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

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。子项目及 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。 及时治疗急性出血事件和坚持出血治疗方案可改善血友病患者的结局。 据信，通过改善血友病社区定义的FVIII浓缩物的便利性特征（更小的输注体积、更快的输注时间和更高的效价），将更好地满足这些目标。 巴克斯特建议将用于复溶的稀释剂SWFI的体积减少至2 mL。未对rAHF-PFM的生产工艺进行变更。 在较小体积的稀释剂中复溶产品，由于体积较小，产品输注速度更快。然而，小瓶中的辅料浓度增加约2.5倍。本研究将检查辅料浓度增加对药代动力学参数和即刻耐受性的可能影响。 在家兔中评价了2 mL（缩小体积）和5 mL复溶体积的rAHF-PFM局部耐受性。 静脉给药后，检测的两种规格的5 mL和2 mL复溶液耐受性良好。然而，以2 mL体积（而非5 mL体积）复溶的动脉内或动脉旁给药制剂引起非常轻度的短期组织反应，观察到非常轻微的发红。2 mL复溶缓冲液对照品也观察到该效应。 巴克斯特临床研究060702将研究与用5 mL SWFI复溶的rAHF-PFM相比，用2 mL SWFI复溶的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要素，rAHF-PFM的药代动力学评价将使用至少3个临床批次。 通过AUC 0 -48 h测量，用2 mL或5 mL SWFI复溶的rAHF-PFM单次给药（50 IU/kg）在治疗重度血友病A患者方面具有等效性。 主要目的：确定在2 mL SWFI中复溶的rAHF-PFM对青少年/成人0- 48 h曲线下面积（AUC）的影响。 次要目的：在两个年龄队列中评价用2 mL SWFI复溶的rAHF-PFM的安全性。确定rAHF-PFM对两个年龄队列中增量恢复的影响;以及青少年/成人队列中的总AUC、终末半衰期（T1/2）、清除率（CL）、平均滞留时间（MRT）、稳态分布容积（Vss）和最大血药浓度（Cmax）。S）。

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).