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Pharmacokinetics of rFVIIIFc at Two Vial Strengths

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ClinicalTrials.gov Identifier: NCT02083965
Recruitment Status : Completed
First Posted : March 11, 2014
Results First Posted : August 19, 2016
Last Update Posted : December 19, 2020
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Bioverativ Therapeutics Inc. )

Brief Summary:
The primary objective of the study is to characterize the pharmacokinetics (PK) of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months for a continued treatment period.

Condition or disease Intervention/treatment Phase
Severe Hemophilia A Biological: rFVIIIFc Phase 1

Detailed Description:
This is a randomized, open-label, crossover study during which each participant receives a single injection of rFVIIIFc from 2 different vial concentrations (PK assessment). After the PK assessment, participants are provided with rFVIIIFc for either prophylactic or episodic (on-demand) treatment for up to 6 months.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of 2 Vial Strengths of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in Previously Treated Subjects With Severe Hemophilia A
Study Start Date : March 2014
Actual Primary Completion Date : October 2014
Actual Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: rFVIIIFc 1000 / 3000 PK Assessment

A single intravenous (IV) injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial.

Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.

Biological: rFVIIIFc
Administered as specified in the treatment arm.
Other Names:
  • Eloctate
  • antihemophilic factor [recombinant] FC fusion protein
  • recombinant coagulation factor VIII Fc fusion protein
  • efmoroctocog alfa
  • BIIB031
  • Elocta

Experimental: rFVIIIFc 3000 / 1000 PK Assessment

A single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial.

Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.

Biological: rFVIIIFc
Administered as specified in the treatment arm.
Other Names:
  • Eloctate
  • antihemophilic factor [recombinant] FC fusion protein
  • recombinant coagulation factor VIII Fc fusion protein
  • efmoroctocog alfa
  • BIIB031
  • Elocta




Primary Outcome Measures :
  1. Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).

  2. Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.


Secondary Outcome Measures :
  1. Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Maximum measured concentration of rFVIIIFc.

  2. Half-life (t½) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Time required for the concentration of the drug to reach half of its original value.

  3. Clearance (CL) as Measured by the aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.

  4. Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)

  5. Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The average time at which the number of absorbed molecules reside in the body, after single-dose administration.

  6. Time of Cmax (Tmax) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Time at which maximum activity (Cmax) is observed.

  7. Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Area under the plasma concentration time-curve from zero to the last measured concentration.

  8. Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    First order rate constant associated with the terminal portion of the curve (lambda z) .

  9. Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Percentage of AUCinf extrapolated from the last data point to infinity.

  10. Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Dose normalized area under the FVIII activity-time curve.

  11. Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    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.

  12. AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).

  13. IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.

  14. Cmax as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Maximum measured concentration of rFVIIIFc.

  15. t½ as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Time required for the concentration of the drug to reach half of its original value.

  16. CL as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.

  17. Vss as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)

  18. MRT as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    The average time at which the number of absorbed molecules reside in the body, after single-dose administration.

  19. Tmax as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Time at which maximum activity (Cmax) is observed.

  20. AUClast as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Area under the plasma concentration time-curve from zero to the last measured concentration.

  21. Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    First order rate constant associated with the terminal portion of the curve (lambda z).

  22. AUCext as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Percentage of AUCinf extrapolated from the last data point to infinity.

  23. DNAUC as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    Dose normalized area under the FVIII activity-time curve.

  24. Vz as Measured by Two-Stage Chromogenic Clotting Assay [ Time Frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection ]
    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.

  25. Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay [ Time Frame: Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only) ]
    An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Have severe hemophilia A
  • Previously treated subject, defined as having at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products (other than any use of rFVIIIFc- study drug or commercial product) at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
  • No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude subjects.
  • No measurable inhibitor activity using the Nijmegen-modified Bethesda assay at Screening.
  • Platelet count ≥100,000 platelets/μL at screening
  • CD4 lymphocytes >200 mm3 if known as HIV antibody positive at screening.
  • Viral load of <400 copies/mL if known HIV antibody positive at screening.

Key Exclusion Criteria:

  • Subject is at high risk of bleeding during the 5-day period between the first and second injections for PK analyses, as per Investigator discretion.
  • Previous treatment with rFVIIIFc as study drug or commercial product.
  • Other coagulation disorder(s) in addition to hemophilia A.
  • History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration.
  • Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except for low-dose ASA as prophylaxis (other nonsteroidal anti-inflammatory drugs are permitted).
  • Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days at a dose of ≤1 mg/kg within 12 weeks prior to Day 1) and/or inhaled steroids.

NOTE: Other protocol-defined inclusion/exclusion Criteria May Apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02083965


Locations
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United States, California
Research Site
Los Angeles, California, United States
United States, Utah
Research Site
Salt Lake City, Utah, United States, 84101
United States, Washington
Research Site
Seattle, Washington, United States
Australia
Research Site
Herston, Australia
Research Site
Perth, Australia
United Kingdom
Research Site
Basingstoke, United Kingdom
Research Site
Cambridge, United Kingdom
Research Site
London, United Kingdom
Sponsors and Collaborators
Bioverativ Therapeutics Inc.
Investigators
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Study Director: Medical Director Bioverativ Therapeutics Inc.
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Responsible Party: Bioverativ Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT02083965    
Other Study ID Numbers: 997HA307
2013-003013-18 ( EudraCT Number )
First Posted: March 11, 2014    Key Record Dates
Results First Posted: August 19, 2016
Last Update Posted: December 19, 2020
Last Verified: May 2017
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants