None listed
Conditions
Brief summary
This is an open-label, randomized, parallel, single-dose, PK study of coagulation factor VIIa (Recombinant), LR769, in subjects with hemophilia A, with or without inhibitors to FVIII. This study is designed to evaluate the PK and safety of a single intravenous dose of 75 or 225 µg/kg in 28 male subjects aged 18 to 75 years, inclusive, with confirmed diagnoses of hemophilia A (with or without inhibitors to FVIII), and who are not experiencing an active bleeding event. This study consists of a screening visit (Day -14 to Day -1), a single-day dosing period (Day 1), and a follow-up phone call (Day 4, ± 1 day). Total study participation may last up to 19 days.
Interventions
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 clini
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 factor family. It is developed for use in hemophilic A or B patients with FVIII or FIX inhibitors. In the presence of both calcium and phospholipids, FVII/VIIa complexed with tissue factor (TF) can activate factor FX to FXa (extrinsic pathway) directly, bypassing the need for FIX or FVIII. This FX to FXa conversion then activates prothrombin to thrombin, which then catalyses conversion of fibrinogen to fibrin and initiate clotting at the bleeding site. PK data collected thus far in the LR769 clinical program have been affected by small study sample sizes or lack of repeated analyses to confirm findings. As a result, this study has been designed to further characterize the PK of LR769 in subjects with congenital hemophilia A, with or without inhibitors to FVIII.
Sponsors
LFB USA, Inc.
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
Male
Age
18 Years to 75 Years
Healthy volunteers
No
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
Exclusion criteria
1. Have any other known coagulation or hematologic disorder(s) or condition(s) in addition to hemophilia A 2. Be immunosuppressed (i.e., the patient may not be receiving systemic immunosuppressive medication; cluster of differentiation 4 (CD4) counts at screening must be >200/µL) 3. Have undergone a major surgical procedure (e.g., orthopedic, abdominal) within 1 month before administration of LR769 4. Be currently receiving treatment for active, ongoing bleeding, or if treatment for a bleeding was stopped within 24 hours of the time of LR769 administration 5. Have a medical history of malignancy within the past 5 years (except for nonmelanoma skin cancer) 6. Have a clinically significant cardiac arrhythmia/dysrhythmia or unstable cardiac disease, based on medication use, recent (< 6 months) medical history or intervention, or ECG results during screening 7. Have positive serology during the 14 day screening period for hepatitis B (hepatitis B surface antigen), hepatitis C virus (except patients with history of cured Hepatitis C proven by a documented HCV RNA negative RT-PCR performed at least 24 weeks after completion of the Hepatitis C treatment, and with normal liver function tests), or human immunodeficiency virus 8. Be currently taking or have taken within 7 days prior to LR769 administration (Day 1) known or suspected anticoagulants, antiplatelet medications, supplements, dietary ingredients, or other medications that may alter platelet aggregation including, but not limited to, the following: • Aspirin • Nonsteroidal anti-inflammatory drugs (commonly known as NSAIDs) • Herbal or natural medications • Supplements or vitamins • Other platelet-inhibiting drugs 9. Have any life-threatening disease, or other disease or condition that, in the investigator’s judgment, could pose a potential hazard to the subject or interfere with study participation or study outcome (e.g., a history of no response to bypassing products or thromboembolic disease) 10. Have any known or suspected hypersensitivity to the active substance in LR769 or to any of its excipients 11. Have any known or suspected allergy or hypersensitivity to rabbits or rabbit proteins 12. Have received a Factor VII- or FVIIa-containing product (either plasma derived or recombinant) within 24 hours prior to administration of LR769 13. Have received an investigational drug within 30 days prior to LR769 administration, or be expected to receive such drug during participation in this study 14. Have platelet count <100,000/µL 15. Have abnormal renal or hepatic function as defined by the following laboratory results at screening: • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) • Serum creatinine concentration >2 times the ULN
Outcome results
None listed