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Thromb Haemost 1997; 77(04): 660-667
DOI: 10.1055/s-0038-1656030
Clinical Studies
Schattauer GmbH Stuttgart

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

G C White II
The Center of Thrombosis and Hemostasis, Departments of Medicine and Pharmacology, University of North Carolina School of Medicine Chapel Hill, NC and the Dept, of Medical and Clinical Affairs, Baxter/Hyland Division, Glendale, CA, USA
,
S Courter
,
G L Bray
The Center of Thrombosis and Hemostasis, Departments of Medicine and Pharmacology, University of North Carolina School of Medicine Chapel Hill, NC and the Dept, of Medical and Clinical Affairs, Baxter/Hyland Division, Glendale, CA, USA
,
M Lee
The Center of Thrombosis and Hemostasis, Departments of Medicine and Pharmacology, University of North Carolina School of Medicine Chapel Hill, NC and the Dept, of Medical and Clinical Affairs, Baxter/Hyland Division, Glendale, CA, USA
,
The Recombinate Previously Treated Patient Study Group,
E D Gomperts
The Center of Thrombosis and Hemostasis, Departments of Medicine and Pharmacology, University of North Carolina School of Medicine Chapel Hill, NC and the Dept, of Medical and Clinical Affairs, Baxter/Hyland Division, Glendale, CA, USA
› Author Affiliations
Further Information

Publication History

Received 20 August 1996

Accepted after revision 29 November 1996

Publication Date:
11 July 2018 (online)

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Summary

A prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

* See Appendix for the complete list of coinvestigators in the Study Group


 

