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

Phase 2

Completed

• Conditions: Congenital Fibrinogen Deficiency; Afibrinogenemia
• Interventions: Biological: Octafibrin; Biological: Haemocomplettan® P or RiaSTAPTM

• Registration Number: NCT01575756
• Lead Sponsor: Octapharma

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 available

Study Timeline

• Study First Submitted: 2012-04-09
• Study First Submitted QC: 2012-04-10
• Study First Posted: 2012-04-11
• Study Start: 2013-06
• Primary Completion: 2015-01
• Study Completion: 2015-01
• Results First Submitted: 2016-10-05
• Results First Submitted QC: 2016-10-05
• Results First Posted: 2016-11-30
• Status Verified: 2018-03
• Last Update Submitted: 2018-03-06
• Last Update Posted: 2018-03-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Octafibrin followed by Haemocomplettan® P or RiaSTAPTM	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.
Haemocomplettan® P or RiaSTAPTM followed by Octafibrin	Octafibrin	Participants received Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously once followed by Octafibrin 70 mg/kg intravenously once 45 days later.
Octafibrin followed by Haemocomplettan® P or RiaSTAPTM	Octafibrin	Participants received Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously once 45 days later.
Haemocomplettan® P or RiaSTAPTM followed by Octafibrin	Haemocomplettan® P or RiaSTAPTM	Participants received Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously once followed by Octafibrin 70 mg/kg intravenously once 45 days later.

Primary Outcome Measures

Name	Time	Method
Ratio of Octafibrin/FIBRYGA® to Haemocomplettan® P/RiaSTAP(TM) for Fibrinogen Activity Normalized Area Under the Curve Unstandardized	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	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.

Secondary Outcome Measures

Name	Time	Method
Fibrinogen Activity Normalized Area Under the Curve Unstandardized	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	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)	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	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	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	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	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)	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)	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)	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	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)	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.

Trial Locations

Locations (10)

Specialized Hospital for Active Treatment "Joan Pavel"; 🇧🇬 Sofia, Bulgaria

Department of Hematology St. John's Medical College Hospital; 🇮🇳 Bangalore, India

Sahyadri Speciality Hospital; 🇮🇳 Prune, India

Department of Hematology University Hospital; 🇨🇭 Zurich, Switzerland

Cohen Children's Medical Center of New York; 🇺🇸 New Hyde Park, New York, United States

University of Colorado Hemophilia & Thrombosis Center; 🇺🇸 Aurora, Colorado, United States

The Centre for Haemostatis and Thrombosis; 🇬🇧 London, United Kingdom

Department of Hematology Christian Medical College; 🇮🇳 Vellore, India

Nemazee Hospital Shiraz University of Medical Sciences; 🇮🇷 Shiraz, Iran, Islamic Republic of

Tehran University of Medical Sciences; 🇮🇷 Tehran, Iran, Islamic Republic of