CLINICAL TRIAL: RITUXIMAB IN SUBJECTS WITH MODERATE TO SEVERE SYSTEMIC LUPUS ERY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 首要目标 这项研究的主要目的是评估利妥昔单抗与安慰剂在实现和维持中重度系统性红斑狼疮(SLE)患者的主要临床应答(MCR)或部分临床应答(PCR)方面的疗效。 次要目标 这项研究的次要目标(比较利妥昔单抗和安慰剂)将评估以下方面： O利妥昔单抗降低整体SLE疾病活动度的能力，通过时间调整后的曲线下面积减去基线(AUCMB)和不列颠岛狼疮评估小组(BILAG)在52周内的评估来衡量 O利妥昔单抗诱导MCR(不包括多药耐药)或多药耐药(包括MCR)的能力 O利妥昔单抗的安全性和耐受性 O接受利妥昔单抗治疗的受试者在24周时达到BILAG C或更好的能力 O利妥昔单抗能够将时间延长至中度或重度红斑 O通过系统性红斑狼疮扩展健康调查(SF-36指数，包括狼疮特有的其他元素)衡量，利妥昔单抗改善生活质量的能力 O接受利妥昔单抗治疗的受试者避免使用皮质类固醇 美罗华在系统性红斑狼疮患者体内的药代动力学 研究设计 这是一项II/III期、随机、双盲、安慰剂对照的多中心研究，目的是评估利妥昔单抗与安慰剂在中、重度系统性红斑狼疮患者中与单一稳定背景免疫抑制药物联合使用时的有效性和安全性。试验的主要疗效终点将在52周时进行评估。这项研究将在美国约55个中心招募约250名受试者。受试者将以2：1的比例随机接受利妥昔单抗+强的松或安慰剂+强的松。随机受试者将接受静脉注射(IV)研究药物+2，间隔15天，重复6个月。此外, 受试者将在每种研究药物(利妥昔单抗或安慰剂)输注前30-60分钟接受100毫克的索鲁美德罗静脉注射。 在参赛时，受试者必须在一个或多个域中获得BILAG A分，或者在两个或更多域中获得BILAG B分。需要的伴随药物有硫唑嘌呤、6-巯基嘌呤、霉酚酸酯(MMF)或甲氨蝶呤(MTX)；加上泼尼松和抗疟疾药(羟氯喹或氯喹)。筛选后，符合条件的受试者将根据他们的BILAG评分和研究前的泼尼松剂量，每天服用强的松(0.5 mg/kg、0.75 mg/kg或1.0 mg/kg)。受试者将从第16天开始接受预先指定的泼尼松减量，为期10周，直到强的松剂量达到=10毫克/天。10周后，受试者将继续减少他们的皮质类固醇耐受性，目标剂量为=5毫克/天，至第52周。52周后，符合条件的受试者可以进入开放标签再治疗研究(根据单独的方案)。没有进入再治疗研究的受试者将在第26周最后一次服用研究药物后被跟踪至少52周。没有进入再治疗研究的受试者将由研究人员跟踪，直到第78周或B细胞恢复，以时间较长者为准。B细胞恢复的定义是指B细胞水平已恢复到基线(第1天)或中心实验室定义的正常下限。

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. PRIMARY OBJECTIVE The primary objective of this study is to assess the efficacy of rituximab compared with placebo in achieving and maintaining a major clinical response (MCR) or partial clinical response (PCR) in subjects with moderate to severe systemic lupus erythematosus (SLE). SECONDARY OBJECTIVES The secondary objectives of this study (comparing rituximab with placebo) will be to evaluate the following: o Ability of rituximab to decrease overall SLE disease activity as measured by time-adjusted area under the curve minus baseline (AUCMB) scoring with the British Isles Lupus Assessment Group (BILAG) assessment over 52 weeks o Ability of rituximab to induce MCRs (excluding PCRs) or PCRs (including MCRs) o Safety and tolerability of rituximab o Ability of rituximab-treated subjects to achieve a BILAG C or better at Week 24 o Ability of rituximab to prolong the time to a moderate or severe flare o Ability of rituximab to improve quality of life as measured by SLE Expanded Health Survey (SF-36 index with additional elements specific to lupus) o Corticosteroid-sparing in subjects receiving rituximab o Pharmacokinetics of rituximab in subjects with SLE STUDY DESIGN This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe SLE. The primary efficacy endpoint of the trial will be evaluated at 52 weeks. The study will enroll approximately 250 subjects at approximately 55 centers in the United States. Subjects will be randomized in a 2:1 ratio to receive rituximab + prednisone or placebo + prednisone. Randomized subjects will receive intravenous (IV) study drug + 2 separated by 15 days that is repeated at 6 months. In addition, subjects will receive 100 mg IV solumedrol 30-60 minutes prior to each study drug (rituximab or placebo) infusion. At entry, subjects must have a BILAG A score in one or more domains or a BILAG B score in two or more domains. Concomitant medications required are azathioprine, 6-mercaptopurine, mycophenolate mofetil (MMF), or methotrexate (MTX); plus prednisone and antimalarials (hydroxychloroquine or chloroquine). After screening, eligible subjects will receive daily oral prednisone (0.5 mg/kg, 0.75 mg/kg, or 1.0 mg/kg), based on their BILAG score and prestudy prednisone dose. Subjects will be assigned a prespecified prednisone taper starting on Day 16 for 10 weeks until a prednisone dose of = 10 mg/day is reached. After 10 weeks, subjects will continue to taper their corticosteroid as tolerated to a target dose of = 5 mg/day to Week 52. After Week 52, eligible subjects may enter an open-label retreatment study (under a separate protocol). Subjects who do not enter the retreatment study will be followed for at least 52 weeks after their last dose of study drug at Week 26. Subjects who do not enter the retreatment study will be followed by the investigator until Week 78 or until B-cell recovery, whichever is longer. B-cell recovery is defined as B-cell levels that have returned to baseline (Day 1) or to the lower limit of normal, as defined by the central laboratory.