C Ross1, S Rangarajan2, M Karimi3, G Toogeh4, S Apte5, T Lissitchkov6, S Acharya7, M J Manco-Johnson8, A Srivastava9, B Brand10, B A Schwartz11, S Knaub12, F Peyvandi13. 1. Department of Hematology, St John's Medical College and Hospital, Bangalore, India. 2. Centre For Haemostasis and Thrombosis, St Thomas' Hospital, London, UK. 3. Hematology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. 4. Thrombosis Hemostasis Research Center, Tehran University of Medical Sciences, Tehran, Iran. 5. Sahyadri Speciality Hospital, Pune, Maharashtra, India. 6. Department of Hemorrhagic Diathesis and Anemia, Specialized Hospital for Active Treatment (SHAT) 'Joan Pavel', Sofia, Bulgaria. 7. Cohen Children's Medical Center of New York, Northwell Health, New Hyde Park, NY, USA. 8. Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 9. Department of Haematology, Christian Medical College, Vellore, India. 10. Department of Haematology, University Hospital Zurich, Zurich, Switzerland. 11. Clinical Research and Development, Octapharma, Hoboken, NJ, USA. 12. Research and Development Department, Octapharma, Lachen, Switzerland. 13. Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Abstract
Essentials Congenital afibrinogenemia causes a potentially life-threatening bleeding and clotting tendency. Two human fibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study. Bioequivalence was not shown for AUCnorm , which was significantly larger for the new HFC. Increases in clot strength were comparable, and no thromboses or deaths occurred in the study. SUMMARY: Background Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenemia. Objectives To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus-inactivated/eliminated, highly purified HFC vs. active control. Patients/Methods In this multinational, randomized, phase II, open-label, crossover study in 22 congenital afibrinogenemia patients aged ≥ 12 years, 70 mg kg-1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan® P/RiaSTAP™, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed. Results The concentrates were not bioequivalent for the primary endpoint, AUCnorm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (Cmaxnorm , IVR, t1/2 , MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and Vss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUCnorm was significantly larger for the new HFC (1.62 ± 0.45 vs. 1.38 ± 0.47 h kg g L-1 mg-1 , P = 0.0001) and mean clearance was significantly slower (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h-1 kg-1 , P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1-hour post-infusion (mean difference, -0.32 mm; 95% CI, -1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred. Conclusions Bioequivalence was not demonstrated for AUCnorm , clearance and Vss . Larger AUCnorm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.
RCT Entities:
Essentials Congenital afibrinogenemia causes a potentially life-threatening bleeding and clotting tendency. Two humanfibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study. Bioequivalence was not shown for AUCnorm , which was significantly larger for the new HFC. Increases in clot strength were comparable, and no thromboses or deaths occurred in the study. SUMMARY: Background Humanfibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenemia. Objectives To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus-inactivated/eliminated, highly purified HFC vs. active control. Patients/Methods In this multinational, randomized, phase II, open-label, crossover study in 22 congenital afibrinogenemiapatients aged ≥ 12 years, 70 mg kg-1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan® P/RiaSTAP™, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed. Results The concentrates were not bioequivalent for the primary endpoint, AUCnorm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (Cmaxnorm , IVR, t1/2 , MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and Vss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUCnorm was significantly larger for the new HFC (1.62 ± 0.45 vs. 1.38 ± 0.47 h kg g L-1 mg-1 , P = 0.0001) and mean clearance was significantly slower (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h-1 kg-1 , P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1-hour post-infusion (mean difference, -0.32 mm; 95% CI, -1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred. Conclusions Bioequivalence was not demonstrated for AUCnorm , clearance and Vss . Larger AUCnorm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.
Authors: Philipp Groene; Tobias Wiederkehr; Tobias Kammerer; Patrick Möhnle; Melanie Maerte; Andreas Bayer; Klaus Görlinger; Markus Rehm; Simon T Schäfer Journal: Transfus Med Hemother Date: 2019-08-16 Impact factor: 3.747
Authors: Fernando F Corrales-Medina; Tamir Miloh; Candelaria O'Farrell; David M Andrews; Akin Tekin; Guillermo De Angulo Journal: J Thromb Haemost Date: 2020-10-06 Impact factor: 16.036