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

Congenital Fibrinogen Deficiency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01575756
• Other study ID #: FORMA-01
• Status: Completed
• Phase: Phase 2
• First received: April 9, 2012
• Last updated: March 6, 2018
• Start date: June 2013
• Est. completion date: January 2015

Study information

• Verified date: March 2018
• Source: Octapharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Afibrinogenemia
• Congenital Fibrinogen Deficiency

Intervention

Biological:
• Octafibrin
Octafibrin was supplied as a powder for reconstitution with water for injection.
• 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.

Locations

Country	Name	City	State
Bulgaria	Specialized Hospital for Active Treatment "Joan Pavel"	Sofia
India	Department of Hematology St. John's Medical College Hospital	Bangalore
India	Sahyadri Speciality Hospital	Prune
India	Department of Hematology Christian Medical College	Vellore
Iran, Islamic Republic of	Nemazee Hospital Shiraz University of Medical Sciences	Shiraz
Iran, Islamic Republic of	Tehran University of Medical Sciences	Tehran
Switzerland	Department of Hematology University Hospital	Zurich
United Kingdom	The Centre for Haemostatis and Thrombosis	London
United States	University of Colorado Hemophilia & Thrombosis Center	Aurora	Colorado
United States	Cohen Children's Medical Center of New York	New Hyde Park	New York

Sponsors (1)

Lead Sponsor	Collaborator
Octapharma

Countries where clinical trial is conducted

United States,  Bulgaria,  India,  Iran, Islamic Republic of,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ratio of Octafibrin/FIBRYGA® to Haemocomplettan® P/RiaSTAP(TM) for Fibrinogen Activity Normalized Area Under the Curve Unstandardized	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)	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Primary	Comparison of Maximum Clot Firmness Between Octafibrin/FIBRYGA® and Haemocomplettan® P/RiaSTAP(TM) at 1 hr Post Infusion	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.	1 hour post-treatment
Secondary	Fibrinogen Activity Normalized Area Under the Curve Unstandardized	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Fibrinogen Activity Normalized Area Under the Curve Standardized	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Maximum Plasma Concentration Normalized (Cmaxnorm)	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Maximum Plasma Concentration (Cmax) Unstandardized	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Maximum Plasma Concentration (Cmax) Standardized	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Incremental in Vivo Recovery	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).	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Classical in Vivo Recovery	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).	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Time to Reach Maximum Plasma Concentration (Tmax)	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Terminal Half-life (t½)	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Mean Residence Time (MRT)	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Clearance	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment
Secondary	Volume of Distribution at Steady State (Vss)	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.	Baseline to 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment