Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency
Journal of Thrombosis and Haemostasis : Jth. 2017;16((2):):253-261
BACKGROUND Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenaemia. 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 afibrinogenaemia patients ≥12 years, 70 mg kg(-1) of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan((R)) 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% 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. This article is protected by copyright. All rights reserved.
A randomized trial of factor VIII and neutralizing antibodies in hemophilia A
The New England Journal of Medicine. 2016;374((21)):2054-64.
BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).