Clinical trial NCT02065882: Pharmacokinetic, Efficacy and Safety of BT524 in Patients With Congenital Fibrinogen Deficiency
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Congenital Afibrinogenemia
Congenital Hypofibrinogenemia
Keywords: fibrinogen, bleeding,
Lead sponsor: Biotest
Sponsor class: INDUSTRY
Collaborators: name: ICON plc
name: SYNLAB Analytics and Services Germany GmbH
name: Phoenix Clinical Research
name: Accovion GmbH
name: Pharmetheus AB
First posted: 2014-02-19
Enrollment: 36
Sex: ALL
Minimum age (years): 0
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to investigate pharmacokinetics, efficacy and safety of BT524 in patients with congenital fibrinogen deficiency.

Detailed description: The present study is designed as a prospective, open-label, multicentre, phase I/III study investigating the 14 day single-dose pharmacokinetic 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.

Eligibility criteria: 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
* 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
* 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 (ECG)
* 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 (e.g., low molecular weight heparin, unfractioned heparin, factor Xa inhibitors, factor IIa inhibitors or 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 standard)
* 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

Primary outcomes:
measure: Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen
timeFrame: 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
measure: Single-dose Pharmacokinetics (PK) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Maximum Concentration (Cmax) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Clearance (CL) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) per kg BW for Fibrinogen Antigen
timeFrame: 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
measure: Single-Dose Pharmacokinetics (PK) for BT524: Incremental Recovery (IR) for Fibrinogen Antigen
timeFrame: Between pre-dose and 4 hours post-dose
measure: Single-Dose Pharmacokinetics (PK) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Antigen
timeFrame: Between pre-dose and 4 hours post-dose
Secondary outcomes:
measure: Single-dose Pharmacodynamics (PD) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Maximum Concentration (Cmax) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Activity
timeFrame: 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
measure: Single-dose Pharmacodynamics (PD) of BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Activity
timeFrame: 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
measure: Single-Dose Pharmacodynamics (PD) for BT524: Clearance (CL) for Fibrinogen Activity
timeFrame: 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
measure: Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Activity
timeFrame: 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
measure: Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) per kg BW for Fibrinogen Activity
timeFrame: 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
measure: Single-Dose Pharmacodynamics (PD) for BT524: Incremental Recovery (IR) for Fibrinogen Activity
timeFrame: Between pre-dose and 4 hours post-dose
measure: Single-Dose Pharmacodynamics (PD) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Activity
timeFrame: Between pre-dose and 4 hours post-dose
measure: Surrogate Efficacy for BT524: Maximum Clot Firmness (MCF)
timeFrame: Part I: pre-dose and at 1 and 8 hours post-end of IV infusion. Part II: pre-dose and at 1 hour post-end of each IV infusion.
measure: Clinical Efficacy for BT524: Overall Hemostatic Response (OHR) to Treatment With BT524 in Study Part II
timeFrame: Part II: Overall assessment after each bleeding event at the day of hospital discharge (if applicable) or at the end of the treated bleeding event.
measure: Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II
timeFrame: Part II: Total loss of blood after each surgical bleeding event
measure: Clinical Efficacy for BT524: Units of Other Fibrinogen-containing Products (FCP) Infused Besides BT524 in Study Part II
timeFrame: Part II: FCP assessed after each surgical bleeding event on BT524 dosing Day 0 or 1 day after
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Site 15
city: Cairo
country: Egypt
facility: Site 11
city: Frankfurt
country: Germany
facility: Site 16
city: Beirut
country: Lebanon
facility: Site 01
city: Sousse
country: Tunisia
facility: Site 14
city: Tunis
country: Tunisia
facility: Site12
Study officials:
affiliation: Hôtel Dieu de France, Dept. of Pediatrics
name: Claudia Djambas Khayat, MD
role: PRINCIPAL_INVESTIGATOR
References: