RITUXIMAB IN SUBJECTS WITH MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS

利妥昔单抗用于中度至重度系统性红斑狼疮患者

• 批准号: 7605227
• 负责人: ELIZA F CHAKRAVARTY
• 金额: $ 0.64万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605227
• 关键词: 6-Mercaptopurine; Adrenal Cortex Hormones; Antimalarials; Area Under Curve; Azathioprine; B-Lymphocytes; Chloroquine; Clinical; Computer Retrieval of Information on Scientific Projects Database; Daily; Disease; Dose; Double-Blind Method; Drug Kinetics; Elements; End Point; Enrollment; Flare; Funding; Grant; Great Britain; Health Surveys; Hydroxychloroquine; Immunosuppressive Agents; Infusion procedures; Institution; Intravenous; Label; Laboratories; Lower Limit of Normal; Lupus; Measures; Medlone 21; Methotrexate; Multicenter Studies; Oral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Prednisone; Protocols documentation; Quality of life; Randomized; Recovery; Research; Research Personnel; Resources; Retreatment; SF-36; Safety; Score; Screening procedure; Source; Systemic Lupus Erythematosus; Time; United States; United States National Institutes of Health; Week; base; day; design; improved; indexing; mycophenolate mofetil; response; 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. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 主要目标 本研究的主要目的是评估利妥昔单抗与安慰剂相比在中度至重度系统性红斑狼疮 (SLE) 受试者中实现和维持主要临床缓解 (MCR) 或部分临床缓解 (PCR) 的疗效。 次要目标 本研究的次要目标（比较利妥昔单抗与安慰剂）将评估以下内容： o 利妥昔单抗降低整体 SLE 疾病活动的能力，通过不列颠群岛狼疮评估组 (BILAG) 评估的 52 周时间调整曲线下面积减去基线 (AUCMB) 评分来衡量 o 利妥昔单抗诱导 MCR（不包括 PCR）或 PCR（包括 MCR）的能力 o 利妥昔单抗的安全性和耐受性 o 利妥昔单抗治疗受试者在第 24 周达到 BILAG C 或更好的能力 o 利妥昔单抗能够延长中度或重度发作的时间 o 通过 SLE 扩展健康调查衡量，利妥昔单抗改善生活质量的能力（SF-36 指数以及狼疮特有的其他元素） o 接受利妥昔单抗治疗的受试者可节省皮质类固醇 o 利妥昔单抗在 SLE 受试者中的药代动力学 研究设计 这是一项 II/III 期、随机、双盲、安慰剂对照、多中心研究，旨在评估利妥昔单抗与安慰剂相比，与单一稳定背景免疫抑制药物联合治疗中度至重度 SLE 受试者的疗效和安全性。该试验的主要疗效终点将在第 52 周时进行评估。该研究将在美国约 55 个中心招募约 250 名受试者。受试者将以 2:1 的比例随机分配接受利妥昔单抗 + 泼尼松或安慰剂 + 泼尼松。随机受试者将接受静脉注射 (IV) 研究药物 + 2 次，间隔 15 天，每 6 个月重复一次。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 mg IV solumedrol。 参赛时，受试者必须在一个或多个领域获得 BILAG A 分数，或在两个或多个领域获得 BILAG B 分数。需要同时服用的药物有硫唑嘌呤、6-巯基嘌呤、吗替麦考酚酯 (MMF) 或甲氨蝶呤 (MTX)；加泼尼松和抗疟药（羟氯喹或氯喹）。筛选后，符合条件的受试者将根据其 BILAG 评分和研究前泼尼松剂量每日接受口服泼尼松（0.5 mg/kg、0.75 mg/kg 或 1.0 mg/kg）。从第 16 天开始，受试者将被分配预先指定的泼尼松逐渐减量，持续 10 周，直到达到泼尼松剂量 = 10 毫克/天。 10周后，受试者将在耐受的情况下继续逐渐减少皮质类固醇剂量，直至目标剂量= 5 mg/天，直至第52周。第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）。未进入再治疗研究的受试者将在第 26 周接受最后一剂研究药物后随访至少 52 周。未进入再治疗研究的受试者将由研究者随访直至第 78 周或直至 B 细胞恢复，以较长者为准。 B 细胞恢复被定义为 B 细胞水平已恢复至基线（第 1 天）或中心实验室定义的正常下限。