Rationale for and Design of a Tolerability and Safety Study of FEIBA Reconstituted in Regular or 50% Reduced Volume and Faster Infusion Rates in Patients with Hemophilia A or B with Inhibitors

The absence of FVIII in hemophilia A (HA) and FIX in hemophilia B (HB) leads to spontaneous bleeding episodes and potentially excessive bleeding following trauma or injury. Treatment for HA and HB is complicated by the development of FVIII or FIX neutralizing antibodies in ~30% and ~2-5% of patients with severe HA and HB respectively which preclude the efficacious use of replacement therapy. The available bypassing agents, FEIBA and recombinant FVIIa are utilized in treatment of inhibitor patients, on-demand to control and prevent bleeding episodes, routine prophylaxis to prevent or reduce bleeding episode frequency and as perioperative management. However, the time required for administration of FEIBA reconstituted at standard volume and recommended rate of 2 U/kg/min may be a burden for the patient and the clinician. Mean infusion rates during routine clinical practice were evaluated by Negrier et al in the FEIBA PASS study and seen to be 3.7 U/kg/ min, with a range of 0.9-23.5. Even with a maximum rate being 12 times higher than that recommended in the SmPC of FEIBA (2.0 U/kg per min), a manual analysis of safety listings did not disclose any adverse events associated with a higher infusion rate.

In light of data from FEIBA PASS and the objective of reducing burden of infusion with FEIBA, the "FEIBA STAR" study was designed to evaluate the tolerability and safety of infusing a 50% reduced volume of FEIBA at standard (2 U/kg/min) infusion rate and at increased (4 U/kg/min and 10 U/kg/min) infusion rates, as compared with regular volume FEIBA at standard infusion rate of 2 U/kg/min. Occurrence of any adverse events, thromboembolic events, hypersensitivity reactions, and infusion site and infusion related reactions in addition to clinically apparent changes in vital signs and clinical laboratory data will be observed in support. Subject treatment preference and monitoring of pre and post-infusion FII concentrations will also be evaluated.

Nonclinical assessments in rats and rabbits of FEIBA reconstituted in 50% reduced volume and administered at increased infusion rates showed comparable efficacy and safety with FEIBA reconstituted and administered at standard volume and infusion rate. A dose-related relative reduction in blood loss was observed with reduced volume FEIBA in rabbits, and no correlation between infusion rate and thrombogenicity was seen. Additionally at infusion rates up to 10-fold the planned clinical infusion rate of the reduced volume reconstitution, there were no concerns regarding adverse clinical signs (Hoebarth 2017).

FEIBA STAR is a two part, prospective, open-label, multi-center trial to be conducted in hemophilia A or B subjects with inhibitor titers ≥0.6 Bethesda units requiring the use of bypassing agents. In the 2-way cross-over design of Part 1, subjects will be randomized 1:1 in Sequence A to receive at standard infusion rate either FEIBA reconstituted in 50% reduced volume SWFI or FEIBA reconstituted in regular volume SWFI. After administration of a total of 3 infusions at 48-hour intervals, subjects receiving 50% reduced volume FEIBA will then crossover to receive standard volume FEIBA every 48-hours for a total of 3 infusions and vice versa in Sequence B. Upon completion of Part 1, all subjects will move to Part 2 where all evaluable subjects (receiving 4 out of 6 planned doses in Part 1) will be sequentially treated every 48-hours with FEIBA reconstituted in 50% reduced volume SWFI for 3-infusions at 4 U/kg/min followed by 3-infusions at 10 U/kg/min. Tolerability, safety, clinically apparent changes in vital signs, infusion rate-related events and infusion site reactions will be monitored throughout.

The results from FEIBA STAR study aims to provide evidence regarding tolerability and safety to support routine clinical practice where higher infusion rates of FEIBA are used, to reduce burden of infusion in patients.