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Trial record 1 of 1 for:    CSL627_1001
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An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01486927
Recruitment Status : Completed
First Posted : December 7, 2011
Results First Posted : August 9, 2016
Last Update Posted : August 9, 2016
Sponsor:
Information provided by (Responsible Party):
CSL Behring

Tracking Information
First Submitted Date  ICMJE November 19, 2011
First Posted Date  ICMJE December 7, 2011
Results First Submitted Date  ICMJE June 24, 2016
Results First Posted Date  ICMJE August 9, 2016
Last Update Posted Date August 9, 2016
Study Start Date  ICMJE February 2012
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2016)
  • Treatment Success [ Time Frame: Up to 24 months ]
    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 ]
    Number of subjects who develop inhibitors to FVIII
  • Annualized Spontaneous Bleeding Rate [ Time Frame: Up to 24 months ]
    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) ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 5, 2011)
  • Treatment Success [ Time Frame: Approximately 12 months ]
    Subjects will receive treatment for any bleeding episode and the investigator will rate the efficacy of the treatment based on a four point rating scale "excellent, good, moderate or poor/no response".
  • 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) ]
    Subjects will receive pre-treatment with rFVIII prior to major surgery. The investigator will rate the efficacy of the treatment based on a four point rating scale of "excellent, good, moderate or poor/no response".
  • Inhibitor Formation to FVIII [ Time Frame: Approximately 12 months ]
    Number of subjecs who develop inhibitors to FVIII
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2016)
  • AUC0-∞ (Part 1) [ Time Frame: Before infusion and at up to 10 time points within 72 hours of infusion ]
    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 ]
    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 ]
    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. ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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) ]
    Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis. The denominator includes all treated bleeding episodes.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 5, 2011)
  • AUC0-t [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    AUC0-t of a single infusion of octocog alfa and CSL627
  • AUC0-∞ [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    AUC0-∞ of a single infusion of octocog alfa and CSL627
  • Percent of area extrapolated [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Percent of area extrapolated of a single infusion of octocog alfa and CSL627
  • Cmax [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Cmax of a single infusion of octocog alfa and CSL627
  • Tmax [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Tmax of a single infusion of octocog alfa and CSL627
  • Elimination constant [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Elimination constant of a single infusion of octocog alfa and CSL627
  • Half-life (t1/2) [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Half-life (t1/2) of a single infusion of octocog alfa and CSL627
  • AUMC0-∞ [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    AUMC0-∞ of a single infusion of octocog alfa and CSL627
  • Mean residence time (MRT) [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Mean residence time (MRT) mean residence time (MRT) of a single infusion of octocog alpha and CSL627
  • Clearance (Cl) [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Clearance (Cl) of a single infusion of octocog alfa and CSL627
  • Volume of distribution at steady-state (Vss) [ Time Frame: 1/2, 1, 4, 8, 10, 24, 28, 48 and 72 hours ]
    Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and CSL627
  • Proportion of bleeding episodes [ Time Frame: Assessed at Months 1, 2, 3, 4, 5, 6, 9, and 12 visit ]
    Proportion of bleeding episodes requiring one, 2, 3 or > 3 infusions of CSL627 to achieve hemostasis
Current Other Pre-specified Outcome Measures
 (submitted: June 24, 2016)
  • Incremental Recovery (Part 3) [ Time Frame: At 30 minutes after infusion ]
    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. ]
    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. ]
    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. ]
    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. ]
    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. ]
    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 ]
    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 ]
    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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia A
Intervention  ICMJE
  • 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)
Study Arms  ICMJE Experimental: Recombinant Factor VIII (rFVIII)
Interventions:
  • Biological: rVIII-SingleChain
  • Biological: Octocog alfa
Publications * Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, Skotnicki A, Boggio LN, Klamroth R, Oldenburg J, Hellmann A, Santagostino E, Baker RI, Fischer K, Gill JC, P'Ng S, Chowdary P, Escobar MA, Khayat CD, Rusen L, Bensen-Kennedy D, Blackman N, Limsakun T, Veldman A, St Ledger K, Pabinger I; AFFINITY Investigators. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016 Aug 4;128(5):630-7. doi: 10.1182/blood-2016-01-687434. Epub 2016 Jun 21.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 9, 2015)
175
Original Estimated Enrollment  ICMJE
 (submitted: December 5, 2011)
104
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 12 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   Czech Republic,   Germany,   Hungary,   Italy,   Japan,   Lebanon,   Malaysia,   Netherlands,   Philippines,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   Ukraine,   United Kingdom,   United States
Removed Location Countries Belgium,   France,   Korea, Republic of,   Sweden
 
Administrative Information
NCT Number  ICMJE NCT01486927
Other Study ID Numbers  ICMJE CSL627_1001
2011-002393-23 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party CSL Behring
Study Sponsor  ICMJE CSL Behring
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Program Director CSL Behring
PRS Account CSL Behring
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP