculosis, hepatitis B, hepatitis C or HIV infection or LEMP
- •History of malignancy- Uncontrolled infection (viral, bacterial and fungal)
- •Vaccination with a live vaccine within 4 weeks prior to assignment/randomization
- •Known hyperprolinemia
- •Hypersensitivity to the active substance (OBI or RTX) or to proteins of murine origin, or to any of the other excipients
- •Pregnancy or breastfeeding or ability to become pregnant and refusal to use effective contraception during the 18 months following the study treatment (only 1 infusion of obinutuzumab/Rituximab at the beginning of the study)
- •Patient without medical insurance coverage (beneficiary or legal)
研究组 & 干预措施
Rituximab 375 mg/m2
single infusion of Rituximab (375 mg/m2)
干预措施: single infusion of Rituximab (Drug)
Obinutuzumab 300 mg/1.73 m2
single infusion of Obinutuzumab 300 mg/1.73 m2
干预措施: single infusion of Obinutuzumab (Drug)
结局指标
主要结局
Occurrence of a relapse within 12 months following the initiation of treatment
时间窗: 12 months
Relapse is defined as a protein to creatinine ratio of 2 g/g of creatinine (0.20 g/mmol) or higher
次要结局
- Time to B-cell depletion(24 months)
- Occurrence of a relapse within 24 months(24 months)
- Duration of relapse-free survival after B-cell reconstitution(24 months)
- Efficiency defined as incremental cost-effectiveness ratio in cost per relapse prevented(24 months)
- Cumulative steroid courses and second line immunosuppressive treatments in patients with relape(24 months)
- Detection of Antidrug Antibodies(24 months)
- Safety associated with drug infusion(24 months)
- Budgetary impact defined as costs and health gains incurred with the generalization of the obinutuzumab strategy(24 months)