Abstract
ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of ReFacto AF for management of surgical hemostasis has been evaluated in an ongoing open label study of at least 25 efficacy evaluable previously treated patients, age ≥12 years, with severe hemophilia A [FVIII:C ≤ 2%] undergoing elective major surgery. ReFacto AF was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator’s discretion, and up to a maximum of 6 weeks following surgery. An interim analysis has been performed on the initial 22 patients. Fourteen (14) patients treated by BI received a total of 647 infusions (range 17 to 72 infusions per patient) for a cumulative total dose of 1,279,150 IU over 457 exposure days (ED), while 8 patients assigned to treatment by CI, including 1 patient who received only 1 dose for PK assessment, received a total dose of 348,618 IU over 140 total ED (range 1 to 64 ED per patient). Of the 21 patients who underwent major surgery, 18 were evaluable for efficacy and had the following procedures: 11 total knee replacements, 3 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings of efficacy at the end of surgery and the initial postoperative period were all excellent or good [72% excellent (13/18) and 28% good (5/18) at the end of surgery; and 94% excellent (15/16) and 6% good (1/16) at the end of the initial postoperative period]. Blood loss was assessed for the intra- and post- operative periods. Sixteen (16) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Ten (10) efficacy-evaluable patients had postoperative blood loss; in 9 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery. Eleven (11) of 18 efficacy-evaluable patients were predicted to require transfusions during the intraoperative period; only 2 were transfused. No intraoperative transfusions were administered to the other 7 efficacy-evaluable patients. During the postoperative period 2 efficacy-evaluable patients received transfusions. One (1) of these had excessive hemorrhage following trauma to the epigastric artery during surgery, the other received 2 units of PRBCs in the postoperative period following normal blood loss. The most frequently reported treatment emergent adverse events (AEs) were fever, anemia and pain, not unexpected in the perioperative setting. Only one AE was related to ReFacto AF: a clinically silent low titer inhibitor was detected in one patient during a routine protocol-specified surveillance test before his surgery, after several injections of a plasma derived FVIII product that were preceded by only 1 dose of ReFacto AF. This patient had a left knee synovectomy, both of his hemostatic efficacy assessments were excellent, and he had less intraoperative blood loss than predicted. These interim data demonstrate that ReFacto AF is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.
Evaluation of the clinical efficacy and safety of nitric oxide synthesized from room air in the postoperative period of cardiac surgery
