STUDY OF TACI-FC5 ADMINISTERED TO PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本研究的目的是评估单剂量本研究药物治疗系统性红斑狼疮（SLE）的安全性、耐受性和有效性。目的：描述单次皮下给药后TACI-Fc5在SLE患者中的药代动力学（PK）和药效学（PD），并监测其对选定的疾病活性生物标志物的影响。研究设计：32名男性和女性患者将被纳入（4个队列，每组8人）。每位患者将在给药前14天内接受研究前访问评估，并接受单次皮下剂量的TACI-Fc5或相应的安慰剂。将评估多达四剂TACI-Fc5。第一组患者将接受单次皮下剂量TACI-Fc5，剂量为0.3 mg/kg。后续队列将根据剂量递增决策算法接受剂量，最高剂量为9 mg/kg。患者将在临床试验用药当天（研究第一天）到诊所就诊，并在12小时的药代动力学/药效学血液样本采集完成后才离开。他们将在门诊的基础上返回诊所进行给药后程序，包括收集药代动力学和药理学样本，并在给药后6周内按预先确定的间隔进行安全性评估。研究后访问计划在给药后6周（2天）进行。研究人群和主要入选标准：年龄在18 - 70岁之间，确诊为SLE的男性和女性患者，在筛查时至少符合4项ACR标准，SLE疾病活动性指数（SELENA SLEDAI）评分为0 - 8。预计将有32名患者分布在美国3个研究地点。试验产品：TACI-Fc5的液体制剂将以小瓶的形式提供，每瓶灌装0.5 mL，含有70mg TACI-Fc5。安慰剂将被装入0.5 mL SQ的小瓶中。数据分析与统计：本研究的主要目的是评估TACI-Fc5在SLE患者中的全身和局部耐受性。这将通过监测：生命体征、心电图和实验室参数（包括血液学、凝血、临床化学和尿液分析）来实现。在整个研究过程中，除了定期评估注射部位是否存在局部反应外，还将密切监测不良事件。该研究的次要目的是表征TACI-Fc5在SLE患者中的药代动力学和药效学特征，并监测其对疾病活动性生物标志物的影响。该研究的其他生物标志物终点将是评估淋巴细胞亚群，游离BLyS， BLyS/TACI-Fc5复合物，IgG和IgM以及抗dsdna抗体的血清浓度，直至给药后6周。抗taci - fc5抗体的血清水平将在第1天给药前和研究后访问时测量。评估将包括随时间推移的评估以及上述所有标记的基线变化。

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. OBJECTIVES: ¿ The purpose of this research study is to assess the safety, tolerability, and effectiveness of a single dose of this investigational agent which is being studied for the treatment of systemic lupus erythematosus (SLE). ¿ To characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of TACI-Fc5 in SLE patients following a single subcutaneous dose, and to monitor its effects on selected biological markers of disease activity. STUDY DESIGN: Thirty-two male and female patients will be included (as 4 cohorts of 8). Each will undergo assessment at a pre-study visit within 14 days before administration of the investigational product, and will receive a single subcutaneous dose of TACI-Fc5 or corresponding placebo. Up to four doses of TACI-Fc5 will be assessed. The first cohort will be administered a single subcutaneous dose of TACI-Fc5 at a dose of 0.3 mg/kg. Subsequent cohorts will receive doses based upon the dose-escalation decision algorithm, up to a maximal dose of 9 mg/kg. Patients will attend the clinic on the day of investigational medicinal product administration (Study Day 1) and remain resident until after the 12 hr Pharmacokinetic/Pharmacodynamic blood samples have been collected. They will return to the clinic on an outpatient basis for post-dose procedures that include collection of pharmacokinetic and pharmacodynamic samples and safety assessments conducted at pre-defined intervals up to 6 weeks following dosing. A post-study visit is scheduled to take place 6 weeks (¿ 2 days) following dosing. STUDY POPULATION AND MAIN ELIGIBILITY CRITERIA: Male and female patients aged 18 to 70 yrs with proven diagnosis of SLE with at least 4 of the ACR criteria at the time of screening and SLE disease activity index (SELENA SLEDAI) score 0 - 8. Thirty-two patients will be expected, distributed between 3 US study sites. INVESTIGATIONAL PRODUCT: The liquid formulation of TACI-Fc5 will be provided in vials filled to deliver 0.5 mL and containing 70 mg of TACI-Fc5. The placebo will be provided in vials filled to deliver 0.5 mL SQ. DATA ANALYSIS AND STATISTICS: The primary objective of the study is to perform an assessment of the systemic and local tolerability of TACI-Fc5 in patients with SLE. This will be achieved through monitoring of: vital signs, ECGs and laboratory parameters (including hematology, coagulation, clinical chemistry and urinalysis). Close monitoring of adverse events will be conducted throughout the study in addition to regular assessments of the injection site for evidence of localized reactions. The secondary objective of the study is to characterize the pharmacokinetics and pharmacodynamics of TACI-Fc5 in SLE patients and to monitor the effects on the biological markers of disease activity. Additional biological markers endpoints of the study will be the assessment of lymphocyte subsets, serum concentrations of free BLyS, BLyS/TACI-Fc5 complex, IgG and IgM and anti-dsDNA antibodies up to 6 weeks post-dose. Serum levels of anti-TACI-Fc5 antibodies will be measured at pre-dose on day 1 and at the post-study visit. The assessment will include the evaluation over time and change from baseline for all the markers above.