The FEIBA^® NovoSeven^® Comparative Study (FENOC)—A Randomized Evaluation of By-Passing Agents in Hemophilia Complicated by Inhibitors.

The occurrence of inhibitors in severe hemophilia A can make replacement with factor VIII concentrates insufficient for treatment of acute hemorrhages. An alternative is use of bypassing agents. The FEIBA® NovoSeven® Comparative Study (FENOC) is a randomized multicenter equivalence trial conducted in Europe and North America to study the efficacy of two bypassing agents. The usual framework of testing for differences between effectiveness of two treatments is not the focus in an equivalency trial. Instead, one tests that there is no clinically significant difference between treatments. In FENOC, the goal was to show that FEIBA® and NovoSeven® differed by less than 15% in efficacy.

Subjects age 2+ with factor VIII deficiency, a history of inhibitor and need for bypassing agents were eligible. An episode of ankle, elbow, or knee bleeding was treated with one dose of FEIBA® and two doses of NovoSeven® with crossover between the options for the following episode. Subjects reported evaluation of the hemostatic effect 2, 6, 12, 24, 36, and 48 hours after treatment. The primary endpoint was hemostatic effect at 6 hours. Differences in pain, rated using the visual analog scale (VAS), and subject’s evaluation of when bleeding had stopped were secondary endpoints. The target sample size was 60 pairs of treatments.

Data were analyzed using a modified version of McNemar’s test proposed by Lee and Lusher (1991). The equivalence hypothesis was tested and an associated confidence interval was calculated. If the confidence interval was within plus or minus 15% (−15%, 15%) significance was declared at the 0.05 level.Sixty-six subjects in 25 sites were enrolled. Twelve withdrew prior to treatment, 2 had 1 treatment, and 4 had unresolved queries at study close. Forty-eight subjects completed both treatments. Results of the intent-to-treat analysis are reported. The median age was 27. Approximately 43% had knee bleeds, 32% elbow, and 20% ankle. The remaining 5% had bleeding episodes involving more than one joint (n=2) or hip (n=2) or shoulder (n=1) joints. One serious adverse event not related to study or treatment was reported. At 6 hours after treatment 80.9% of recipients of FEIBA® and 78.7% of recipients of NovoSeven® reported the treatment was effective. The confidence interval for the treatment difference was −11.4% to 15.7%, (p=0.059). About 32% of the recipients had effective relief with one treatment but not the other. The mean within pair difference in VAS scores at 6 hours (FEIBA®-NovoSeven®) was −2.3 mm. At 6 hours 76.1% of those treated with FEIBA® reported that bleeding had stopped compared to 65.2% of those treated with NovoSeven®. The confidence interval was −2.7%, 24.5% so we could not conclude that the difference between the two products was less than 15%. However, the treatments were determined to be equivalent with respect to subjects’ evaluation of cessation of bleeding at 24 and 48 hours. FEIBA® and NovoSeven® may have similar efficacy in the treatment of acute hemorrhages in patients with inhibitors, although this was not consistently demonstrated in the FENOC study. There appears to be variation among patients in response to each product.