A PHASE II TRIAL OF RITUXAN IN MULTIPLE SCLEROSIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Rituxan(Genetech)是一种人源化的针对B细胞特异性抗原CD20的单抗。它已用于非霍奇金淋巴瘤的治疗已有多年。有在数百名人类受试者中使用这种药物的经验，但在多发性硬化症患者中没有。该药将分4次静脉注射，间隔一周375 mg/m2。该剂量可在治疗后6个月内完全消除循环中的B细胞。有大量数据表明B细胞和/或抗体可能参与MS的发病机制，然而，要确定B细胞是否真正发挥作用，将需要评估它们的消除是否有利于MS的病程。因此，作为第一步，我们建议对30名患者进行Rituxan安全性和有效性的II期试验，30名活动期、复发性MS患者在试验期间将继续服用标准剂量的β-干扰素。参加试验的受试者必须在三种治疗前脑部核磁共振成像中的任何一种上有两个镓强化病变的证据，并且在登记前的18个月内至少有一次临床复发，尽管正在接受β-干扰素治疗。终点将是安全的，就药物的毒性和MS恶化的可能性而言，以及基于MRI活动替代测量的有效性。与治疗前每月三次的磁共振成像相比，治疗后每月进行一次的脑部磁共振成像的主要疗效终点将是Gd增强病变的体积减少。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rituxan (Genetech) is a humanized monoclonal antibody directed against the B-cell specific antigen, CD20. It has been used for several years in the therapy of non-Hodgkin's lymphoma. There is experience using this agent in several hundred human subjects, but not in MS patients. The agent will be administered intravenously in 4 doses, one week apart of 375mg/m2. This dose eliminates circulating B cells completely for up to 6 months following therapy. There is considerable data that B cells and/or antibody may be involved in the jpathogenesis of MS. However, to determine whether B cells truly play a role will require an assessment of whether their eliminiation benefits the course of MS. Therefore, as a first step we propose a 30 patient, Phase II trial of the safety and efficacy of Rituxan in 30 patients with active, relapsing MS. Patients will continue taking the standard dose of beta-interferon while in the trial. Subjects enrolled in the trial must have evidence of two gadolinium0enhacing lesions on any of three pre-treatment brain MRIs, and will have had at least one clinical relapse in the 18months prior to enrollment, despite being on beta-interferon therapy. The endpoints will be safety, in terms of toxicity of the agent and the possibility of worsening of MS, and efficacy based on the surrogate measure of MRI activity. The primary efficacy endpoint will be reduction in volume of gadolinium-enhancing lesions on the 3-once-monthly brain MRIs performed post-treatment in comparison to the three once-monthly MRIs performed pre-treatment.