Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency

A Prospective, Open-label, Phase I/III Study Investigating Pharmacokinetic Properties of BT524 and Efficacy and Safety of BT524 in the Treatment and Prophylaxis of Bleeding in Patients With Congenital Fibrinogen Deficiency

This was a prospective, open-label, multicenter, phase I/III study investigating the 14-day single-dose pharmacokinetic and pharmacodynamic properties, efficacy and safety of BT524 following intravenous administration in the treatment or prophylaxis of bleeding in patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia.

The study was divided into two parts (Part I and Part II). Part I focused on the primary endpoint of the study, 14-day single-dose pharmacokinetics (PK) and 14-day single-dose pharmacodynamics (PD), as well as the assessment of maximum clot firmness (MCF) as a surrogate parameter for efficacy. Part I of the study was followed by Part II, which evaluated the efficacy and safety of single and repetitive administration of BT524 in patients undergoing on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) for various bleeding events [e.g., elective surgery, spontaneous or post-traumatic major bleeding]. All patients who participated in the PK assessment (Part I) without severe post-administration complications ideally continued treatment with BT524 for ODP and/or ODT in Part II.

Inclusion Criteria:

• Known congenital afibrinogenemia or severe congenital hypofibrinogenemia
• Plasma fibrinogen activity ≤ 0.5 g/l and antigen ≤ 0.5 g/l
• Male or female
• Age 0 to 75 years, with the first ten patients will be 18 years or older
• Presumed to be compliant with the study procedures and to terminate the study as scheduled
• Willing and able to be hospitalized for 3 days for the pharmacokinetic assessment (if applicable)
• Willing and able to be hospitalized - if required - in case of interventions (e.g., surgical procedures, major bleeds)
• Written informed consent by the patient, his/her parents or by the patient's legal/authorized representative as applicable

Exclusion Criteria:

• Known congenital dysfibrinogenemia (not applicable for adult patients with hypodysfibrinogenemia in study part II)
• Known bleeding disorder other than congenital fibrinogen deficiency
• History of esophageal variceal bleeding
• Known presence or history of venous/arterial thrombosis or thromboembolic event in the preceding 6 months
• Known presence or history of fibrinogen inhibitory antibodies
• Known presence or history of hypersensitivity to human fibrinogen or human plasma proteins e.g., immunoglobulins, vaccines or hypersensitivity to any of the excipients
• Known positive serology for HIV-1 and HIV-2
• Clinically relevant biochemical or hematological findings (except due to underlying disease or emergency bleeding) outside the normal range (at the investigator's discretion)
• Clinically relevant pathological findings in physical examination including electrocardiogram
• Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 2 weeks prior to infusion of BT524
• Concomitant medication interacting relevantly with the coagulation system such as: low molecular weight heparin or unfractioned heparin, factor Xa inhibitors, thrombin inhibitors (factor II a inhibitors), antiplatelet drugs (PY12 inhibitors) within 2 weeks prior to infusion of BT524
• Recent vaccination (within 3 weeks prior to infusion)
• Body weight (BW) below 22 kg for patients ≥ 6 years; BW below the 5th percentile of the normal range for children < 6 years (refers to local standards)
• End stage disease
• Abuse of drugs
• Unable to understand and follow the study requirements
• Participation in another interventional clinical study within 30 days before entering the study or during the study
• Pregnant/ nursing woman, or woman of childbearing potential not using reliable/ effective contraceptive method(s) during the study and at least one month after the last administration of study drug (e.g., oral/ injectable/ implantable/ insertable/ topical hormonal contraceptives, intrauterine devices, female sterilization, partner's vasectomy or condoms)
• Any other condition that, to the investigator's judgment, could have an impact on patient's safety or the study results
• Elective surgery during the 14 day PK blood sampling period
• Acute infection
• Clinically relevant increase or decrease in body temperature
• Actively bleeding or anticipated bleeding (including female menorrhea) at the time point of or within 7 days prior to infusion of BT524
• Surgery within 7 days prior to infusion of BT524
• Immobilization within 7 days prior to infusion of BT524
• Intake of alcohol or significantly increased intake of caffeine containing products within 24 hours prior to infusion of BT524
• Blood donation or comparable blood loss within 60 days prior to infusion of BT524
• Excessive physical exercise (extreme sports activities, sauna) within 72 hours prior to infusion of BT524