E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia. |
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E.1.1.1 | Medical condition in easily understood language |
Inherited fibrinogen deficiency. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016075 |
E.1.2 | Term | Factor I deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the 14 day single-dose pharmacokinetics of BT524 following intravenous infusion in patients with congenital fibrinogen deficiency (afibrinogenemia or severe hypofibrinogenemia). |
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E.2.2 | Secondary objectives of the trial |
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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | 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)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After a single intravenous infusion pharmacokinetics will be assessed for 14 days. |
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E.5.2 | 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 |
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Egypt |
Germany |
Italy |
Lebanon |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |