Congenital Afibrinogenemia, Congenital Hypofibrinogenemia
Conditions
Keywords
fibrinogen, bleeding,
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.
Interventions
DRUGBT524 (Part I)
Single intravenous infusion of 70 mg BT524 per kg body weight.
DRUGBT524 (Part II)
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.
Sponsors
ICON plc
Phoenix Clinical Research
Accovion GmbH
Biotest
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) 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: 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: 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: 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) 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: 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: 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: 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: 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). |
| 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: 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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: 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). |
| 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). |
| 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: 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). |
| 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) 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) 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: 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) 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: 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). |
| 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: 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) 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) 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 |
Countries
Bulgaria, Egypt, Germany, Lebanon, Tunisia
Participant flow
Recruitment details
Part I and Part II of the study were conducted consecutively, enrolling a total of 67 participants. The total number of participants enrolled (N=67) is smaller than the sum of participants enrolled in Part I (N=35) and Part II (N=59), because 27 participants who successfully completed Part I were subsequently enrolled in Part II. Of the enrolled participants, N=27 in Part I and N=36 in Part II were treated with BT524, with 18 participants receiving BT524 in both parts of the study.
Participants by arm
| Arm | Count |
|---|---|
| BT524 (Human Fibrinogen Concentrate) 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. | 67 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part II: Clinical Efficacy | Adverse Event | 5 |
| Part II: Clinical Efficacy | No Bleeding Event | 11 |
| Part II: Clinical Efficacy | Protocol Violation | 3 |
| Part II: Clinical Efficacy | Regulatory Authority Decision | 3 |
| Part II: Clinical Efficacy | Screening failure | 7 |
| Part II: Clinical Efficacy | Withdrawal by Subject | 2 |
| Part I: PK/PD | Adverse Event | 1 |
| Part I: PK/PD | Screening failure | 5 |
| Part I: PK/PD | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | BT524 (Human Fibrinogen Concentrate) |
|---|---|
| Age, Categorical Part I <=18 years | 12 Participants |
| Age, Categorical Part I >=65 years | 0 Participants |
| Age, Categorical Part I Between 18 and 65 years | 15 Participants |
| Age, Categorical Part II <=18 years | 16 Participants |
| Age, Categorical Part II >=65 years | 0 Participants |
| Age, Categorical Part II Between 18 and 65 years | 20 Participants |
| Age, Continuous Part I | 17.6 years STANDARD_DEVIATION 11.82 |
| Age, Continuous Part II | 19.6 years STANDARD_DEVIATION 11.76 |
| Disease characteristics Part I Afibrinogenemia | 27 Participants |
| Disease characteristics Part I Severe Hypofibrinogenemia | 0 Participants |
| Disease characteristics Part II Afibrinogenemia | 34 Participants |
| Disease characteristics Part II Severe Hypofibrinogenemia | 2 Participants |
| Ethnicity (NIH/OMB) Part I Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Part I Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Part I Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Part II Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Part II Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Part II Unknown or Not Reported | 0 Participants |
| Fibrinogen Activity Part I: Adolescents, 12 to <18 years | 0.1750 g/L STANDARD_DEVIATION 0 |
| Fibrinogen Activity Part I: Adults | 0.1750 g/L STANDARD_DEVIATION 0 |
| Fibrinogen Activity Part I: Children, 6 to <12 years | 0.1750 g/L STANDARD_DEVIATION 0 |
| Fibrinogen Activity Part I: Children, <6 years | 0.1500 g/L STANDARD_DEVIATION 0 |
| Fibrinogen Activity Part II: Adolescents, 12 to <18 years | 0.1578 g/L STANDARD_DEVIATION 0.01611 |
| Fibrinogen Activity Part II: Adults | 0.1681 g/L STANDARD_DEVIATION 0.01856 |
| Fibrinogen Activity Part II: Children, 6 to <12 years | 0.1553 g/L STANDARD_DEVIATION 0.02385 |
| Fibrinogen Activity Part II: Children, <6 years | 0.1500 g/L STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part I: Adolescents, 12 to <18 years | 1.0 mm STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part I: Adults | 1.2 mm STANDARD_DEVIATION 0.58 |
