Rituximab, Cyclophosphamide, and Corticosteroids at Low Cumulative Doses to Induce Remission in Primary Membranous Nephropathy
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Partial clinical remission (PR) and complete clinical remission (CR)
研究概览
简要总结
This exploratory study aims to assess the efficacy, safety of the experimental treatment based on a combination of rituximab (RTX), intravenous (IV) cyclophosphamide (CYC), and corticosteroids (S) administrated at lower cumulative doses (RCP) for the induction of early remission in subjects with anti-PLA2R antibody-positive primary membranous nephropathy (PMN) having nephrotic syndrome (NS).
详细描述
BACKGROUND
PMN is a glomerular disease associated with autoantibodies targeting podocyte antigens, mostly the phospholipase A2 receptor (anti-PLA2R). The formation of subepithelial immune complexes and complement-mediated injury to podocyte and glomerular basement membrane leads, in most cases, to the development of NS and the risk of its life-threatening complications: thromboembolic, infectious, and metabolic. Standard renoprotective approaches are not sufficient for many patients with PMN and persistent NS. In randomized clinical trials of immunosuppressive therapies, up to 68% of patients failed to achieve remission during the first 12 months without substantial differences in efficacy between immunosuppressive regimens. Treatment failures are increased in high-risk patients, including those with heavier proteinuria and higher serum anti-PLA2R levels. As a result, a significant proportion of patients remain for a long time at high risk of severe complications due to persistent high-level proteinuria and NS, and disease progression.
PROPOSED NEW TREATMENT APPROACH
Collectively, in the past decades no significant progress has been achieved in the treatment of patients with PMN, and up to 40% of the patients still progress to dialysis. In this context, therapies that may result in a higher response and lower relapse rates at an acceptable rate of adverse effects are warranted. Particularly, developing of treatment approaches to rapid induction of remission is critically important to prevent life-threatening NS complications, stop disease progression, and improve long-term prognosis, especially in high-risk patients.
We conducted a pilot open-label trial in 14 patients (mean age 51±12 years, men - 70%) with PMN and NS and high serum level of anti-PLA2R treated with RTX, CYC and S. The overall remission was achieved in 100% of cases (of which complete remissions (CR) in 21.4%) with the median time-to-remission of 2.5 (1.0; 3.5) months. The most commonly observed side effects were infusion related (flu-like symptoms, chills/rigors, fever, fatigue, headache, hypotension,) and typically responded to antihistamines. No patient, except one, had a major drug-related adverse event in 15.7 patient-years. This adverse event was transient elevation of transaminases in induction phase, leading to several days delay in administration of next dose of CYC and prolongation of hospital stay. Thus, according to these results, the use of multi-targeted therapy with RTX, CYC, and S at low dosages seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 years.
- •Biopsy-proven primary membranous nephropathy (PMN) defined upon the exclusion of any significant concomitant disease (infectious, autoimmune, neoplastic) by careful clinical work-up at the time of kidney biopsy.
- •Signed informed consent
- •Increased serum level of anti-PLA2R antibodies (>20 RU/ml).
- •Absence of contraindications to immusuppressive therapy.
- •Presence of nephrotic syndrome (NS) with one of the following conditions:
- •persistence for >6 months despite treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with or without immunosuppression and NS complications.
- •persistence for <6 months at the presence of complications related to NS (thromboembolic or infectious event or estimated GFR by CKD-EPI equation (eGFR) decrease >20%.
- •recurrence after remission with a prior immunosuppressive treatment.
- •treatment failure of an alternative immunosuppressive regimen.
排除标准
- •Presence of a secondary cause of membranous nephropathy (e.g. hepatitis B, systemic lupus erythematosus, medications, malignancies).
- •Presence of Type 1 or 2 diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy.
- •Acute or chronic infection, including: current use of suppressive therapy for chronic infection, hospitalization for treatment of infection in the past 60 days, or parenteral anti-microbial (including anti-bacterial, anti-viral, or anti- fungal agents) use in the past 60 days for infection.
- •Women of child-bearing potential who are pregnant, nursing, or unwilling to be sexually inactive or use FDA-approved contraception until study week.
- •A history of mental illness (including any history of suicidal behavior in the last 6 months, any suicidal ideation in the last 2 months, or who, in the investigator's judgment, pose a significant suicide risk).
- •A history of immunodeficiency, including other acquired or congenital immunodeficiency diseases, or organ transplantation.
- •Vaccination with a live vaccine within the past 30 days.
- •Evidence of current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence in the past 12 months.
- •Inability to comply with study and follow-up procedures.
- •Laboratory tests meeting any of the following: Hemoglobin <80 g/L; Platelet <80 x 109/ L; Neutrophil <1.0×109/ L; Aspartate aminotransferase (AST) or amino acid aminotransferase (ALT) >2.5× upper limit of normal.
- •Any patient judged by the investigator to be ineligible for enrollment in the trial.
- •eGFR ≤30 ml/min/1.73m2 in one measurement performed at baseline
研究组 & 干预措施
Rituximab, Cyclophosphamide, and Corticosteroids group
The experimental treatment group: 40 participants will receive combined immunosuppressive therapy with Rituximab, Cyclophosphamide, and Corticosteroids.
干预措施: Rituximab, Cyclophosphamide, and Corticosteroids (Drug)
结局指标
主要结局
Partial clinical remission (PR) and complete clinical remission (CR)
时间窗: Up to 1 year
Including the proportion of participants with complete and partial responses by month 12 since the treatment initiation; CR defined as proteinuria of \<0.3 g/1.73 m2/24h and serum albumin \>30 g/l; PR defined as a ≥50% reduction in proteinuria from baseline accompanied by a regress of nephrotic syndrome (NS)
Time to clinical remission
时间窗: Up to 1 year
Cumulative rate of overall (complete and partial) clinical remission and complete clinical remission by month 12
次要结局
- The change in proteinuria(Up to 1 year)
- The change in serum albumin(Up to 1 year)
- The time to immunologic remission(Through study completion, an average of 2 years)
- The change in circulating CD19+ cells(Up to 1 year)
- The change in estimated GFR (eGFR)(Through study completion, an average of 2 years)
- Adverse events (AEs)(Through study completion, an average of 2 years)
- Disease relapse since the RCP treatment initiation (in experimental group received Rituximab, Cyclophosphamide, and Corticosteroids at low cumulative doses)(Through study completion, an average of 2 years)
研究者
Ivan S Moiseev
Vice-director for science RM Gorbacheva Institute
St. Petersburg State Pavlov Medical University