Recombinant Factor VIIa [(rFVIIa) NovoSeven® by Single Dose for Home Treatment of Joint Bleeds in Hemophilia Patients with Inhibitors: A Pilot, Double-Blind Study Versus Standard Multiple Doses of NovoSeven® and an Activated Prothrombin Complex Concentrate [aPCC (FEIBA®)

Abstract

The optimization of rFVIIa treatment regimens may provide for increased efficacy and/or convenience in the home treatment of joint bleeds in patients with hemophilia and inhibitors. Home treatment facilitates early intervention which is associated with increased efficacy, and clinical data suggest that single rFVIIa doses greater than currently indicated may deliver enhanced thrombin generation without compromising safety. This was a randomized, multi-center, cross-over, double-blind study comparing the efficacy and safety of two rFVIIa dosing regimens and a single dose of open-label aPCC. Subjects with congenital hemophilia and inhibitors with a history of two or more joint bleeds within the last 12 months were eligible. Six treatment sequences were generated from three dosing regimens: 270 mg/kg rFVIIa at hour 0; 90 mg/kg rFVIIa at hours 0, 3 and 6; or 75 U/kg aPCC at hour 0, and were assigned at random in a 1:1:1 ratio. Subjects received each treatment (a different treatment for each bleeding episode) and were assessed for nine hours after dosing. The primary efficacy endpoint was a binary global treatment response (success or failure) determined by a pilot algorithm assessing changes in pain and mobility at hours 1, 3, 6 and 9 according to the following response table:Global Response AlgorithmPainMobilityMoreNo DifferenceLessMoreNo DifferenceLess1 hrFSSSSF3 hrsFSSSSF6 hrsFFSSFF9 hrsFFSSFFF: failure, S:success ≥6S:treatment success, <6S: treatment failure21 patients completed the trial. The global success rate was 54.5%, 37.5%, and 27.3% of episodes treated with rFVIIa 3×90 μg/kg, rFVIIa 270 μg/kg: and aPCC, respectively (p=NS). Secondary efficacy endpoints included the separate responses to pain and mobility evaluated using the same response table. A positive response was defined as ≥ 3 successes over the 9-hour period; < 3 successes defined a negative response. For pain, the success rate was 54.5% for rFVIIa 3×90 μg/kg; 45.8% for rFVIIa 270 μg/kg; and 27.3% for the aPCC, however this difference did not reach statistical significance (p=0.219). Nor was any statistically significant difference in mobility noted (p=0.903). The need for additional hemostatics to control bleeding was also assessed. The percentage of subjects requiring rescue medication within 9 hours after initial dosing was significantly greater for the aPCC treatment group than for the 270 μg/kg rFVIIa group (36.4% and 8.3%, respectively, p<0.03) but not the rFVIIa 3×90 μg/kg treatment group. Key efficacy data are summarized below:Efficacy DatarFVIIa 3×90 μg/kgrFVIIa 270 μg/kgaPCC 75U/kgGlobal Treatment Response55%38%27%Pain Relief55%46%27%Required Rescue Dose Within 9 Hours9%8%36%No safety issues with the use of either dose of rFVIIa or the aPCC were identified in this trial. The efficacy rates reported here cannot be directly compared with data from most other trials as the algorithm used here differs from more commonly used scales. Reasons for this will be discussed in the poster. That these efficacy rates are lower than those reported elsewhere is likely due to rigid efficacy criteria (success at multiple time points for both pain and mobility assessments). A single 270 μg/kg dose of rFVIIa appears a safe home treatment option for hemophilia A or B patients with inhibitors.