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

Phase 3

Completed

Conditions: Congenital Afibrinogenemia
Congenital Hypofibrinogenemia

Interventions: Drug: BT524 (Part I)
Drug: BT524 (Part II)

Registration Number: NCT02065882

Lead Sponsor: Biotest

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 67

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
BT524	BT524 (Part I)	Part I: A single intravenous infusion of BT524 for assessment of PK/PD of BT524. Part II: A single or repetitive intravenous infusion(s) of BT524 for on-demand prophylaxis/on-demand treatment of bleeding events.
BT524	BT524 (Part II)	Part I: A single intravenous infusion of BT524 for assessment of PK/PD of BT524. Part II: A single or repetitive intravenous infusion(s) of BT524 for on-demand prophylaxis/on-demand treatment of bleeding events.

Primary Outcome Measures

Name	Time	Method
Single-dose Pharmacokinetics (PK) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Time of occurence of Cmax relative to dosing (Tmax) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Tmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/required).
Single-Dose Pharmacokinetics (PK) for BT524: Incremental Recovery (IR) for Fibrinogen Antigen	Between pre-dose and 4 hours post-dose	IR is the dose-adjusted maximum fibrinogen increase in plasma within 4 hours after the end of infusion.
Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Vdss: Volume of distribution at presumed steady-state for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Vdss was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Antigen	Between pre-dose and 4 hours post-dose	CIR: maximum fibrinogen increase in plasma within 4 hours after the end of infusion divided by the maximum theoretical fibrinogen increase
Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	T1/2 of fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. T1/2 was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Maximum Concentration (Cmax) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Maximum observed plasma concentration (Cmax) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Cmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUCextr: extent of AUC extrapolation beyond last concentration for fibrinogen antigen, was determined from samples taken at several time points during the 14 day sampling period. AUCextr was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUC0-tz: Area under the time course of the plasma concentrations calculated from time zero up to the last quantifiable plasma concentration for fibrinogen antigen, was determined from samples taken at several time points during the 14 day sampling period. AUC0-tz was derived from time-concentration profiles using adapted methodology (noncompartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUC0-∞: AUC from time 0 to infinity for fibrinogen antigen, was determined from samples taken at several time points during the 14 day sampling period. AUC0-∞ was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Clearance (CL) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	CL: Total clearance (CL) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. CL was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	MRT0-∞: Mean Residence Time (MRT) extrapolated to infinity for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. MRT0-∞ was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Antigen	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Vdss per kg BW: Volume of distribution at presumed steady-state per kg bodyweight for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Vdss per kg BW was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

Secondary Outcome Measures

Name	Time	Method
Single-dose Pharmacodynamics (PD) of BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUCextr: extent of AUC extrapolation beyond last concentration for fibrinogen activity, was determined from samples taken at several time points during the 14 day sampling period. AUCextr was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Vdss: Volume of distribution at presumed steady-state for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. Vdss was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Vdss per kg BW: Volume of distribution at presumed steady-state per kg bodyweight for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. Vdss per kg BW was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-dose Pharmacodynamics (PD) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	T1/2 of fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. T1/2 was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUC0-tz: Area under the time course of the plasma concentrations calculated from time zero up to the last quantifiable plasma concentration for fibrinogen activity, was determined from samples taken at several time points during the 14 day sampling period. AUC0-tz was derived from time-concentration profiles using adapted methodology (noncompartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	AUC0-∞: AUC from time 0 to infinity for fibrinogen activity, was determined from samples taken at several time points during the 14 day sampling period. AUC0-∞ was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-dose Pharmacodynamics (PD) of BT524: Maximum Concentration (Cmax) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Maximum observed plasma concentration (Cmax) for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. Cmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacodynamics (PD) for BT524: Clearance (CL) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	CL: Total clearance (CL) for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. CL was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Single-Dose Pharmacodynamics (PD) for BT524: Incremental Recovery (IR) for Fibrinogen Activity	Between pre-dose and 4 hours post-dose	IR is the dose-adjusted maximum fibrinogen increase in plasma within 4 hours after the end of infusion.
Single-dose Pharmacodynamics (PD) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	Time of occurence of Cmax relative to dosing (Tmax) for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. Tmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/required).
Single-Dose Pharmacodynamics (PD) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Activity	Between pre-dose and 4 hours post-dose	CIR: maximum fibrinogen increase in plasma within 4 hours after the end of infusion divided by the maximum theoretical fibrinogen increase
Single-dose Pharmacodynamics (PD) of BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Activity	Pre-dose on Dosing Day 0, at the end of the infusion and 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 240 and 336 hours post-dose	MRT0-∞: Mean Residence Time (MRT) extrapolated to infinity for fibrinogen activity was determined from samples taken at several time points during the 14 day sampling period. MRT0-∞ was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).
Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion	Part I: pre-dose and at 1 hour post-end of infusion. Part II: pre-dose and at 1 hour post-end of infusion of each bleeding event.	Maximum Clot Firmness (MCF), assessed by rotational thromboelastometry (ROTEM), was used as a surrogate marker of haemostatic efficacy following administration of BT524. In Part I, MCF was measured before and 1 hour after the end of a single BT524 infusion. In Part II, MCF was measured before and 1 hour after the end of each BT524 infusion administered to treat bleeding events. The variable was the change in MCF from pre-dose to 1 hour post-end of infusion.
Clinical Efficacy for BT524: Units of Other Fibrinogen-containing Products (FCP) Infused Besides BT524 in Study Part II	Part II: Up to 24 hours after end of infusion, or on day of hospital discharge (if between 24 hours and 49 days post-infusion); at the latest on day 49 after the treated bleeding event.	Units of other fibrinogen-containing products (FCP) infused besides BT524 eg, fresh frozen plasma (FFP) or cryoprecipitate or alternative commercially available fibrinogen concentrates given to counteract hemodynamic instability were documented and analyzed descriptively on event level for the FBE.
Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II	Part II: Up to 24 hours after end of infusion, or on day of hospital discharge (if between 24 hours and 49 days post-infusion); at the latest on day 49 after the treated bleeding event.	Overall hemostatic response (OHR) to treatment with BT524 for each surgical procedure and each treated bleed was rated on a 4-point scale ("none", "moderate", "good" or "excellent"). The sum of good and excellent ratings was defined as "success" in the analysis. Frequencies and percentages of OHR on event level (Success rate in % = number of successfully treated bleeding events / total number of bleeding events).
Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II	Part II: Up to 24 hours after end of infusion, or on day of hospital discharge (if between 24 hours and 49 days post-infusion); at the latest on day 49 after the treated bleeding event.	Total loss of blood was rated by the investigator per surgical bleeding events (eg, intra- and post-operatively, rebleedings) using the classifications of "lower than expected", "within the expected range", and "higher than expected". The ratings were analyzed descriptively (frequencies and percentages) on event level for the Full Bleeding Event Set (FBE).

Trial Locations

Locations (6): Site 15
🇧🇬
Sofia, Bulgaria
Site 11
🇪🇬
Cairo, Egypt
Site 16
🇩🇪
Frankfurt, Germany
Site 01
🇱🇧
Beirut, Lebanon
Site 14
🇹🇳
Sousse, Tunisia
Site12
🇹🇳
Tunis, Tunisia
Site 15
🇧🇬Sofia, Bulgaria