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

基本信息

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
项目类别：
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

项目摘要

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）：重症肌无力 (MG) 是一种神经肌肉传递的自身免疫性疾病，估计年发病率为每 100,000 人中约 1-2 例，患病率高达每 100,000 人 20-50 例。治疗包括乙酰胆碱酯酶抑制剂的对症治疗和免疫治疗，例如皮质类固醇、硫唑嘌呤、环孢菌素、血浆置换 (PLEX) 和静脉注射免疫球蛋白 (IVIg)。尽管有目前的治疗方法，部分患者仍然难以治疗或具有无法忍受的药物副作用。由于有效药物很少，因此需要另一种药物来治疗 MG。安全、耐受性良好、有效且节省类固醇的治疗方法是非常理想的。我们提出的研究将有助于确定一种新的 MG 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）已经证明了 B 细胞耗竭利妥昔单抗治疗对 MG 患者的益处。我们完成了一项小型回顾性研究，以评估 B 细胞靶向治疗治疗难治性全身性 MG 的效果。在这项分析中，我们表明，利妥昔单抗在减少或停止其他免疫疗法的同时，也带来了持续的临床改善。我们现在计划利用无效设计进行多中心随机、双盲、安慰剂对照的 II 期临床试验。该研究将包括乙酰胆碱受体（AChR）抗体阳性的全身性重症肌无力患者。这项研究还提供了研究药物和疾病机制的独特机会，因为与使用利妥昔单抗的许多其他自身免疫性疾病不同，MG 提供了参与该疾病免疫病理学的抗原特异性成分的研究。这项工作将进一步加深我们对 MG 免疫病理学的理解，它代表着更全面地了解利妥昔单抗治疗 MG 的免疫机制的第一步，从而找到治疗该疾病的新方法。本研究的具体主要目的是确定利妥昔单抗是否安全，并显示出作为 MG 的类固醇节省疗法是否有足够的前景，以保证在 III 期疗效试验中进行进一步研究。此外，我们计划收集样本以进行一项由 NIAID 资助的辅助探索性生物标志物研究，重点是确定治疗如何改变 MG 的免疫病理学。