| Maximum Clot Firmness Part I: Children, 6 to <12 years | 1.0 mm STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part I: Children, <6 years | 1.0 mm STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part II: Adolescents, 12 to <18 years | 1.0 mm STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part II: Adults | 2.1 mm STANDARD_DEVIATION 4.03 |
| Maximum Clot Firmness Part II: Children, 6 to <12 years | 1.0 mm STANDARD_DEVIATION 0 |
| Maximum Clot Firmness Part II: Children, <6 years | 1.0 mm STANDARD_DEVIATION 0 |
| Race (NIH/OMB) Part I American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part I Asian | 0 Participants |
| Race (NIH/OMB) Part I Black or African American | 1 Participants |
| Race (NIH/OMB) Part I More than one race | 0 Participants |
| Race (NIH/OMB) Part I Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part I Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part I White | 26 Participants |
| Race (NIH/OMB) Part II American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Part II Asian | 0 Participants |
| Race (NIH/OMB) Part II Black or African American | 0 Participants |
| Race (NIH/OMB) Part II More than one race | 0 Participants |
| Race (NIH/OMB) Part II Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Part II Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Part II White | 36 Participants |
| Region of Enrollment Bulgaria | 2 participants |
| Region of Enrollment Egypt | 12 participants |
| Region of Enrollment Germany | 1 participants |
| Region of Enrollment Lebanon | 39 participants |
| Region of Enrollment Tunisia | 13 participants |
| Sex: Female, Male Part I Female | 13 Participants |
| Sex: Female, Male Part I Male | 14 Participants |
| Sex: Female, Male Part II Female | 14 Participants |
| Sex: Female, Male Part II Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 1 / 36 |
| other Total, other adverse events | 10 / 27 | 25 / 36 |
| serious Total, serious adverse events | 2 / 27 | 7 / 36 |
Outcome results
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Antigen | 144 g*h/L | Standard Deviation 38.9 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Antigen | 173 g*h/L | Standard Deviation 45.4 |
Primary
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
Time frame: Between pre-dose and 4 hours post-dose
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Antigen | 118 % of expected increase in fibrinogen | Standard Deviation 29.4 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Clearance (CL) for Fibrinogen Antigen | 0.0206 L/h | Standard Deviation 0.00961 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Antigen | 17.1 percentage | Standard Deviation 3.58 |
Primary
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.
Time frame: Between pre-dose and 4 hours post-dose
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Incremental Recovery (IR) for Fibrinogen Antigen | 2.63 (mg/dL)/(mg/kg dose) | Standard Deviation 0.652 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Maximum Concentration (Cmax) for Fibrinogen Antigen | 1.81 g/L | Standard Deviation 0.423 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Antigen | 133 hours | Standard Deviation 17.4 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Antigen | 2.70 Liter | Standard Deviation 1.34 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacokinetics (PK) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Antigen | 57.8 mL/kg | Standard Deviation 19.1 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacokinetics (PK) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Antigen | 67.9 hours | Standard Deviation 15.3 |
Primary
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacokinetics (PK) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Antigen | 0.843 hours | Standard Deviation 0.361 |
Secondary
Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion
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.
Time frame: 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.
Population: Full analysis set (FAS I/II): all patients who received any portion of BT524 and had at least one efficacy assessment in part I/part II
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Adults | 11.1 mm | Standard Deviation 5.07 |
| BT524 (Human Fibrinogen Concentrate) | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Adolescents, 12 to <18 years | 11.0 mm | Standard Deviation 2.83 |
| BT524 (Human Fibrinogen Concentrate) | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Children, 6 to <12 years | 16.5 mm | Standard Deviation 3.54 |
| BT524 (Human Fibrinogen Concentrate) | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Children, <6 years | 9.3 mm | Standard Deviation 1.53 |
| Part II | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Children, <6 years | 8.7 mm | Standard Deviation 5.51 |
| Part II | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Adults | 11.1 mm | Standard Deviation 5.55 |
| Part II | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Children, 6 to <12 years | 11.1 mm | Standard Deviation 4.57 |
| Part II | Change in Maximum Clot Firmness at 1 Hour Post-end of Infusion | Adolescents, 12 to <18 years | 9.8 mm | Standard Deviation 5.28 |
p-value: <0.0001t-test, 2 sided
Secondary
Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II
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).
