Understanding the blood level of a new coagulant factor VIIa in participants with congenital Haemophilia A

INTERVENTION: Within 14 days of screening, eligible subjects will return to the study site for the single‐day dosing period (Day 1). Subjects will be randomized (1:1) to receive one of the following intravenous single doses of LR769: 75 or 225 µg/kg. Randomization will be stratified by FVIII inhibitor status (with or without) with a minimum of 2 and a maximum of 5 subjects with inhibitors to FVIII enrolled in each treatment group. LR769 will be administered by a qualified health care professional in a clinic or hospital setting as an intravenous bolus injection within 2 minutes according to the Instruction for Use (IFU). The study staff will record the date, start, and stop times, dose, and actual volume of infusion of the LR769 IV administration in source documents and on the appropriate electronic case report form (eCRF) pages. In addition, IMP accountability logs will be completed by the study staff. The study monitor will review these logs, and any discrepancies will be documented. Hemophilia A is an inherited coagulation disorder due to deficiency of coagulation factor FVIII. Thus, the current standard of care for treatment of individuals with hemophilia A consists of replacing FVIII. However, in hemophilia A patients, inhibitor development is a major concern. When foreign (non‐self) factor proteins are introduced, the immune system produces inhibitors (antibodies that inactivate clotting proteins), resulting in the infusion being ineffective. Individuals with severe hemophilia A develop inhibitors more often (up to 30%) than those with hemophilia B (<5%), although reasons for this are unclear. LR769, a transgenically produced recombinant human factor VIIa (rhFVIIa) derived from a transgenic rabbit line, is part of the vitamin K‐dependent coagulation fact CONDITION: Blood ‐ Clotting disorders Congenital Hemophilia A in subjects with or without Inhibitors to Factor VIII; ; Congenital Hemophilia A in subjects with or without Inhibitors to Factor VIII Human Genetics and Inherited Disorders ‐ Other human genetics and inherited disorders SECONDARY OUTCOME: The secondary objective of this study is to characterize safety data collected before and after administration of a single dose of LR769. ; ; Safety endpoints will include, but not limited to, the frequency and severity of treatment‐emergent AEs (TEAEs). Subjects will be evaluated after administration of the investigational medicinal product (IMP) for TEAEs throughout the study. ; ; Information on the subject’s medical history will be obtained at the screening visit. A physical examination, including vital signs, will be performed, and blood samples will be obtained for clinical laboratory assessments. Before administration of IMP during the treatment period (Day 1), vital signs will be collected from all subjects. Subjects will also be interviewed for AEs, and concomitant medications at every visit. [Subjects will be monitored for AEs/SAEs from the time of informed consent to the end of the safety follow‐up (Day 4, ± 1 day), including when at the site for dosing (Day 1). A follow‐up telephone call will be made to the subject on Day 4 (±1 day) to determine the subject’s safety status. To summarise, these are the timepoints: ; ; Days ‐14 to ‐1: ; ‐ Screening ; ; Day 1: ; ‐ Before dose ; ‐ 0 min ; ‐ 5 (±1) minutes after infusion ; ‐ 15 (±2) minutes after infusion ; ‐ 30 (±5) minutes after infusion ; ‐ 1 hour (±10 minutes) after infusion ; ‐ 2 hours (±10 minutes) after infusion ; ‐ 4 hours (±10 minutes) after infusion ; ‐ 6 hours (±10 minutes) after infusion ; ‐ 8 hours (±10 minutes) after infusion ; ‐ 12 hours (±10 minutes) after infusion ; ; Day 4 ± 1 day: ; ‐ Safety follow‐up/ early termination] PRIMARY OUTCOME: The primary objective of this study is to evaluate the single‐dose PK of LR769 at 75 and 225 µg/kg in subjects with hemophilia A, with and without inhibitors to FVIII. ; ; FVIIa concentrations will be determined using a validated activity assay. Noncompartmental and compartmental PK analysis will be performed, and the following PK parameters will be calculated: ; ; ‐ Maximum plasma concentration (Cmax); ‐ Area under the plasma concentration‐time curve from Time 0 (dosing) to the time of the last measurable concentration (AUC0‐last); ‐ Area under the plasma concentration‐time curve from Time 0 (dosing) extrapolated to infinity (AUC0‐inf); ‐ Time to Cmax (tmax); ‐ Terminal elimination half‐life(t1/2): alpha (distribution) and beta (elimination) phases, for compartmental analysis; ‐ Clearance (CL); ‐ Volume of distribution (Vd); ‐ Mean residence time (MRT); ‐ Area under the first moment curve (AUMC); ‐ Incremental recovery (IR); ; For this study, the PK parameters of primary interest are Cmax and AUC0‐inf.[Blood samples (approximately 4.5 mL per time point) for assessment of FVIIa serum concentrations will be collected at the following time periods:; ; Day 1:; ‐ Before dosing; ‐ 5 (±1) minutes after infusion; ‐ 15 (±2) minutes after infusion; ‐ 30 (±5) minutes after infusion; ‐ 1 hour (±10 minutes) after infusion; ‐ 2 hours (±10 minutes) after infusion; ‐ 4 hours (±10 minutes) after infusion; ‐ 6 hours (±10 minutes) after infusion; ‐ 8 hours (±10 minutes) after infusion; ‐ 12 hours (±10 minutes) after infusion] INCLUSION CRITERIA: 1. Have the ability to provide informed consent, including privacy authorization, before study participation 2. Be judged by the investigator as willing and able to comply with the study procedures and visit schedules 3. Be a male, aged 18 to 75 years, inclusive, at the time of informed consent 4. Have a confirmed diagnosis of congenital hemophilia A (with or without inhibitors to FVIII) of any severity and not be experiencing an active bleeding episode 5. If enrolled with a medical history of inhibitors to FVIII, have a positive inhibitor test result (5 Bethesda Units (BU) and above) at the local laboratory during the 14 day screening period