Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Participants With Congenital Afibrinogenemia

NCT02281500 | Completed Phase 1 Results FDA Drug

• 1 other identifier: IG0902
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 6

Brief Summary

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.

Conditions

Congenital Afibrinogenemia

Outcome Measures

Primary Outcomes (19)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Baseline to 1-hour post-infusion

Secondary Outcomes (7)

• Mean Change in Clotting Time (CT) From Baseline to 1-hour Post-infusion

  Baseline to 1-hour post-infusion

• Clot Formation Time (CFT) at 1-hour Post-infusion

  1-hour post-infusion

• Mean Change in Alpha Angle (α) From Baseline to 1-hour Post-infusion

  Baseline to 1-hour post-infusion

• Mean Change in Prothrombin Time (PT) From Baseline to 1-hour Post-infusion

  Baseline to 1-hour post-infusion

• Mean Change in Thrombin Time (TT) From Baseline to 1-hour Post-infusion

  Baseline to 1-hour post-infusion

Study Arms (1)

Single

EXPERIMENTAL

Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols)

Biological: Human Plasma-Derived Fibrinogen Concentrate

Interventions

Human Plasma-Derived Fibrinogen Concentrate BIOLOGICAL

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

Single

Eligibility Criteria

• Age: Up to 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants less than 70 years old.
• Sign the written Informed Consent Form (ICF), or the subjects parent or legal guardian signs the ICF where applicable, and the subjects. Authorization Form where applicable. Pediatric subjects, as defined by local regulations, will be asked to sign an age appropriate assent form.
• Subjects diagnosed with congenital fibrinogen deficiency manifested as afibrinogenemia.
• Subjects with a fibrinogen level undetectable or equal or less than 30 mg/dL determined by both Clauss and antigen methods at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit) or at Screening Visit (sample drawn at least 14 days prior to infusion on Day 0 Visit).
• Female subjects of child-bearing potential must have a negative test for pregnancy blood or urine human chorionic gonadotropin (HCG-based assay) at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit).
• Female subjects of child-bearing potential and their partners have agreed to practice contraception using a method of proven reliability (i.e., hormonal methods; barrier methods; intrauterine devices methods) to prevent a pregnancy during the course of the clinical trial.
• Subjects ants must be willing to comply with all aspects of the clinical trial protocol, including blood sampling, for the whole duration of the study.

You may not qualify if:

• Subjects who received any fibrinogen-containing product within 21 days prior to Day 0 Visit - infusion day.
• Subjects who present with active bleeding within 10 days prior to infusion on Day 0 Visit.
• Subjects with acquired (secondary) fibrinogen deficiency.
• Subjects diagnosed with dysfibrinogenemia.
• Subjects with documented history of deep vein thrombosis, pulmonary embolism, or arterial thrombosis within 1 year prior to enrollment in this clinical trial.
• Subjects with known antibodies against fibrinogen.
• Subjects with a history of anaphylactic reactions or severe reactions to any blood-derived product.
• Subjects with a history of intolerance to any component of the investigational products.
• Subjects with a documented history of Immunoglobulin A (IgA) deficiency and antibodies against IgA.
• Females who are pregnant or are breastfeeding.
• Subjects with renal impairment (i.e., serum creatinine exceeds more than 2.0 times the upper limit of normal \[ULN\] at baseline \[sample drawn within 24 hours prior to infusion on Day 0 Visit\]).
• Subjects with aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the ULN at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit).
• Subjects with a history of chronic alcoholism or illicit drug addiction in the preceding 12 months prior to enrollment in this clinical trial.
• Subjects with any medical condition which is likely to interfere with the evaluation of the study drugs and/or the satisfactory conduct of the clinical trial according to the investigator's judgment (e.g., congenital or acquired bleeding disorders other than congenital fibrinogen deficiency, planned surgery needing blood transfusion).
• Subjects received aspirin-containing products and nonsteroidal anti-inflammatory drugs within 7 days prior to Day 0 Visit.

Sponsors & Collaborators

• Grifols Therapeutics LLC: lead
• Instituto Grifols, S.A.: collaborator

Study Sites (6)

Northshore Long Island Jewish Medical Center

New Hyde Park, New York, 11040, United States

Location

S.S. Institute of Medical Sciences and Research Centre

Davangere, Karnataka, India

Location

St. Johns Medical College and Hospital

Bangalore, India

Location

Sahyadri Specialty Hospital

Pune, India

Location

Agenzia per l'Emofilia Centro di Riferimento Regionale per le Coaugulopatie Congenite A.O. di Carreggi

Florence, 50134, Italy

Location

Hôtel-Dieu de France Hospital

Beirut, Lebanon

Location

MeSH Terms

Conditions

Afibrinogenemia

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Jordi Navarro Puerto
• Organization: Instituto Grifols S.A.

jordi.navarro@grifols.com

+34 935712200

Study Officials

• Flora Peyvandi, MD

  Centro Emofilia & Trombosi Angelo Bianchi Bonomi

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2014
• First Posted: November 3, 2014
• Study Start: July 22, 2016
• Primary Completion: November 11, 2019
• Study Completion: November 11, 2019
• Last Updated: March 31, 2022
• Results First Posted: October 29, 2020

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); IN (3); IT (1); LE (1)