A Phase 1/2 interventional study of Human Plasma-Derived Fibrinogen Concentrate in Congenital Afibrinogenemia, sponsored by Grifols Therapeutics LLC. Completed at 6 sites in 4 countries. Open to participants aged Up to 70 Years. Per ClinicalTrials.gov, last updated 2022-03-31.
Sponsored by Grifols Therapeutics LLC · Phase 1/2, Interventional, and Treatment
The main objective of this study was to evaluate the pharmacokinetics (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate FIB Grifols after a single-dose 70 milligrams/kilogram (mg/kg) body weight administration.
This study is a phase I-II, multi-center, prospective, open-label, single-arm, clinical trial to evaluate Pharmacokinetic (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate (FIB Grifols) in adult and pediatric participants with congenital afibrinogenemia.
Approximately 10 adult participants (≥18 years) with congenital afibrinogenemia will be administered a single dose of FIB Grifols at 70 mg/kg body weight and will be followed for PK, efficacy, and safety assessments.
After the safety of fibrinogen concentrate FIB Grifols is assessed in at least 10 adult participants and no safety issues are raised by the sponsor, the study will start to enroll approximately 10 pediatric subjects (\<18 years) who will be dosed with study drug and followed for PK, efficacy, and safety assessments.
All enrolled participants (both adult and pediatric) will have documented congenital fibrinogen deficiency manifested as afibrinogenemia but will not have received any fibrinogen-containing product therapy within the preceding 21 days before the infusion of study drug.
All participants (both adult and pediatrics) will be infused with the investigational product at 70 mg/kg body weight. PK parameters that will be calculated from plasma fibrinogen levels measured at different time points include: incremental in vivo recovery [IVR], area under the curve (AUC) calculated as AUC from zero to 14 days (AUC\^0-14days) and AUC from zero to infinity (AUC\^0-∞), maximum plasma concentration (C\^max), time to the observed maximum plasma concentration (t\^max), half-life (t\^1/2), mean residence time (MRT), volume of distribution (Vd), and clearance (Cl).
Hemostatic efficacy of the investigational product will be assessed by means of rotational thromboelastometry (ROTEM) measure of maximum clot firmness (MCF) at baseline and 1 hour post-infusion. Other thromboelastographic measures as well as standard coagulation tests will be also determined pre- and post-infusion.
Clinical safety, viral safety, and immunogenicity will be assessed in this clinical trial. Safety variables include adverse events (AEs), vital signs, physical assessments, laboratory tests, viral markers, and antibodies against human fibrinogen.
A monitoring plan will be implemented by the sponsor to carefully monitor and evaluate allergic/hypersensitivity reactions and thrombotic events during the study.
Stopping criteria have been established for immunogenic and thrombogenic events. If a single case of any these events is reported after a participants has been dosed with study drug, any further enrollment and dosing of participants in the study will be suspended until the event can be adequately assessed by the sponsor. The enrollment and dosing will only resume if the sponsor deems it is safe to do so.
Grifols Therapeutics LLC is the lead sponsor of 43 studies on the registry; 4 are open to participants now.
Of its 12 completed or terminated interventional studies of FDA-regulated products, 11 (92%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols)
Biological: Human Plasma-Derived Fibrinogen Concentrate
A sterile freeze-dried fibrinogen concentrate filled in vials containing 1 g of FIB Grifols. FIB Grifols contains 20 mg/ml of active substance fibrinogen when reconstituted.
Also known as: FIB Grifols
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method used for those arising from decreasing concentrations. Plasma fibrinogen activity determined by the Clauss method in the central laboratory of the study. Pharmacokinetic (PK) parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Enzyme-Linked Immunosorbent Assay (ELISA) Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration versus (vs) time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time\^-1 units (1/h). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time\^-1 units (1/h). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Cmax was obtained directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Cmax was obtained directly from directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by ELISA Method
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Residence Time (MRT) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half-life of infusion. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Residence Time (MRT) of FIB Grifols Assessed Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half life of infusion.PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of Distribution (Vd) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of Distribution (Vd) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance (Cl) of FIB Grifols Determined By Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance (Cl) of FIB Grifols Determined By ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
In Vivo Recovery (IVR) of FIB Grifols Determined by Clauss Method
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram \[mg/dL\]/\[mg/kg\]. IVR was determined for every participants using the following formula: (\[FIB max (mg/dL)\] - \[FIB pre-infusion (mg/dL)\])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participant. FIB administered was the actual administered dose calculated using the actual volume administered to the participant, the declared potency, and the true concentration of FIB in the batch used.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
In Vivo Recovery (IVR) of FIB Grifols Determined by ELISA Method
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram \[mg/dL\]/\[mg/kg\]. IVR was determined for every participants using the following formula: (\[FIB max (mg/dL)\] - \[FIB pre-infusion (mg/dL)\])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participants. FIB administered was the actual administered dose calculated using the actual volume administered to the participants, the declared potency, and the true concentration of FIB in the batch used.
