Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors

A Randomized, Multicenter, Double-blind Clinical Trial Comparing Pharmacodynamic, Pharmacokinetic and Safety of a Biosimilar Eptacog Alfa (AryoSeven) and Novoseven®, in Patients With Hemophilia A or B With Inhibitors.

The purpose of this multicentre, randomized, double-blinded, single dose, two-way cross-over study, is to compare the pharmacokinetics (PK) and pharmacodynamic (PD) of two different doses of the biosimilar eptacog alfa (activated) with Novoseven in 48 patients, adult and children (>12 years), not bleeding, with hemophilia A or B with inhibitors. Patients will be randomized to receive either a single dose of eptacog alfa biosimilar 90 μg/kg or 270 μg/kg and one single dose of NovoSeven 90 μg/kg or 270 μg/kg, or vice versa, with doses separated by a washout period. All patients will be followed 12 months and will receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data.

Forty-eight patients enrolled, not bleeding, will be randomized to receive two injections separated by a washout period of 3 days (t1/2 = 2.3h). Patients are centrally registered and randomized to receive in a 2x2 cross-over setting either a single dose of two for the following products: A: AryoSeven 90 µg/kg and B: NovoSeven 90 µg/kg - or - C: AryoSeven 270 µg/kg and D: NovoSeven 270 µg/kg.

Patients will be hospitalized at the time of study medication administration and plasma sampling. Before any treatment, a blood sample will be obtained in all patients for testing for immunogenicity.

Inclusion Criteria:

• Confirmed diagnosis of congenital hemophilia A or B with inhibitors to FVIII or FIX titer >5 Bethesda Units (BU)
• with > 2 episodes of bleeding/year requiring treatment with FVII infusions, non in bleeding status
• male subjects
• adult and children (>12 years)
• written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent.
• For the PK/PD phase, patients will be hospitalized at the time of study medication administration for plasma sampling (2 times during the study).

Exclusion Criteria:

• Any other type of congenital or acquired coagulopathy, such as liver disease (hepatitis), vitamin k deficiency, uremia, malignancy.
• Antibodies against Factor VII
• Ongoing bleeding prophylaxis regimens with Novoseven or planned to occur during the trial
• Patients who have received routine (prophylactic) treatment with rFVIIa in the period between screening visit (visit 1) and visit 2 of this study (first dose administration)
• Platelet count less than 100.000 platelets/microliter (at screening visit)
• Any clinical sign or known history of an arterial thrombotic event or deep venous- thrombosis or pulmonary embolism
• HIV positive with current CD4+ count of less than 200/µL
• Liver cirrhosis
• Factor VIII/IX immune tolerance induction regimen planned to occur during the trial
• Known hypersensitivity to the study medication
• Parallel participation in another experimental drug trial.
• Parallel participation in another marketed drug trial that may affect the primary endpoint of the study