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Pharmacokinetics of rFVIIIFc at Two Vial Strengths

16 décembre 2020 mis à jour par: Bioverativ Therapeutics Inc.

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

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.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Description détaillée

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.

Type d'étude

Interventionnel

Inscription (Réel)

19

Phase

  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • Australie
      • Herston, Australie
        • Research Site
      • Perth, Australie
        • Research Site
  • Royaume-Uni
      • Basingstoke, Royaume-Uni
        • Research Site
      • Cambridge, Royaume-Uni
        • Research Site
      • London, Royaume-Uni
        • Research Site
  • États-Unis
    • California
      • Los Angeles, California, États-Unis
        • Research Site
    • Utah
      • Salt Lake City, Utah, États-Unis, 84101
        • Research Site
    • Washington
      • Seattle, Washington, États-Unis
        • Research Site

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

12 ans et plus (Enfant, Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Homme

La description

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

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation croisée
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: 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.
Biologique: rFVIIIFc
Administered as specified in the treatment arm.
Autres noms:
  • Elocter
  • protéine de fusion recombinante facteur VIII de coagulation Fc
  • BIIB031
  • efmoroctocog alfa
  • Elocta
  • antihemophilic factor [recombinant] FC fusion protein
Expérimental: 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.
Biologique: rFVIIIFc
Administered as specified in the treatment arm.
Autres noms:
  • Elocter
  • protéine de fusion recombinante facteur VIII de coagulation Fc
  • BIIB031
  • efmoroctocog alfa
  • Elocta
  • antihemophilic factor [recombinant] FC fusion protein

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay
Délai: 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 - ∞).
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
Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay
Délai: 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.
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

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
Délai: 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.
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
Half-life (t½) as Measured by aPTT Clotting Assay
Délai: 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.
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
Clearance (CL) as Measured by the aPTT Clotting Assay
Délai: 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.
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
Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
Délai: 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.)
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
Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
Délai: 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.
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 of Cmax (Tmax) as Measured by aPTT Clotting Assay
Délai: 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.
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 Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
Délai: 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.
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
Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
Délai: 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) .
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 From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
Délai: 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.
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 Curve (DNAUC) as Measured by aPTT Clotting Assay
Délai: 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.
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
Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT
Délai: 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.
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
AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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 - ∞).
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
IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Cmax as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
t½ as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
CL as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Vss as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.)
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
MRT as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Tmax as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
AUClast as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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).
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
AUCext as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Vz as Measured by Two-Stage Chromogenic Clotting Assay
Délai: 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.
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
Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay
Délai: 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.
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)

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Bioverativ Therapeutics Inc.

Les enquêteurs

  • Directeur d'études: Medical Director, Bioverativ Therapeutics Inc.

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 mars 2014

Achèvement primaire (Réel)

1 octobre 2014

Achèvement de l'étude (Réel)

1 mai 2015

Dates d'inscription aux études

Première soumission

7 mars 2014

Première soumission répondant aux critères de contrôle qualité

7 mars 2014

Première publication (Estimation)

11 mars 2014

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

19 décembre 2020

Dernière mise à jour soumise répondant aux critères de contrôle qualité

16 décembre 2020

Dernière vérification

1 mai 2017

Plus d'information

Termes liés à cette étude

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • 997HA307
  • 2013-003013-18 (Numéro EudraCT)

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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