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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的主要目的是确定利妥昔单抗与常规治疗相比对ANCA相关性血管炎患者诱导缓解的作用，并比较利妥昔单抗与常规治疗的安全性。 其他目的包括确定利妥昔单抗在缓解诱导后是否会诱导持久效应，从而在利妥昔单抗停药后维持缓解（临床耐受性），并通过一系列详细的机制研究确定利妥昔单抗对特定免疫参数的影响。 韦格纳肉芽肿病（WG）和显微镜下多血管炎是与抗中性粒细胞胞浆抗体（ANCA）相关的系统性血管炎的两种主要形式。 这些疾病在美国的发病率为每年约6，000例新发病例，估计患病率为25 - 30，000例。 这些疾病被称为ANCA相关血管炎（AAV），因为它们与这些高度特异性的自身抗体有很强的相关性。 AAV是自身免疫性疾病，其中对两种自身抗原（蛋白酶3（PR 3）或髓过氧化物酶（MPO））之一的耐受性已经丧失，导致PR 3-ANCA或MPO-ANCA的产生。 临床观察表明，内皮损伤和组织损伤依赖于ANCA的促炎作用，其由这些特异性抗体与活化的中性粒细胞和单核细胞表面上的靶抗原相互作用引起。 有初步证据表明，抗CD 20治疗（利妥昔单抗）可以重建对ANCA靶抗原的耐受性。 如果不治疗，AAV的结局是死亡。 常规疗法与高百分比的治疗失败、疾病复发和实质性毒性相关。 本研究是一项随机、多中心、双重要求、安慰剂对照试验。 共228名受试者将以1：1的比例随机分配至对照组或实验组，两个治疗组的患者将接受3天的甲泼尼龙静脉冲击，随后接受泼尼松。 在缓解诱导期，对照组将接受每周一次利妥昔单抗安慰剂输注（4次）和每日一次环磷酰胺（CYC）治疗3至6个月，随后在缓解维持期接受硫唑嘌呤（AZA）治疗12个月。 在缓解诱导期，实验组将接受每周利妥昔单抗输注（4次）和每日CYC安慰剂，持续3 - 6个月，随后在缓解维持期接受AZA安慰剂，持续12个月。 定义为治疗失败（随机化后前6个月内）的患者将交叉至另一个治疗组。