Study of Artificial Intelligence-based Personalized Rituximab Treatment Protocol in Membranous Nephropathy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 24
- 主要终点
- Clinical remission (complete or partial) after 6 months of rituximab initiation
研究概览
简要总结
Membranous nephropathy is an autoimmune disease affecting the kidney, and the most common cause of nephrotic syndrome in non-diabetic Caucasian adults. The course of this disease is highly variable from one individual to another, ranging from spontaneous remission to progressive chronic kidney disease.
The identification of autoantibodies - e.g., the phospholipase A2 receptor type 1 (PLA2R1) - has promoted the use of immunosuppressive drugs such as rituximab which is now a safe and effective first-line treatment for the management of membranous nephropathy. However, up to 40% of patients do not respond to a first course of rituximab treatment. In nephrotic patients, due to urinary drug loss, rituximab blood level is lower than in other autoimmune diseases treated with rituximab without proteinuria. This high urinary drug loss decreases the drug exposure, potentially explaining why rituximab regimen with low dose infusions (375 mg/m2) did not demonstrate efficacy after month-6 compared to a non-immunosuppressive antiproteinuric treatment in a previous study. In contrast, a regimen of two 1-g infusions two weeks apart was associated with a significantly greater remission rate after 6 months.
Recently, the investigators have shown that after two 1-g rituximab infusions, the rituximab blood level 3 months after the first rituximab infusion, was correlated with the likelihood of remission after 6 and 12 months of the rituximab treatment. Patients with positive rituximab blood level 3 months after treatment had a higher chance of remission at month-6 and at month-12 than patients with an undetectable rituximab level at month-3.
Nowadays, machine learning algorithms are increasingly used in medicine, especially in pharmacology, to predict the exposure to a drug, the initial dose to administer or the interval between two infusions.
The objective of this study is to use a machine learning algorithm predicting the risk of having an undetectable residual level of rituximab 3 months after treatment, in order to propose a personalized treatment management with early additional doses of rituximab for the patients at risk.
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
- •Age ≥ 18 years
- •Ongoing episode of membranous nephropathy diagnosed by the presence of anti-PLA2R1 antibodies detected by ELISA (≥ 14 RU/ml, EUROIMMUN): the result must be validated by the Coordination team before randomization.
- •Nephrotic syndrome defined by proteinuria > 3.5 g/24h (or UPCR > 3.5 g/g) and serum albumin < 30 g/L at diagnosis
- •Estimated Glomerular Filtration Rate (CKD-EPI formula) > 30 mL/min/1,73 m2
- •Indication for rituximab treatment according to the KDIGO and French guidelines
- •Non-immunosuppressive antiproteinuric treatment at stable dose for 2 weeks according to French guidelines, including a renin angiotensin aldosterone system inhibitor, a diuretic and a low-salt diet at maximal tolerated dose (i.e., absence of orthostatic hypotension and no increase in creatinine > 30%)
排除标准
- •Secondary Membranous nephropathy related to cancer, infection, systemic lupus, drug
- •Diagnosis of PLA2R1-associated Membranous nephropathy not confirmed by the Coordination team (validation mandatory for randomization)
- •Pregnancy or breastfeeding
- •Immunosuppressive treatment (including rituximab) in the 6 months preceding inclusion
- •Presence of anti-rituximab antibodies detected by Central Lab
- •Cancer under treatment
- •Patients with active, severe infections
- •Hypersensitivity to the active substance or excipients
- •Patients severely immunocompromised
- •Severe heart failure or severe, uncontrolled cardiac disease
研究组 & 干预措施
Standard-of-care
rituximab treatment 1gram x 2 (day-0, day-15)
干预措施: RiTUXimab Injection (Drug)
Personalised treatment
personalized treatment based on the algorithm for assessing the risk of having undetectable rituximab level after 3 months:
- Patients with a risk between 0 and 50% will receive 1gram x2 (day-0, day-15)
- Patients with a risk between 51 and 75% will receive 1gram x 3 (day-0, day-15, day-30)
- Patients with a risk between 76 and 100% will receive 1gram x 4 (day-0, day-15, day-30, day-45)
干预措施: RiTUXimab Injection (Drug)
结局指标
主要结局
Clinical remission (complete or partial) after 6 months of rituximab initiation
时间窗: 6 months
Clinical remission (complete or partial) according to KDIGO and French guidelines: * Complete: urine protein/creatinine ratio (UPCR) \<0.3 g/g and serum albumin\>30 g/L and Glomerular Filtration Rate (estimated by CKD-EPI formula) \>60 ml/min/1.73m2 * Partial: UPCR \<3.5 g/g with a decrease \>50% from baseline (i.e., at first rituximab infusion) and serum albumin improvement or normalization and stable serum creatinine (or increase \<30%).
次要结局
- Serious adverse events(84 months)
- Change in renal function(12 months)
- Change in urine protein/creatinine ratio (UPCR)(12 months)
- Change in serum creatinine(12 months)
- Appearance of anti-drug antibodies after rituximab treatment(12 months)
- Effect of rituximab on immune profiles(6 months)
- Rituximab underdosed patients(3 months)
- Complete clinical remission after 12 months of rituximab initiation(12 months)
- Partial clinical remission after 12 months of rituximab initiation(12 months)
- Immunological remission: anti-PLA2R1 depletion(12 months)
- Model improvement through machine learning(6 months)
- Change in the immunological status of the disease(12 months)
- Adaptation of symptomatic treatment(84 months)