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

Brief Title

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

Official Title

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

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.
    

Detailed Description

      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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

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

Condition

Congenital Afibrinogenemia

Intervention

Human Plasma-Derived Fibrinogen Concentrate

Study Arms / Comparison Groups

 Single
Description:  Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

24

Start Date

July 22, 2016

Completion Date

November 11, 2019

Primary Completion Date

November 11, 2019

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - 70 Years

Accepts Healthy Volunteers

No

Contacts

Flora Peyvandi, MD, , 

Location Countries

India

Location Countries

India

Administrative Informations


NCT ID

NCT02281500

Organization ID

IG0902


Responsible Party

Sponsor

Study Sponsor

Grifols Therapeutics LLC

Collaborators

 Instituto Grifols, S.A.

Study Sponsor

Flora Peyvandi, MD, Study Chair, Centro Emofilia & Trombosi Angelo Bianchi Bonomi


Verification Date

October 2020