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

Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients With Congenital Afibrinogenemia

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.

Inclusion Criteria:

1. Male or female participants less than 70 years old.
2. 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.
3. Subjects diagnosed with congenital fibrinogen deficiency manifested as afibrinogenemia.
4. 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).
5. 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).
6. 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.
7. 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.

Exclusion Criteria:

1. Subjects who received any fibrinogen-containing product within 21 days prior to Day 0 Visit - infusion day.
2. Subjects who present with active bleeding within 10 days prior to infusion on Day 0 Visit.
3. Subjects with acquired (secondary) fibrinogen deficiency.
4. Subjects diagnosed with dysfibrinogenemia.
5. Subjects with documented history of deep vein thrombosis, pulmonary embolism, or arterial thrombosis within 1 year prior to enrollment in this clinical trial.
6. Subjects with known antibodies against fibrinogen.
7. Subjects with a history of anaphylactic reactions or severe reactions to any blood-derived product.
8. Subjects with a history of intolerance to any component of the investigational products.
9. Subjects with a documented history of Immunoglobulin A (IgA) deficiency and antibodies against IgA.
10. Females who are pregnant or are breastfeeding.
11. 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]).
12. 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).
13. Subjects with a history of chronic alcoholism or illicit drug addiction in the preceding 12 months prior to enrollment in this clinical trial.
14. 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).
15. Subjects received aspirin-containing products and nonsteroidal anti-inflammatory drugs within 7 days prior to Day 0 Visit.
16. Subjects currently receiving, or having received within 3 months prior to enrollment into this clinical trial, any investigational drug or device.
17. Subjects who were previously administered the investigational product FIB Grifols during this clinical trial (i.e., every subject can only participate in the study once).
18. Subjects who are unlikely to adhere the protocol requirements, or are likely to be uncooperative, or unable to provide a storage serum sample prior to investigational drug infusion.