RITUXIMAB THERAPY FOR THE INDUCTION REMISSION AND TOLERANCE IN ANCA-ASSOCIATE

Rituximab（利妥昔单抗）治疗对 ANCA-ASSICATE 的诱导缓解和耐受

• 批准号: 7608186
• 负责人: Carol Langford
• 金额: $ 1.01万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608186
• 关键词: Antibodies; Antigen Targeting; Antineutrophil Cytoplasmic Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Azathioprine; Cessation of life; Clinical; Computer Retrieval of Information on Scientific Projects Database; Condition; Cyclophosphamide; Daily; Disease; Disease remission; Funding; Genetic Crossing Over; Grant; Immune; Incidence; Infusion procedures; Injury; Institution; Intravenous; Maintenance; Methylprednisolone; Microscopic polyangiitis; Outcome; Participant; Patients; Peroxidase; Phase; Physiologic pulse; Placebos; Prednisone; Prevalence; Production; Proteinase 3; Pulse taking; Randomized; Recurrent disease; Remission Induction; Remission Induction Therapy; Research; Research Personnel; Resources; Safety; Series; Source; Surface; Time; Tissues; Toxic effect; Treatment Failure; United States National Institutes of Health; Upper arm; Vasculitis; Wegener' s Granulomatosis; day; monocyte; neutrophil; placebo controlled study; rituximab

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. The primary objectives of this study are to determine the effect of rituximab on remission induction in patients with ANCA associated vasculitis as compared with conventional therapy and to compare the safety profile of rituximab with conventional therapy. Other aims include to determine if rituximab will induce a lasting effect after remission induction, thereby maintaining remission after rituximab is discontinued (clinical tolerance), and to determine the effect of rituximab on specific immune parameters through a series of detailed mechanistic studies. Wegener's granulomatosis (WG) and microscopic polyangiitis are the two major forms of systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). The incidence of these disorders in the US is about 6,000 new cases per year, with the estimated prevalence at 25 - 30,000. These conditions are termed ANCA-associated vasculitides (AAV) because of their strong associations with these hightly specific autoantibodies. AAV are autoimmune disorders in which tolerance for one of two self-antigens (proteinase 3 (PR3) or myeloperoxidase (MPO), has been lost, leading to the production of PR3-ANCA or MPO-ANCA. Clinical observations indicate that endothelial injury and tissue damage are dependent upon the proinflammatory effects of ANCA that result from the interaction of these specific antibodies with their target antigens on the surface of activated neutrophils and monocytes. There is preliminary evidence that anti-CD20 therapy (rituximab) may reestablish tolerance to the ANCA target antigens. If untreated, the outcome of AAV is death. Conventional therapies are associated with a high percentage of treatment failures, disease relapses and substantial toxicity. The study is a randomized, multicenter, doublemasked, placebo controlled trial. A total of 228 participants will be randomized 1:1 to either the control arm or the experimental arm. Patients in both treatment arms will receive a 3 day intravenous pulse of methylprednisolone followed by prednisone. During the remission induction phase, the control arm will receive weekly rituximab placebo infusions (times 4) and daily cyclophosphamide (CYC) for between 3 and 6 months, followed by azathioprine (AZA) for 12 months in the remission maintenance phase. During the remission induction phase, the experimental arm will receive weekly rituximab infusions (times 4) and daily CYC placebo for 3 - 6 months, followed by AZA placebo for 12 months in the remission maintenance phase. Patients who are defined as treatment failures (within the first 6 months after randomization) will be crossed over to the other treatment arm.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这项研究的主要目标是确定利妥昔单抗与常规疗法相比，对ANCA相关血管炎患者的缓解诱导的影响，并比较利妥昔单抗的安全性与常规疗法的安全性。 其他目的包括确定利妥昔单抗是否会在缓解诱导后产生持久作用，从而在利妥昔单抗中停止（临床耐受性）后保持缓解，并通过一系列详细的机械研究来确定利妥昔单抗对特定免疫参数的影响。 Wegener的肉芽肿病（WG）和微观多血管炎是与抗中性嗜性胞质抗体（ANCA）相关的两种主要形式的全身性血管炎。 这些疾病在美国的发生率每年约为6,000例新病例，估计患病率为25-30,000。 这些条件称为与ANCA相关的血管（AAV），因为它们与这些特异性自身抗体有着密切的关联。 AAV是自身免疫性疾病，其中一种自我抗原之一（蛋白酶3（PR3）或脊髓过氧化物酶（MPO））丧失，导致产生PR3-ANCA或MPO-ANCA。临床疾病的产生激活的中性粒细胞和单核细胞表面上有抗原。 如果未经治疗，AAV的结果就是死亡。 常规疗法与治疗失败，疾病复发和实质性毒性相关。 这项研究是一项随机，多中心，doublemaker，安慰剂对照试验。 共有228名参与者将被随机分配给对照组或实验组。 两种治疗臂的患者将接受3天的甲基泼尼松龙静脉静脉脉冲，然后再接受泼尼松。 在缓解诱导阶段，控制臂将每周接受Rituximab安慰剂输注（时间4）和每日环磷酰胺（CYC）3至6个月之间，然后在缓解阶段进行12个月的硫唑嘌呤（AZA）。 在缓解诱导阶段，实验组将每周接受利妥昔单抗输注（次4）和CYC安慰剂3-6个月，然后在缓解阶段进行12个月的AZA安慰剂。 被定义为治疗失败的患者（在随机分组后的前6个月内）将越过另一个治疗臂。