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

NCT02065882 | Completed Phase 3 Results

• 2 other identifiers: Biotest 9842011-004154-25
• Study Type: interventional
• Target: 67
• Locations: 5 countries
• Sites: 6

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.

Conditions

Congenital Afibrinogenemia; Congenital Hypofibrinogenemia

Keywords

fibrinogen, bleeding,

Outcome Measures

Primary Outcomes (12)

• Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen

  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).

  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

• Single-dose Pharmacokinetics (PK) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Maximum Concentration (Cmax) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Clearance (CL) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Antigen

  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).

  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

• Single-Dose Pharmacokinetics (PK) for BT524: Incremental Recovery (IR) for Fibrinogen Antigen

  IR is the dose-adjusted maximum fibrinogen increase in plasma within 4 hours after the end of infusion.

  Between pre-dose and 4 hours post-dose

• Single-Dose Pharmacokinetics (PK) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Antigen

  CIR: maximum fibrinogen increase in plasma within 4 hours after the end of infusion divided by the maximum theoretical fibrinogen increase

  Between pre-dose and 4 hours post-dose

Secondary Outcomes (16)

• 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

• 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

• 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

• 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

• 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

Study Arms (1)

BT524

EXPERIMENTAL

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.

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

Interventions

BT524 (Part I) DRUG

Single intravenous infusion of 70 mg BT524 per kg body weight.

Also known as: Human Fibrinogen Concentrate

BT524

BT524 (Part II) DRUG

Single or repetitive intravenous infusion(s) of BT524, depending on the severity of the disorder, location and extent of the bleeding and patient's clinical condition. Dosage based on individual body weight and fibrinogen level.

Also known as: Human Fibrinogen Concentrate

BT524

Eligibility Criteria

• Age: Up to 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Biotest: lead
• ICON plc: collaborator
• Phoenix Clinical Research: collaborator
• Accovion GmbH: collaborator

Study Sites (6)

Site 15

Sofia, Bulgaria

Location

Site 11

Cairo, Egypt

Location

Site 16

Frankfurt, Germany

Location

Site 01

Beirut, Lebanon

Location

Site 14

Sousse, Tunisia

Location

Site12

Tunis, Tunisia

Location

MeSH Terms

Conditions

Afibrinogenemia; Hemorrhage

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Christina Erb
• Organization: Biotest AG

christina.erb@biotest.com

00496103801

Study Officials

• Claudia Djambas Khayat, MD

  Hôtel Dieu de France, Dept. of Pediatrics

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study was divided into two parts: PK/PD Part I and Efficacy Part II. Patients eligible for PK/PD Part I received a fixed dose of 70 mg BT524 per kilogram body weight (BW) via a single intravenous infusion. Part I was followed by Part II. In Part II, patients received a variable, individually tailored dose of BT524 for on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) in case of bleeding events.

Study Record Dates

• First Submitted: February 3, 2014
• First Posted: February 19, 2014
• Study Start: March 1, 2013
• Primary Completion: May 18, 2020
• Study Completion: November 18, 2020
• Last Updated: July 3, 2025
• Results First Posted: July 3, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1); LE (1); BU (1); DE (1); TU (2)