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

This study is a phase I-II, multi-center, prospective, open-label, single-arm, clinical trial
to evaluate PK, efficacy, and safety of human plasma-derived fibrinogen concentrate (FIB
Grifols) in adult and pediatric subjects with congenital afibrinogenemia.

Approximately 10 adult subjects (≥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
subjects 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 subjects (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 subjects (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 subject has been dosed with study drug, any
further enrollment and dosing of subjects 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 subjects less than 70 years old.

2. Sign the written Informed Consent Form (ICF), or the subject's parent or legal
guardian signs the ICF where applicable, and the Subject 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 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 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