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

Baylor College Of Medicine, Houston TX

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Abstract

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).