An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
CSL Behring
ClinicalTrials.gov Identifier:
NCT01486927
First received: November 19, 2011
Last updated: June 24, 2016
Last verified: June 2016
  Purpose
This is an open-label, non-randomized, efficacy, safety and pharmacokinetic (PK) study comparing octocog alfa and rVIII-SingleChain. The study consists of three parts, a PK period (Part 1), a continuation of dosing safety and efficacy period (Part 2) and a safety, efficacy, and repeat PK period (Part 3) and also includes a surgical sub-study for subjects enrolled in Parts 2 and 3.

Condition Intervention Phase
Hemophilia A
Biological: rVIII-SingleChain
Biological: Octocog alfa
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/III Open-label, Multicenter, Crossover Safety, Efficacy and Pharmacokinetic Study of Recombinant Coagulation Factor VIII (rFVIII) Compared to Recombinant Human Antihaemophilic Factor VIII (rFVIII; INN: Octocog Alfa) in Subjects With Hemophilia A, and a Repeat PK, Safety and Efficacy Study

Resource links provided by NLM:


Further study details as provided by CSL Behring:

Primary Outcome Measures:
  • Treatment Success [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    The investigator rated the efficacy of the treatment based on a 4-point rating scale "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.

  • Inhibitor Formation to FVIII [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    Number of subjects who develop inhibitors to FVIII

  • Annualized Spontaneous Bleeding Rate [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    The annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest).

  • Treatment Success During the Peri-operative Surgical Sub-study [ Time Frame: From the start of surgery through the post-operative recovery (generally up to 14 days after surgery) ] [ Designated as safety issue: No ]
    Subjects received rVIII-SingleChain before and during surgery based on the type of surgery and the clinical status of the subject. The investigator rated the efficacy of the treatment based on a 4-point surgical treatment rating scale of "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point. The rate of success, defined as the percentage of surgeries with a rating of excellent or good for hemostatic efficacy on the surgical treatment scale is presented for the Surgical Population, based on the total number of surgeries (N=16) as denominator.


Secondary Outcome Measures:
  • AUC0-∞ (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    AUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.

  • Cmax (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    Cmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.

  • Tmax (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain.

  • Half-life (t1/2) (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion. ] [ Designated as safety issue: No ]
    Half-life (t1/2) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Mean Residence Time (MRT) (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    Mean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Clearance (Cl) (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    Clearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.

  • Volume of Distribution at Steady-state (Vss) (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ] [ Designated as safety issue: No ]
    Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.

  • Incremental Recovery (Part 1) [ Time Frame: At 30 minutes after infusion ] [ Designated as safety issue: No ]
    Incremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.

  • Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    The annualized bleeding rate was derived for each subject as follows: 365.25*(number of bleeding episodes requiring treatment) / (observed treatment period of interest).

  • Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis [ Time Frame: During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24) ] [ Designated as safety issue: No ]
    Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis. The denominator includes all treated bleeding episodes.


Other Outcome Measures:
  • Incremental Recovery (Part 3) [ Time Frame: At 30 minutes after infusion ] [ Designated as safety issue: No ]
    Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.

  • Volume of Distribution at Steady-state (Vss) (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion. ] [ Designated as safety issue: No ]
    Volume of distribution at steady-state (Vss) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Clearance (Cl) (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion. ] [ Designated as safety issue: No ]
    Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Mean Residence Time (MRT) (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion. ] [ Designated as safety issue: No ]
    Mean residence time (MRT) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Half-life (t1/2) (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion. ] [ Designated as safety issue: No ]
    Half-life (t1/2) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.

  • Tmax (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion. ] [ Designated as safety issue: No ]
    Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after an initial and repeat infusion of rVIII-SingleChain.

  • Cmax (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion ] [ Designated as safety issue: No ]
    Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.

  • AUC0-∞ (Part 3) [ Time Frame: Before infusion and at up to 12 time points within 96 hours of infusion ] [ Designated as safety issue: No ]
    AUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.


Enrollment: 175
Study Start Date: February 2012
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Recombinant Factor VIII (rFVIII) Biological: rVIII-SingleChain
In Part 1 of the study, subjects received a single intravenous infusion of 50 IU/kg recombinant, single-chain coagulation factor VIII (rVIII-SingleChain) preceded by a 4-day washout period. In Parts 2 and 3 of the study, subjects received repeat injections of rVIII-SingleChain either as an on-demand or prophylaxis regimen at a dose and frequency determined by their study doctor. Subjects participating in the Part 3 PK analyses received a single infusion of 50 IU/kg rVIII-SingleChain and a repeat dose of the same strength of rVIII-SingleChain after 3 to 6 months. Subjects from Parts 2 and 3 participating in the surgical substudy received an individualized dose regimen of rVIII-SingleChain, based on the type of surgery and the clinical status of the subject.
Other Names:
  • Recombinant Factor VIII (rFVIII)
  • CSL627
Biological: Octocog alfa
In Part 1 of the study, subjects received a single intravenous infusion of 50 IU/kg of octocog alfa preceded by a 4-day washout period. Octocog alfa is the international nonproprietary name (INN) for recombinant human coagulation factor VIII.
Other Name: Human coagulation factor VIII (rDNA)

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult)
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of severe hemophilia A defined as <1% FVIII:C documented in medical records.
  • Males between 18 and 65 years of age (Parts 1 and 2).
  • Males between 12 and 65 years of age (Part 3).
  • Subjects who have received or are currently receiving FVIII products (plasma-derived and/or recombinant FVIII) and have had >150 exposure days (EDs) with a FVIII product
  • Written informed consent for study participation obtained before undergoing any study specific procedures.

Exclusion Criteria:

  • Any history of or current FVIII inhibitors
  • Any first order family history of FVIII inhibitors
  • Use of an Investigational Medicinal Product within 30 days prior to the first rVIII-SingleChain administration.
  • Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain or reference product.
  • Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein.
  • Any known congenital or acquired coagulation disorder other than congenital FVIII deficiency.
  • Platelet count < 100,000/µL at screening.
  • Human immunodeficiency virus (HIV) positive subjects with a CD4 count < 200/mm3, in their medical history or at screening if available results are older than one year. (HIV positive subjects may participate in the study and antiviral therapy are permitted, at the discretion of the Investigator).
  • Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment.
  • Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values > 5 times (x) the upper limit of normal (ULN) at Screening.
  • Subjects with serum creatinine values > 2 x ULN at Screening.
  • Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1.
  • Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months prior to Day 1.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01486927

  Show 56 Study Locations
Sponsors and Collaborators
CSL Behring
Investigators
Study Director: Program Director CSL Behring
  More Information

Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT01486927     History of Changes
Other Study ID Numbers: CSL627_1001  2011-002393-23 
Study First Received: November 19, 2011
Results First Received: June 24, 2016
Last Updated: June 24, 2016
Health Authority: United States: Food and Drug Administration
Germany: Paul-Ehrlich-Institut
Austria: Agency for Health and Food Safety
Austria: Federal Office for Safety in Health Care
Sweden: Medical Products Agency
Italy: Ministry of Health
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Japan: Pharmaceuticals and Medical Devices Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Spain: Spanish Agency of Medicines
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
Czech Republic: State Institute for Drug Control

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants

ClinicalTrials.gov processed this record on August 30, 2016