CLINICAL TRIAL: A PHASE I, PROSPECTIVE, RANDOMIZED, CROSSOVER STUDY TO COMPARE

临床试验：I 期、前瞻性、随机、交叉研究进行比较

• 批准号: 8166732
• 负责人: DONALD MAHONEY
• 金额: $ 0.31万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166732
• 关键词: Acute; Adherence; Adolescent; Adult; Age; Area Under Curve; Buffers; Characteristics; Clinical Research; Clinical Trials; Communities; Computer Retrieval of Information on Scientific Projects Database; Cross-Over Studies; Dose; Drug Kinetics; Elements; Evaluation; Excipients; Funding; Grant; Guidelines; Half-Life; Hemophilia A; Hemorrhage; Infusion procedures; Institution; Measures; Oryctolagus cuniculus; Outcome; Patients; Pharmaceutical Preparations; Phase; Plasma; Randomized; Reaction; Recombinants; Recovery; Research; Research Personnel; Resources; Safety; Source; Testing; Time; Tissues; Treatment Protocols; United States National Institutes of Health; Vial device; clinical lot; cohort; improved; intravenous administration; manufacturing process; meetings; prospective; reconstitution; residence

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. Prompt treatment of acute bleeding episodes and adherence to bleeding treatment regimens improve outcomes in hemophilia patients. It is believed that these objectives will be better met by improving the convenience characteristics of FVIII concentrates as defined by the hemophilia community: smaller infusion volume, faster infusion times, and higher potency. Baxter is proposing to decrease the volume of diluent SWFI used for reconstitution to 2 mL. No changes have been made to the manufacturing process of rAHF-PFM. Reconstitution of the product in a smaller volume of diluent leads to a faster infusion of the product due to lesser volume. However, the excipient concentration in the vial increases ~ 2.5 fold. The possible effect of this increase in excipient concentration on pharmacokinetic parameters and immediate tolerability will be examined in this study. The local tolerance of rAHF-PFM was evaluated in rabbits for the 2 mL (reduced volume) and the 5 mL reconstitution volumes. The 5 mL and the 2 mL reconstitutions of both strengths tested were well tolerated after intravenous administration. However, intra-arterially or paravenously administered drug product, reconstituted in the 2 mL volume (but not the 5 mL volume), caused a very mild, short-term tissue reaction, observed as a very slight reddening. This effect was also observed for the 2 mL reconstituted buffer control. Baxter clinical study 060702 will investigate the effects of rAHF-PFM reconstituted in 2 mL SWFI on pharmacokinetic parameters and safety compared to rAHF-PFM reconstituted in 5 mL SWFI. The basic elements used in this study conform to those outlined in the Committee for Proprietary Medicinal Products (CPMP) guidelines for recombinant FVIII concentrates, and the pharmacokinetic evaluation of rAHF-PFM will utilize a minimum of 3 clinical lots. rAHF-PFM reconstituted with either 2mL or 5mL SWFI as measured by the AUC0-48 h with a single dose (50 IU/kg) will be equivalent in treatment of patients with severe hemophilia A. Primary Objective:To determine the effect of rAHF-PFM reconstituted in 2 mL SWFI on the area under the curve (AUC) 0-48h in adolescents/adults. Secondary objectives:To evaluate the safety of rAHF-PFM reconstituted in 2 mL SWFI in both age cohorts. To determine the effect of rAHF-PFM on incremental recovery in both age cohorts; and total AUC, terminal half-life (T1/2), clearance (CL), mean residence time (MRT), volume of distribution at steady state (Vss) and maximum plasma concentration (Cmax) in the adolescent/adult cohort. S).

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 对于中心来说，它不一定是研究者的机构。 及时治疗急性出血事件并坚持出血治疗方案可改善血友病患者的预后。 据信，通过改善血友病界定义的 FVIII 浓缩物的便利特性，可以更好地实现这些目标：更小的输注量、更快的输注时间和更高的效力。 百特建议将用于重构的稀释液 SWFI 体积减少至 2 mL。 rAHF-PFM 的制造工艺没有发生任何变化。 由于体积较小，用较小体积的稀释剂重构产品可加快产品的输注速度。然而，小瓶中的赋形剂浓度增加约 2.5 倍。本研究将探讨辅料浓度增加对药代动力学参数和即时耐受性的可能影响。 在兔子中评估了 2 mL（减少体积）和 5 mL 重构体积的 rAHF-PFM 的局部耐受性。 所测试的两种规格的 5 mL 和 2 mL 重构液在静脉注射后均具有良好的耐受性。然而，动脉内或静脉旁给药的药物产品，以 2 mL 体积（但不是 5 mL 体积）重构，引起非常轻微的短期组织反应，观察到非常轻微的变红。 2 mL 重构缓冲液对照也观察到了这种效应。 Baxter 临床研究 060702 将研究与在 5 mL SWFI 中重构的 rAHF-PFM 相比，在 2 mL SWFI 中重构的 rAHF-PFM 对药代动力学参数和安全性的影响。本研究中使用的基本要素符合专利药品委员会 (CPMP) 重组 FVIII 浓缩物指南中概述的内容，rAHF-PFM 的药代动力学评估将使用至少 3 个临床批次。 用 2mL 或 5mL SWFI 重构的 rAHF-PFM（通过单剂量（50 IU/kg）的 AUC0-48 小时测量）对于严重 A 型血友病患者的治疗效果是等效的。 主要目的：确定在 2 mL SWFI 中重构的 rAHF-PFM 对青少年/成人 0-48 小时曲线下面积 (AUC) 的影响。 次要目标：评估在两个年龄组中用 2 mL SWFI 重构的 rAHF-PFM 的安全性。确定 rAHF-PFM 对两个年龄组逐渐恢复的影响；青少年/成人队列中的总 AUC、终末半衰期 (T1/2)、清除率 (CL)、平均停留时间 (MRT)、稳态分布容积 (Vss) 和最大血浆浓度 (Cmax)。 S）。