Time frame: 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.
Population: Full bleeding event set (FBE): All bleeding events treated with any portion of BT524 and with at least one efficacy assessment during part II of the study.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II | Excellent | 150 Bleeding Events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II | Good | 23 Bleeding Events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II | Moderate | 2 Bleeding Events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Overall Hemostatic Response to Treatment With BT524 in Study Part II | None | 0 Bleeding Events |
Secondary
Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II
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).
Time frame: 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.
Population: Full bleeding event set (FBE): All bleeding events treated with any portion of BT524 and with at least one efficacy assessment during part II of the study.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II | Loss of blood is lower than expected for the procedure performed. | 3 Surgical bleeding events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II | Loss of blood is within the expected range for the procedure performed. | 45 Surgical bleeding events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II | Loss of blood is higher than expected for the procedure performed. | 4 Surgical bleeding events |
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Total Loss of Blood for Surgical Bleeding Events in Study Part II | Missing | 2 Surgical bleeding events |
Secondary
Clinical Efficacy for BT524: Units of Other Fibrinogen-containing Products (FCP) Infused Besides BT524 in Study Part II
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.
Time frame: 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.
Population: Full bleeding event set (FBE): All bleeding events treated with any portion of BT524 and with at least one efficacy assessment during part II of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Clinical Efficacy for BT524: Units of Other Fibrinogen-containing Products (FCP) Infused Besides BT524 in Study Part II | 0 Number of FCP |
Secondary
Single-Dose Pharmacodynamics (PD) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Activity
CIR: maximum fibrinogen increase in plasma within 4 hours after the end of infusion divided by the maximum theoretical fibrinogen increase
Time frame: Between pre-dose and 4 hours post-dose
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacodynamics (PD) for BT524: Classical in Vivo Recovery (CIR) for Fibrinogen Activity | 84.8 % of expected increase in fibrinogen | Standard Deviation 27.5 |
Secondary
Single-Dose Pharmacodynamics (PD) for BT524: Clearance (CL) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacodynamics (PD) for BT524: Clearance (CL) for Fibrinogen Activity | 0.0351 L/h | Standard Deviation 0.0179 |
Secondary
Single-Dose Pharmacodynamics (PD) for BT524: Incremental Recovery (IR) for Fibrinogen Activity
IR is the dose-adjusted maximum fibrinogen increase in plasma within 4 hours after the end of infusion.
Time frame: Between pre-dose and 4 hours post-dose
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacodynamics (PD) for BT524: Incremental Recovery (IR) for Fibrinogen Activity | 1.88 (mg/dL)/(mg/kg dose) | Standard Deviation 0.61 |
Secondary
Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) for Fibrinogen Activity | 4.31 Liter | Standard Deviation 2.36 |
Secondary
Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-Dose Pharmacodynamics (PD) for BT524: Volume of Distribution at Presumed Steady-state (Vdss) Per kg Body Weight (BW) for Fibrinogen Activity | 92.4 mL/kg | Standard Deviation 34.7 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) for Fibrinogen Activity | 88.2 g*h/L | Standard Deviation 29.3 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) for Fibrinogen Activity | 104 g*h/L | Standard Deviation 33.5 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Extent of Area Under the Curve (AUC) Extrapolation Beyond Last Concentration (AUCextr) for Fibrinogen Activity | 15.4 percentage (extent of AUC extrapolation) | Standard Deviation 3.41 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Maximum Concentration (Cmax) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Maximum Concentration (Cmax) for Fibrinogen Activity | 1.26 g/L |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) for Fibrinogen Activity | 124 hours | Standard Deviation 16.2 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Terminal Elimination Half-life (t1/2) for Fibrinogen Activity | 60.3 hours | Standard Deviation 13.3 |
Secondary
Single-dose Pharmacodynamics (PD) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Activity
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).
Time frame: 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
Population: PK Set: consists of all patients of part I with PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BT524 (Human Fibrinogen Concentrate) | Single-dose Pharmacodynamics (PD) of BT524: Time to Maximum Concentration (Tmax) for Fibrinogen Activity | 0.843 hours | Standard Deviation 0.361 |