A Phase II Trial of Rituximab In Myasthenia Gravis

利妥昔单抗治疗重症肌无力的 II 期试验

• 批准号: 8644497
• 负责人: Richard J. Barohn
• 金额: $ 130.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644497
• 关键词: Acetylcholinesterase Inhibitors; Activities of Daily Living; Adrenal Cortex Hormones; Adverse effects; Adverse event; Advisory Committees; Affect; Americas; Antigens; Area; Autoimmune Diseases; Autoimmunity; Azathioprine; B-Lymphocytes; Biological Markers; Blood specimen; Clinical; Clinical Trials; Clinical Trials Design; Cyclosporine; Disease; Dose; Double-Blind Method; Effectiveness; Eyelid structure; Failure; Fc Receptor; Flare; Foundations; Frequencies; Funding; Futility; Future; Generalized Myasthenia Gravis; Immune; Immunosuppression; Immunotherapy; Incidence; Intervention; Intravenous Immunoglobulins; Investigation; Leg; Maintenance; Measurable; Measures; Medical; Monitor; Muscle; Myasthenia Gravis; National Institute of Allergy and Infectious Disease; Observational Study; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebo Control; Plasma Exchange; Prednisone; Prevalence; Quality of life; Randomized; Recovery; Refractory; Research; Research Design; Retrospective Studies; Safety; Schedule; Signal Transduction; Specimen; Staging; Steroids; Symptoms; Therapeutic; Time; United States National Institutes of Health; Work; arm; base; design; efficacy trial; immunopathology; improved; interest; neuromuscular transmission; novel; public health relevance; pyridostigmine; response; rituximab; treatment strategy; trend

DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an estimated annual incidence of about 1-2 per 100,000 and prevalence as high as 20-50 per 100,000. Treatment consists of symptomatic therapy with acetylcholinesterase inhibitors and immunotherapy such as corticosteroids, azathioprine, cyclosporine, and plasma exchange (PLEX) and intravenous immunoglobulin (IVIg). Despite current therapies, subset of patients remains medically refractory or has intolerable medication adverse effects. There is need for another agent in the management of MG as there are few effective drugs. Safe, well- tolerated, efficacious and steroid-sparing therapeutics are very desirable. Our proposed research will be instrumental in identifying a novel treatment strategy for MG that may be more effective than current approaches. Several recent studies, including two performed by our group, have demonstrated the benefits of B cell depletion rituximab treatment in MG patients. We completed a small retrospective study to evaluate B cell targeted therapy in medically refractory generalized MG. In this analysis we showed that rituximab led to a sustained clinical improvement in parallel to a reduction or discontinuation of other immunotherapies. We now plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholie receptor (AChR) antibody positive generalized MG patients. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease. The specific primary aim of this study is to determine whether rituximab is safe and shows sufficient promise as a steroid sparing therapeutic for MG to warrant further study in a phase III efficacy trial. Additionally, we plan on collecting specimens to conduct an ancillary exploratory biomarker study, funded by NIAID, focused on identifying how treatment modifies the immunopathology of MG.

描述（由申请人提供）：肌无力重症（MG）是一种神经肌肉传播的自身免疫性疾病，估计的年发病率约为每100,000次约1-2，患病率高达20-50 / 100,000。治疗包括对乙酰胆碱酯酶抑制剂的症状治疗以及免疫疗法，例如皮质类固醇，硫唑嘌呤，环孢菌素和血浆交换（PLEX）和静脉内免疫球蛋白（IVIG）。尽管目前疗法，但患者的子集仍然在医学上难治性或无法忍受的药物不良反应。由于很少有有效的药物，因此在MG管理中需要另一个代理商。安全，耐受性，有效且具有类固醇的治疗是非常可取的。我们提出的研究将有助于确定MG的新型治疗策略，该策略可能比目前的方法更有效。最近的几项研究，包括我们小组进行的两项研究，证明了B细胞耗尽利妥昔单抗治疗对MG患者的好处。我们完成了一项小型回顾性研究，以评估医学上难治性的普通MG中B细胞靶向疗法。在此分析中，我们表明利妥昔单抗在与其他免疫疗法的减少或停药并行相关的临床改善中得到了持续的临床改善。现在，我们计划使用徒劳的设计进行多中心随机，双盲，安慰剂控制的II期临床试验。该研究将包括乙酰胆碱受体（ACHR）抗体阳性通用MG患者。这项研究还为研究药物和疾病机制提供了独特的机会，因为与许多其他使用利妥昔单抗的自身免疫性疾病不同，MG调查了参与该疾病免疫病理学的抗原特异性成分。这项工作将进一步了解MG免疫病理学，它代表了对使用Rituximab对MG治疗的免疫机制获得更完整理解的第一步，从而导致了治疗该疾病的新方法。这项研究的具体主要目的是确定利妥昔单抗是否安全，并显示出足够的希望作为MG的类固醇保留治疗方法，可以在III期有效性试验中进行进一步研究。此外，我们计划 收集标本以进行由NIAID资助的辅助探索性生物标志物研究，重点是确定治疗方法如何修饰MG的免疫病理学。