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Pharmacokinetic, Efficacy, and Safety Study of Octafibrin Compared to Haemocomplettan/Riastap

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ClinicalTrials.gov Identifier: NCT01575756
Recruitment Status : Completed
First Posted : April 11, 2012
Results First Posted : November 30, 2016
Last Update Posted : March 9, 2018
Sponsor:
Information provided by (Responsible Party):
Octapharma

Tracking Information
First Submitted Date  ICMJE April 9, 2012
First Posted Date  ICMJE April 11, 2012
Results First Submitted Date  ICMJE October 5, 2016
Results First Posted Date  ICMJE November 30, 2016
Last Update Posted Date March 9, 2018
Study Start Date  ICMJE June 2013
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Ratio of Octafibrin/FIBRYGA® to Haemocomplettan® P/RiaSTAP(TM) for Fibrinogen Activity Normalized Area Under the Curve Unstandardized [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The mean ratio of normalized area under the curve was calculated as Octafibrin/FIBRYGA® over Haemocomplettan® P/RiaSTAP(TM)
  • Comparison of Maximum Clot Firmness Between Octafibrin/FIBRYGA® and Haemocomplettan® P/RiaSTAP(TM) at 1 hr Post Infusion [ Time Frame: 1 hour post-treatment ]
    Thromboelastometry (ROTEM®) was used to measure maximum clot firmness. Thromboelastometry is a method for the continuous measurement of clot formation. Maximum clot firmness is a functional parameter that depends on the activation of coagulation, the platelet and fibrinogen content of the blood sample, and the polymerisation and cross-linking of the fibrin network. In order to obtain comparable results from all study centres, maximum clot firmness data were assessed from frozen citrated plasma samples in a central laboratory. As these samples did not contain platelets that would be found in the whole blood assay, the fibrinogen content primarily defined the maximum clot firmness.
Original Primary Outcome Measures  ICMJE
 (submitted: April 10, 2012)
Pharmacokinetics [ Time Frame: 1 year ]
A comparison of the area under the curve (AUC) between Octafibrin and Haemocomplettan/Riastap
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Fibrinogen Activity Normalized Area Under the Curve Unstandardized [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Fibrinogen Activity Normalized Area Under the Curve Standardized [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The normalized area under the curve was standardized to a dose of 70 mg/kg.
  • Maximum Plasma Concentration Normalized (Cmaxnorm) [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Maximum Plasma Concentration (Cmax) Unstandardized [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Maximum Plasma Concentration (Cmax) Standardized [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The maximum plasma concentration was standardized to a dose of 70 mg/kg.
  • Incremental in Vivo Recovery [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Incremental in vivo recovery was calculated as the maximum increase in plasma fibrinogen (fibrinogen activity assay data) within 4 hours post-treatment as compared with pre-treatment (expressed as an absolute mg/dL concentration in plasma), divided by the exact dose of Octafibrin/FIBRYGA® or Haemocomplettan® P/RiaSTAP(TM) (expressed as mg/kg dosed).
  • Classical in Vivo Recovery [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Classical in vivo recovery was calculated as: 100 x the maximum increase in plasma fibrinogen (fibrinogen activity assay data) within 4 hours post-treatment as compared with pre-treatment (expressed as an absolute mg/dL concentration in plasma) x the plasma volume (mL), divided by the exact dose of Octafibrin/FIBRYGA® or Haemocomplettan® P/RiaSTAP(TM) (expressed as mg).
  • Time to Reach Maximum Plasma Concentration (Tmax) [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Terminal Half-life (t½) [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Mean Residence Time (MRT) [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Clearance [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
  • Volume of Distribution at Steady State (Vss) [ Time Frame: Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment ]
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, and at 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 10, 2012)
Efficacy [ Time Frame: 1 year ]
Comparison of MCF between Octafibrin and Haemocomplettan/Riastap at 1 hour post infusion
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetic, Efficacy, and Safety Study of Octafibrin Compared to Haemocomplettan/Riastap
Official Title  ICMJE A Prospective, Controlled, Randomised, Crossover Study Investigating the Pharmacokinetic Properties, Surrogate Efficacy and Safety of Octafibrin Compared to Haemocomplettan® P/RiaSTAPTM in Patients With Congenital Fibrinogen Deficiency
Brief Summary The purpose of this study is to investigate pharmacokinetic properties, surrogate efficacy and safety of Octafibrin compared to Haemocomplettan® P/RiaSTAPTM in patients with congenital fibrinogen deficiency
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Congenital Fibrinogen Deficiency
  • Afibrinogenemia
Intervention  ICMJE
  • Biological: Octafibrin
    Octafibrin was supplied as a powder for reconstitution with water for injection.
    Other Name: Plasma derived fibrinogen concentrate
  • Biological: Haemocomplettan® P or RiaSTAPTM
    Commercially available Haemocomplettan® P or RiaSTAPTM (same product with different names in different markets) were supplied as powders for reconstitution with water for injection.
    Other Name: Plasma derived fibrinogen concentrate
Study Arms  ICMJE
  • Experimental: Octafibrin followed by Haemocomplettan® P or RiaSTAPTM
    Participants received Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously once 45 days later.
    Interventions:
    • Biological: Octafibrin
    • Biological: Haemocomplettan® P or RiaSTAPTM
  • Experimental: Haemocomplettan® P or RiaSTAPTM followed by Octafibrin
    Participants received Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously once followed by Octafibrin 70 mg/kg intravenously once 45 days later.
    Interventions:
    • Biological: Octafibrin
    • Biological: Haemocomplettan® P or RiaSTAPTM
Publications * Not Provided

*   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: October 14, 2015)
22
Original Estimated Enrollment  ICMJE
 (submitted: April 10, 2012)
18
Actual Study Completion Date  ICMJE January 2015
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥ 12 years.
  • Documented congenital fibrinogen deficiency (afibrinogenemia).

Exclusion Criteria:

  • Life expectancy > 6 month.
  • Bleeding disorder other than congenital fibrinogen deficiency.
  • Presence or history of hypersensitivity to study medication.
  • Presence or history of deep vein thrombosis or pulmonary embolism within 1 year prior to enrollment.
  • Presence or history of arterial thrombosis with 1 year prior to enrollment.
  • Hypersensitivity to human plasma products.
  • Acute bleeding.
  • Pregnant or currently breast-feeding women.
  • Suspicion of an anti-fibrinogen inhibitor as indicated by previous in vivo recovery (if available).
  • Blood or plasma donation in the 3 months prior to enrollment.
  • Human immunodeficiency virus (HIV) positive with a viral load > 200 particles/µl or > 400000 copies/mL.
  • End-stage liver disease.
  • History of oesophageal varicose bleeding.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (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 Bulgaria,   India,   Iran, Islamic Republic of,   Switzerland,   United Kingdom,   United States
Removed Location Countries Germany,   Italy
 
Administrative Information
NCT Number  ICMJE NCT01575756
Other Study ID Numbers  ICMJE FORMA-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Octapharma
Study Sponsor  ICMJE Octapharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Sigurd Knaub, PhD Octapharma
PRS Account Octapharma
Verification Date March 2018

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