Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors

S V Antunes, S Tangada, O Stasyshyn, V Mamonov, J Phillips, N Guzman-Becerra, A Grigorian, B Ewenstein, W-Y Wong, S V Antunes, S Tangada, O Stasyshyn, V Mamonov, J Phillips, N Guzman-Becerra, A Grigorian, B Ewenstein, W-Y Wong

Abstract

Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti-inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high-titre inhibitors or low-titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1-year period, 17 subjects were treated prophylactically (85 ± 15 U kg(-1) every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on-demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode-free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on-demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on-demand treatment, and the safety of prophylaxis is comparable to that of on-demand treatment.

Keywords: FEIBA; Prophylaxis; haemophilia A/B; inhibitors; on-demand.

© 2013 John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Subject disposition flow diagram.
Figure 2
Figure 2
Comparison of ABRs (ITT analysis set). (a) Median ABRs during treatment regimens. (b) Median (IQR) ABRs and per cent reductions during Prophylaxis vs. On-demand therapies.
Figure 3
Figure 3
New target joints and associated bleeding episodes.

References

    1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group. The World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1–14.
    1. Berntorp E, Boulyjenkov V, Brettler D, et al. Modern treatment of haemophilia. Bull World Health Organ. 1995;73:691–701.
    1. National Hemophilia Foundation. National Hemophilia Foundation (NHF); 2007. Recommendation concerning prophylaxis (Regular administration of clotting factor concentrate to prevent bleeding); Report No.: MASAC 179.
    1. DiMichele D, Negrier C. A retrospective postlicensure survey of FEIBA efficacy and safety. Haemophilia. 2006;12:352–62.
    1. Hilgartner MW, Makipernaa A, DiMichele DM. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia. 2003;9:261–8.
    1. Valentino LA. FEIBA prophylaxis for patients with haemophilia and inhibitors. Haemophilia. 2006;12(Suppl. 5):26–31.
    1. Leissinger CA, Becton DL, Ewing NP, Valentino LA. Prophylactic treatment with activated prothrombin complex concentrate (FEIBA©) reduces the frequency of bleeding episodes in paediatric patients with haemophilia A and inhibitors. Haemophilia. 2007;13:249–55.
    1. Valentino LA. The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series. Haemophilia. 2009;15:733–42.
    1. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost. 2007;5:1904–13.
    1. Hoots WK, Ebbesen LS, Konkle BA, et al. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors. Haemophilia. 2008;14:466–75. Novoseven (F7HAEM-1505) Investigators.
    1. Ekert H, Brewin T, Boey W, Davey P, Tilden D. Cost-utility analysis of recombinant factor VIIa (NovoSeven) in six children with long-standing inhibitors to factor VIII or IX. Haemophilia. 2001;7:279–85.
    1. Scalone L, Mantovani LG, Mannucci PM, Gringeri A COCIS Study Investigators. Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors. Haemophilia. 2006;12:154–62.
    1. Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011;365:1684–92.
    1. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII: C inhibitors: improved specificity and reliability. Thromb Haemost. 1995;73:247–51.
    1. Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D) Br J Rheumatol. 1997;36:551–9.
    1. Gringeri A, Mantovani L, Mackensen SV. Quality of life assessment in clinical practice in haemophilia treatment. Haemophilia. 2006;12(Suppl. 3):22–9.
    1. von Mackensen S, Bullinger M Haemo-Qol Group. Development and testing of an instrument to assess the quality of life of children with haemophilia in Europe (Haemo-QoL) Haemophilia. 2004;10(Suppl. 1):17–25.
    1. Choiniere M, Amsel R. A visual analogue thermometer for measuring pain intensity. J Pain Symptom Manage. 1996;11:299–311.
    1. Beyer JE, Aradine CR. Patterns of pediatric pain intensity: a methodological investigation of a self-report scale. Clin J Pain. 1987;3:130–41.
    1. Walters SJ, Brazier JE. Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D. Qual Life Res. 2005;14:1523–32.
    1. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70.
    1. Varadi K, Negrier C, Berntorp E, et al. Monitoring the bioavailability of FEIBA with a thrombin generation assay. J Thromb Haemost. 2003;1:2374–80.
    1. Escuriola Ettingshausen C, Kreuz W. Early long-term FEIBA prophylaxis in haemophilia A patients with inhibitor after failing immune tolerance induction: a prospective clinical case series. Haemophilia. 2010;16:90–100.
    1. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med. 1994;236:391–9.
    1. Blanchette VS, Shapiro AD, Liesner RJ, et al. Plasma and albumin free recombinant factor VIII (rAHF-PFM): pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost. 2008;6:1319–26.
    1. Shapiro A, Gruppo R, Pabinger I, et al. Integrated analysis of safety and efficacy of a plasma and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther. 2009;9:273–83.
    1. Valentino LA, Mamonov V, Hellmann A, et al. The Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012;10:359–67.
    1. Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study) J Thromb Haemost. 2011;9:700–10.

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