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Change on Maximum Clot Firmness (MCF) From Baseline to 1-hour Post-infusion
MCF was as a functional parameter of blood's ability to coagulate, provides an indirect measure of hemostatic efficacy of replacement treatment with fibrinogen concentrates in participants with fibrinogen deficiency. Rotational thromboelastography (ROTEM) was performed on frozen plasma samples by the central laboratory to measure MCF. Undetectable MCF values were set to 0.
Time frame: Baseline to 1-hour post-infusion
Mean Change in Clotting Time (CT) From Baseline to 1-hour Post-infusion
Difference in adult participants plasma samples in CT from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: Baseline to 1-hour post-infusion
Clot Formation Time (CFT) at 1-hour Post-infusion
CFT value in participants plasma samples in CFT at 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: 1-hour post-infusion
Mean Change in Alpha Angle (α) From Baseline to 1-hour Post-infusion
Difference in participants plasma samples in alpha angle from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: Baseline to 1-hour post-infusion
Mean Change in Prothrombin Time (PT) From Baseline to 1-hour Post-infusion
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: Baseline to 1-hour post-infusion
Mean Change in Thrombin Time (TT) From Baseline to 1-hour Post-infusion
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: Baseline to 1-hour post-infusion
Mean Change in Activated Partial Thromboplastin Time (aPTT) From Baseline to 1-hour Post-infusion
Difference in participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with a fibrinogen concentrate in participants with fibrinogen deficiency.
Time frame: Baseline to 1-hour post-infusion
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participants hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Treatment-emergent defined as adverse events/serious adverse events that started or worsened on or after the start of the investigational product infusion.
Time frame: From the start of the investigation product infusion up to Week 4
The study was conducted in India, Lebanon, and the United States of America (USA) between 22 Jul 2016 (first participants first visit) and 11 Nov 2019 (last participant last visit).
| Milestone | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Started | 22 |
| Completed | 22 |
| Not completed | 0 |
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method used for those arising from decreasing concentrations. Plasma fibrinogen activity determined by the Clauss method in the central laboratory of the study. Pharmacokinetic (PK) parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour*grams per liter (h*g/L) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 145.67 ± 43.441 |
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour*milligram per milliliter (h*mg/mL) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Enzyme-Linked Immunosorbent Assay (ELISA) Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 186.63 ± 95.734 |
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration versus (vs) time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time\^-1 units (1/h). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hours*gram per liter (h*g/L) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 166.78 ± 54.081 |
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time\^-1 units (1/h). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| h*mg/mL | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 242.94 ± 117.567 |
Cmax was obtained directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| gram per liter (g/L) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 1.99 ± 0.404 |
Cmax was obtained directly from directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| milligram per milliliter (mg/mL) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 2.88 ± 0.859 |
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 1.40 (1.0 to 24.5) |
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by ELISA Method | 1.80 (1.1 to 24.5) |
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 76.94 ± 20.215 |
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 66.92 ± 16.789 |
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half-life of infusion. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Residence Time (MRT) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 72.67 ± 12.185 |
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half life of infusion.PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| hour (h) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Residence Time (MRT) of FIB Grifols Assessed Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 62.64 ± 19.142 |
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| milliliter per kilogram (mL/kg) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Volume of Distribution (Vd) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 47.932 ± 7.5997 |
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| mL/kg | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Volume of Distribution (Vd) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 31.264 ± 10.9702 |
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| mL per hour per kilogram (mL/h/kg) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Clearance (Cl) of FIB Grifols Determined By Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 0.454 ± 0.1216 |
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
| mL/h/kg | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Clearance (Cl) of FIB Grifols Determined By ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration | 0.341 ± 0.1360 |
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram \[mg/dL\]/\[mg/kg\]. IVR was determined for every participants using the following formula: (\[FIB max (mg/dL)\] - \[FIB pre-infusion (mg/dL)\])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participant. FIB administered was the actual administered dose calculated using the actual volume administered to the participant, the declared potency, and the true concentration of FIB in the batch used.
