Clinical 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

• Register: EUCTR
• Last refreshed on: 20 June 2016
• Main ID: EUCTR2011-004154-25-IT
• Date of registration: 20/02/2013
• Prospective Registration: Yes
• Primary sponsor: Biotest AG
• Public title: Clinical 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
• Scientific title: A prospective, open-label, phase I/II 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
• Date of first enrolment: 25/06/2013
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004154-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Egypt, Germany, Italy, Lebanon

Contacts

• Name: Corporate Clinical Research
• Affiliation: Biotest AG

• Name: Corporate Clinical Research
• Affiliation: Biotest AG

Key inclusion & exclusion criteria

Inclusion criteria:
1.Congenital afibrinogenemia or severe congenital hypofibrinogenemia defined by plasma fibrinogen activity = 0.5 g/l and antigen = 0.5 g/l
2.Male or female
3.Age 6 to 75 years, with the first ten patients will be 18 years or older
4.Presumed to be compliant with the study procedures and to terminate the study as scheduled
5.Willing and able to be hospitalized for 3 days for the pharmaco-kinetic assessment
6.Willing and able to be hospitalized - if required - in case of interventions (e.g., surgical procedures, major bleeds)
7.Written informed consent by the patient, his/her parents or by the patient's legal / authorized representative as applicable

Are the trial subjects under 18? yes
Number of subjects for this age range: 6
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
General exclusion criteria:
1.Known congenital dysfibrinogenemia
2.Known bleeding disorder other than congenital fibrinogen deficiency
3.History of esophageal variceal bleeding
4.Known presence or history of venous/arterial thrombosis or thromboembolic event in the preceding 6 months
5.Known presence or history of fibrinogen inhibitory antibodies
6.Known presence or history of hypersensitivity to human fibrinogen or human plasma proteins e.g., immunoglobulins, vaccines
7.Known positive serology for HIV-1 and HIV-2
8.Clinically relevant biochemical or hematological findings (except due to underlying disease or emergency bleeding) outside the normal range (at the investigator's discretion)
9.Clinically relevant pathological findings in physical examination including electrocardiogram (ECG)
10.Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 2 weeks prior to infusion of BT524
11.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
12.Recent vaccination (at least 3 weeks)
13.Body weight below 22 kg
14.End stage disease
15.Abuse of drugs
16.Unable to understand and follow the study requirements
17.Participation in another interventional clinical study within 30 days before entering the study or during the study
18.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)
19.Any other condition that, to the investigator's judgment, could have an impact on patient's safety or the study results

PK-specific exclusion criteria:
20.Elective surgery during the 14 day PK blood sampling period
21.Acute infection
22.Clinically relevant increase or decrease in body temperature
23.Actively bleeding or anticipated bleeding (including female menorrhea) at the time point of or within 7 days prior to infusion of BT524
24.Surgery within 7 days prior to infusion of BT524
25.Immobilization within 7 days prior to infusion of BT524
26.Intake of alcohol or significantly increased intake of caffeine containing products within 24 hours prior to infusion of BT524
27.Blood donation or comparable blood loss within 60 days prior to infusion of BT524
28.Excessive physical exercise (extreme sports activities, sauna) within 72 hours prior to infusion of BT524


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia.
MedDRA version: 14.1 Level: PT Classification code 10016075 Term: Factor I deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: Fibrinogen Concentrate from Human Plasma
Product Code: BT524
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Human Fibrinogen Concentrate
CAS Number: 9001-32-5
Current Sponsor code: BT524
Other descriptive name: Human Fibrinogen Concentrate
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: range
Concentration number: 14-26

Primary Outcome(s)

Primary end point(s): Pharmacokinetics
Single-dose pharmacokinetics of fibrinogen antigen will be assessed by the following variables:
•Terminal Elimination Half-life (t1/2) for fibrinogen antigen
•Time to reach Maximum Concentration (tmax)
•Maximum Concentration (Cmax)
•Area Under the Concentration-Time Curve (AUC) calculated to the last measured concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf)
•Clearance (CL)
•Mean Residence Time (MRT)
•Volume of Distribution (Vss)
•Incremental Recovery (IR)
•Classical in vivo Recovery (IVR)

Timepoint(s) of evaluation of this end point: After a single intravenous infusion pharmacokinetics will be assessed for 14 days.

Secondary Objective: To investigate the 14 day single-dose pharmacodynamics, the surrogate efficacy and safety of the single intravenous infusion of BT524.
To investigate efficacy, surrogate efficacy and safety, of single and/or repetitive intravenous infusions of BT524 for on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) of bleeding events.

Main Objective: To investigate the 14 day single-dose pharmacokinetics of BT524 following intravenous infusion in patients with congenital fibrinogen deficiency (afibrinogenemia or severe hypofibrinogenemia).

Secondary Outcome(s)

Secondary end point(s): Pharmacodynamics
Single-dose pharmacodynamics of fibrinogen activity will be assessed by the following variables:
•Terminal Elimination Half-life (t1/2) for fibrinogen activity
•Time to reach Maximum Concentration (tmax)
•Maximum Concentration (Cmax)
•Area Under the Concentration-Time Curve (AUC) calculated to the last measured concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf)
•Clearance (CL)
•Mean Residence Time (MRT)
•Volume of Distribution (Vss) Incremental
•Recovery (IR) Classical in vivo Recovery (IVR)

Surrogate Efficacy
Maximum clot firmness (MCF, mm)
measured by rotational thromboelastometry
Part I
-Comparison of MCF pre-dose and at 1 and 8 hours post-end of IV infusion --Correlation between MCF and fibrinogen activity pre-dose and at 1 and 8 hours post-end of IV infusion

Part II
-Comparison of MCF pre-dose and at 1 hour post-end of each IV infusion -Correlation between MCF and fibrinogen activity pre-dose and at 1 hour post-end of each IV infusion

Clinical Efficacy
The following efficacy parameters will be assessed after each bleeding event:
•Overall hemostatic response to treatment with BT524 for each surgical procedure and each major bleed as assessed by the investigator according to a 4 point scale: "none", "moderate", "good" or "excellent"
•Total loss of blood (e.g., intra- and postoperatively, re-bleedings), if applicable
•Units of other fibrinogen-containing products infused besides BT524 e.g., fresh frozen plasma or cryoprecipitate
•Units of transfusion products infused e.g., allogenic or autologous blood (packed red blood cells, fresh whole blood), platelets
•Consumption of BT524 (dose per kilogram body weight required pre-, intra- or post-operatively for effective treatment)

The following efficacy parameter will be assessed after wound healing is expected to be resolved
•Quality of wound healing, if applicable

Safety
•Electrocardiogram
•Adverse events
•Development of fibrinogen antibodies
•Changes in vital signs e.g., blood pressure, heart rate, body temperature
•Change in physical examination
•Change in clinical laboratory assessments of hematology, biochemistry, and urine analysis
•Change in markers of coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer

Timepoint(s) of evaluation of this end point: After a single intravenous infusion pharmacodynamics will be assessed for 14 days.
Maximum total duration of individual study participation in both study parts is approximately 15 months.

Secondary ID(s)

984

Source(s) of Monetary Support

Biotest AG