The Use of Rituximab in the Treatment of Idiopathic Membranous Nephropathy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Mayo Clinic
- 入组人数
- 15
- 试验地点
- 2
- 主要终点
- 1. Change from baseline in proteinuria at six and twelve months following treatment
研究概览
简要总结
Membranous glomerulopathy (MN) is a common immune-mediated glomerular disease and the leading cause of nephrotic syndrome in Caucasian adults. 1 Because of its frequency, it remains the second or third cause of end-stage renal disease caused by a primary glomerulonephritis. 2 At presentation, 70% to 80% of patients have the nephrotic syndrome. 1, 3, 4 Proteinuria greater than 2.0 grams per day is found in > 80% of patients at presentation, with greater than 10 grams found in as many as 30%. 5 The disease affects patients of all ages, but it is most often diagnosed in middle age with the peak incidence during the fourth and fifth decades of life. There is close to a two-to-one predominance of males to females diagnosed with the disease. Idiopathic MN affects all races. Current therapeutic options include corticosteroids alone or in combination with alkylating agents, cyclosporin A, and mycophenolate mofetil. The most widely recognized, and best-validated regimen is combination therapy with corticosteroids and an alkylating agent, but its use is associated with significant adverse effects. Recent meta-analysis confirmed that present day treatments are far from ideal 6 Thus, it should not come as a surprise that the outcome of MN has not substantially improved over the past 30 years, and up to 40% of patients still progress to end-stage renal failure. 7 Like in other glomerular diseases the amount of protein in the urine correlates well with long term prognosis. Thus, this parameter has been used in previous studies, and will be used in this study, as the primary indicator of effectiveness of therapy. We proposed to do a pilot study to test the hypothesis that selective B lymphocyte depletion will result in disappearance of pathogenic antibodies and induction of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. Our population will be 10 adults. The study will be conducted between our Nephrology Divisions at Mayo Clinic Rochester, Jacksonville, and Scottsdale. We will enroll patients with a GFR 25 ml/min as estimated by creatinine clearance and proteinuria > 4g/24h, while receiving an ACEI or ARB and with BP controlled of < 130/80 mmHg. Patients will receive Rituximab 1g on Day 1 and 15. Patients followed for 1 years following completion of treatment. The primary outcome will be change in urinary protein excretion at 6 months. Secondary outcomes will be changes in serum albumin, serum lipid?s profile, the number of partial remissions, time to remission, and incidence of relapses. We will also perform a pharmacokinetic study to evaluate the effect of proteinuria on the bio-availability and effects of the drug.
详细描述
There is convincing evidence from both experimental and human studies that MN is mediated by the deposition of IgG antibodies in the subepithelial aspect of the GBM. More debatable, is the mechanism(s) of deposition of these antibodies in that location. Given the key role of IgG antibodies in MN, it is reasonable to postulate that suppression of antibody production by depleting B cells and/or plasma cells may improve or even resolve the glomerular pathology as reflected by a reduction in proteinuria. There is evidence that this strategy is effective in the treatment of other antibody-mediated diseases and preliminary studies in MN are promising. Data from animal studies suggest that immune deposition resulting from B cell activation promote injury to the glomerular filtering barrier and proteinuria.103 In humans, as discussed above, there is evidence that therapy directed against B cells, e.g. cyclophosphamide, is effective in MN. Cyclophosphamide has striking direct effects on B cell function, and suppresses the secretion of immunoglobulins.104 Thus, a case could be made for using an agent capable of depleting B cells, and therefore halting the production of nephrotoxic immunoglobulins. This approach could stop the pathogenic events at their initial stages and potentially result in resolution of the pathological process. The rationale for using such an approach can be further substantiated by the fact that Th2 pathway for antibody response is activated and that inhibition of B cells and of pathogenic antibodies is strictly associated with beneficial effects of immunosuppressive drugs in experimental MN.
This is a open-label Phase I/II pilot study. Patients will receive Rituximab at a total dose of 1g on Day 1 and Day 15 according to infusion guidelines. Patient experience complete clinical response (as per response criteria outlined below), AND Patient subsequently experiences clinical relapse, defined as return of proteinuria to 4 g/24h, and in whom CD20+ cell count have normalized, will receive a second course of Rituximab. Patients who relapse but who remain B cell depleted will not be retreated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- 未提供
排除标准
- 未提供
结局指标
主要结局
1. Change from baseline in proteinuria at six and twelve months following treatment
Toxicity/Safety
PK/bioavailability
次要结局
- Partial Remission at 6 months
- Complete and Partial Remission at 6 months
- Time to CR and time to CR or PR
- Rates of decline in GFR and UP