A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 17
- 主要终点
- mRS 17 weeks after first administration of the investigational product
研究概览
简要总结
Evaluation of the efficacy and safety of bortezomib in patients with severe autoantibody-positive autoimmune encephalitis
详细描述
Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming for a reduction of pathogenic antibodies and containing the autoimmune process. In first line, patients are treated with plasmapheresis and cortisone. In second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments are, however, often delayed and insufficient.
Therefore, we need a specific therapy aiming at the antibody-producing plasma cells.
Bortezomib is a proteasome inhibitor which interferes with NF-kB (nuclear factor kB) and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis - like plasma cells - and induces cell death in these cells. Bortezomib is used since more than a decade in chemotherapy of the multiple myeloma. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells and therefore reduces the number of pathogenic antibodies and improves clinical outcome. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with 5 patients.
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)
盲法说明
The study drug will be provided blinded by the local pharmacy.
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Clinically diagnosed severe autoimmune encephalitis (defined as mRS ≥ 3)
- •Autoantibodies against neuronal surface proteins in cerebrospinal fluid or serum serum, detection must not be older than 4 weeks, calculated before randomization
- •Pre-treatment with rituximab
- •Age ≥ 18 years
- •Written informed consent of the patient or the patient “under witness” (if the patient cannot write for motor reasons) cannot write themselves) or the legal representative (=guardian) or the authorized representative
- •Potentially fertile patient (up to 2 years after menopause): negative pregnancy test
排除标准
- •Acute infiltrative lung disease
- •Acute infiltrative pericardial disease
- •Malignant tumor under ongoing or newly started chemotherapy
- •Concurrent participation in another intervention study
- •Previous participation in this study
- •Known hypersensitivity to any ingredient of the investigational product
- •Continued therapy with glucocorticoids/rituximab during the duration of the study (last administration must be completed before first administration of investigational product)
结局指标
主要结局
mRS 17 weeks after first administration of the investigational product
mRS 17 weeks after first administration of the investigational product
次要结局
- mRS and GCS 3, 6, 9 and 13 weeks after first administration of the investigational product; GCS 17 weeks after first administration of the investigational product
- Length of stay in hospital/intensive care unit
- Antibody titers and destruction markers (in serum and cerebrospinal fluid), cellular immune response (FACS, in cerebrospinal fluid) at the baseline visit and 17 weeks after first administration of the investigational product
- Neurocognitive function (MoCA, MMST, VLMT and NPI) at the baseline visit and 17 weeks after the first visit and 17 weeks after first administration of the investigational product
- Number of all (serious) adverse events within 17 weeks after the first 17 weeks after first administration of the investigational product
- Bortezomib safety with regard to polyneuropathy, increase in liver enzymes liver enzymes, hematotoxicity, gastrointestinal toxicity and secondary infections.
研究者
Prof. Dr. Christian Geis
Scientific
Friedrich-Schiller-Universitaet Jena