| milligram per deciliter (mg/dL)/ (mg/kg) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| In Vivo Recovery (IVR) of FIB Grifols Determined by Clauss Method | 2.380 ± 0.6689 |
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram \[mg/dL\]/\[mg/kg\]. IVR was determined for every participants using the following formula: (\[FIB max (mg/dL)\] - \[FIB pre-infusion (mg/dL)\])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participants. FIB administered was the actual administered dose calculated using the actual volume administered to the participants, the declared potency, and the true concentration of FIB in the batch used.
| (mg/dL)/(mg/kg) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| In Vivo Recovery (IVR) of FIB Grifols Determined by ELISA Method | 3.474 ± 1.3607 |
MCF was as a functional parameter of blood's ability to coagulate, provides an indirect measure of hemostatic efficacy of replacement treatment with fibrinogen concentrates in participants with fibrinogen deficiency. Rotational thromboelastography (ROTEM) was performed on frozen plasma samples by the central laboratory to measure MCF. Undetectable MCF values were set to 0.
| millimeter (mm) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change on Maximum Clot Firmness (MCF) From Baseline to 1-hour Post-infusion | 10.71 ± 4.122 |
Difference in adult participants plasma samples in CT from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
| Seconds (sec) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change in Clotting Time (CT) From Baseline to 1-hour Post-infusion | -3462.0 ± NA |
CFT value in participants plasma samples in CFT at 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
| sec | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Clot Formation Time (CFT) at 1-hour Post-infusion | 68.0 ± NA |
Difference in participants plasma samples in alpha angle from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
| degree | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change in Alpha Angle (α) From Baseline to 1-hour Post-infusion | 34.9 ± 34.52 |
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
| sec | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change in Prothrombin Time (PT) From Baseline to 1-hour Post-infusion | -102.79 ± 2.101 |
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
| sec | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change in Thrombin Time (TT) From Baseline to 1-hour Post-infusion | -200.41 ± 58.178 |
Difference in participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with a fibrinogen concentrate in participants with fibrinogen deficiency.
| sec | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean Change in Activated Partial Thromboplastin Time (aPTT) From Baseline to 1-hour Post-infusion | -97.16 ± 10.580 |
An AE was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participants hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Treatment-emergent defined as adverse events/serious adverse events that started or worsened on or after the start of the investigational product infusion.
| Participants | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Participants with AEs | 9 |
| Participants with Serious AEs | 0 |
Collected over From the start of the investigational product infusion up to Week 4. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| FIB Grifols 70 mg/kg Body Weight | 0/22 (0%) | 0/22 (0%) | 9/22 (40.9%) |
| Event | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| EpistaxisRespiratory, thoracic and mediastinal disorders | 3/22 |
| Abdominal painGastrointestinal disorders | 1/22 |
| Traumatic haematomaInjury, poisoning and procedural complications | 1/22 |
| Blood pressure diastolic decreasedInvestigations | 1/22 |
| Blood pressure systolic decreasedInvestigations | 1/22 |
| Body temperature increasedInvestigations | 1/22 |
| Heart rate increasedInvestigations | 1/22 |
| HeadacheNervous system disorders | 1/22 |
| ParaesthesiaNervous system disorders | 1/22 |
| MenorrhagiaReproductive system and breast disorders | 1/22 |
Safety population included all participants who received infusion (at any dose) of the investigational product.
| Age, Continuous(years) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Mean | 16.65 ± 9.523 |
| Sex: Female, Male(Participants) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Female | 12 |
| Male | 10 |
| Race/Ethnicity, Customized(Participants) | FIB Grifols 70 mg/kg Body Weight |
|---|---|
| Not Hispanic or Latino | 22 |
| Asian | 14 |
| White | 8 |
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Afibrinogenemia
Grifols Therapeutics LLC