  • References

  • 1 Columbo M, Camelli V, Gazengel C, Mannucci PM, Savidge GF, Schimpf K. and the European Study Group. Transmission of non-A, non-B hepatitis by heat-treated Factor VIII concentrate. Lancet 1985; 02: 01-04
    PubMedGoogle Scholar
  • 2 Fletcher ML, Trowell JM, Craske J, Pavier K, Rizza CR. Non-A, non-B hepatitis after transfusion of Factor VIII in infrequently treated patients. Br J Med 1983; 287: 1754-1757
    CrossrefPubMedGoogle Scholar
  • 3 Hay CRM, Tuger DR, Preston FE, Underwood JCE. Progressive liver disease in haemophilia: an understood problem?. Lancet 1985; 01: 1495-1498
    PubMedGoogle Scholar
  • 4 Kemoff PBA, Lee CA, Karayiannis P, Thomas HC. High risk of non-A, non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin. Br J Haematol 1985; 60: 469-479
    CrossrefPubMedGoogle Scholar
  • 5 Ludlum CA, Peutherer JF. Hepatitis B infection in haemophilia. Lancet 1982; 02: 776-777
    PubMedGoogle Scholar
  • 6 Norkrans G, Widell A, Teger-Nilsson AC, Kjellman H, Frosner G, Twarson S. Acute hepatitis non-A, non-B following administration of Factor VIII concentrates. Vox Sang 1981; 41: 129-133
    CrossrefPubMedGoogle Scholar
  • 7 Yap P. Hepatitis transmission by blood products. J. Hosp. Inf 1988; 11: 166-174
    CrossrefPubMedGoogle Scholar
  • 8 Centers for Disease Control. Update: Acquired immunodeficiency syndrome (AIDS) in persons with hemophilia. Mortality and Morbidity Weekly Report 1984; 33: 589-592
    PubMedGoogle Scholar
  • 9 Centers for Disease Control. Changing patterns of acquired immunodeficiency syndrome in hemophilia patients. Mortality and Morbidity Weekly Report 1985; 34: 241-243
    PubMedGoogle Scholar
  • 10 Azzi A, Ciappi S, Zakvrzewska K, Morfini M, Mariani G, Mannucci PM. Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates. Am J Hematol 1992; 39: 2328-2330
    PubMedGoogle Scholar
  • 11 Lyon DJ, Chapman CS, Martin C, Brown KE, Clewley JP, Flower AJ, Mitchel VE. Symptomatic parvovirus B19 infection and heat-treated factor IX concentrate. Lancet 1989; 01: 1085 (letter).
    PubMedGoogle Scholar
  • 12 Bemtorp E, Nilsson IM, Ljung R, Widell A. Hepatitis C virus transmission by monoclonal antibody purified factor VIII concentrate. Lancet 1990; 335: 1531-1532
    PubMedGoogle Scholar
  • 13 Mannucci PM, Zanetti AR, Colombo M, Chistolini A, De BiasiR, Musso R, Tamponi G. Antibody to hepatitis C virus after a vapor-treated factor VIII concentrate. The Study Group of the Fondazione dell'Emofilia. Thromb Haemost 1990; 64: 232-234
    PubMedGoogle Scholar
  • 14 Lusher JM. Transfusion Safety Study Group. Hepatitis C virus (HCV) transmission with clotting factor concentrates in current use. Blood 1991; 78 (Suppl. 01) 1409 (Abstract).
    PubMedGoogle Scholar
  • 15 Kleim JP, Bailly E, Schneweis KE. et al. Acute HIV-1 infection in patients with hemophilia B treated with P-propriolactone-UV-inactivated clotting factor. Thromb Haemost 1990; 64: 336-337
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Schoemaker C, Orr EC. et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-347
    CrossrefPubMedGoogle Scholar
  • 17 Kaufman RJ, Wasley LC, Domer AJ. Synthesis, processing, and secretion of recombinant human Factor VIII expressed in mammalian cells. J Biol Chem 1988; 263: 6352-6362
    PubMedGoogle Scholar
  • 18 Kaufman RJ, Wasley LC, Davies MV, Wise RJ, Israel DI. and Dorner AJ. Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese Hamster Ovary cells. Molecular and Cellular Biology 1989; 09: 1233-1239
    CrossrefPubMedGoogle Scholar
  • 19 White II GC, McMillan CW, Kingdon HS, Shoemaker CB. Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med 1989; 320: 166-170
    CrossrefPubMedGoogle Scholar
  • 20 Andersson LO, Forsman N, Huang K, Larsen K, Lundin A, Pavlu B, Sandberg H, Sewerin K, Smart J. Isolation and characterization of human Factor VIII: Molecular forms in commercial Factor VIII concentrate cryoprecipi-tate and plasma. Proc. Natl. Acad Sci. USA 1986; 85: 2979-2983
    PubMedGoogle Scholar
  • 21 Eaton D, Rodriquez H, Vehar GA. Proteolytic processing of human Factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of Factor VIII coagulant activity. Biochemistry 1986; 25: 505
    CrossrefPubMedGoogle Scholar
  • 22 Fulcher CA, Roberts JR, Holland LA, Zimmerman TS. Human Factor VIII procoagulant protein. Monoclonal antibodies define precursor-product relationships and functional epitopes. J Clin Invest 1985; 76: 117-224
    CrossrefPubMedGoogle Scholar
  • 23 Rotblat F, O'Brien DP, O'Brien FJ, Goodall AH, Tuddenham EGD. Purification of human factor VIII:c and its characterization by Western blotting using monoclonal antibodies. Biochemistry 1985; 24: 4294-4300
    CrossrefPubMedGoogle Scholar
  • 24 Kasper CK, Aledort LM, Counts RB, Edson JR, Frantoni J, Green D, Hamptom JW, Hilgartner MW, Lazerson J, Levin PM, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van EysJ. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-872
    PubMedGoogle Scholar
  • 25 Brinkhous KM, Sandberg H, Garris JB, Mattsson C, Palm M, Griggs T, Read MS. Purified human Factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophiliac and von Willebrand disease dogs. Pro. Natl Acad Sci USA 1985; 82: 8752-8756
    CrossrefPubMedGoogle Scholar
  • 26 Douglas AS. Antihemophilic globulin assay following plasma infusion in hemophilia. J Lab Clin Med 1958; 51: 850-859
    PubMedGoogle Scholar
  • 27 Over J, Sixma JJ, Bruine MH, Trieschnigg MC, Vlooswijk RA, Beeser-Vis-ser NH, Bouma BN. Survival of iodine-125-labeled factor-VIII in normals and patients with classic hemophilia-observations on heterogeneity of human Factor VIII. J Clin Invest 1978; 62: 223-234
    CrossrefPubMedGoogle Scholar
  • 28 Tuddenham EGD, Lane RS, Rotblat F, Johnson AJ, Snape TJ, Middleton S, Kemoff PBA. Response to infusions of polyelectrolyte fractionated human Factor VIII concentrate in human hemophilia A and von Willebrand's disease. Br J Haematol 1982; 52: 259-267
    CrossrefPubMedGoogle Scholar
  • 29 Weiss HJ, Sussman II, Hoyer LW. Stabilization of Factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated Factor VIII and in patients with von Willebrand's disease. J Clin Invest 1977; 60: 390-404
    CrossrefPubMedGoogle Scholar
  • 30 Lee ML, Poon WY, Kingdon HS. A two-phase linear regression model for biological half-life data. J Lab Clin Med, 1990; 115: 745-748
    PubMedGoogle Scholar
  • 31 Lee ML, Gomperts ED, Kingdon HS. A note on the calculation of recovery for Factor VIII infusions. Thromb Haemost 1992; 68: 433-435
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Shanbrom E, Thelin GM. Experimental prophylaxis of severe hemophilia with a Factor VIII concentrate. JAMA 1969; 208: 1853-1856
    CrossrefPubMedGoogle Scholar
  • 33 Abildgaard CF, Simone JV, Corrigan JJ, Seeler RA, Edelstein G, Vander-heiden J, Schulman I. Treatment of hemophilia with glycine-precipitated Factor VIII. N Engl J Med 1966; 275: 471-475
    CrossrefPubMedGoogle Scholar
  • 34 Dunn OJ, Clark VA. Applied Statistics: Analysis of Variance and Regressions. 2. John Wiley & Sons; New York, NY: 1987. pp 236-237
    Google Scholar
  • 35 Schimpf K, Mannucci PM, Kreutz W, Brackmann HH, Auerswald G, Ciavarella N, Mosseler J, DeRosa V, Kraus B, Brueckmann C, Mancuso G, Mittler U, Hascheke F, Morfini M. Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions. N Engl J Med 1987; 316: 918
    CrossrefPubMedGoogle Scholar
  • 36 Schimpf K, Brackmann HH, Kreuz W, Kraus B, Haschke F, Schramm W, Moesseler J, Auerswald G, Sutor AH, Koehler K, Hellstern P, Muntean W, Scharrer I. Absence of anti-human immunodeficiency virus types 1 and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate. N Engl J Med 1989; 321: 1148
    CrossrefPubMedGoogle Scholar
  • 37 Horowitz MS, Horowitz B, Rooks C, Hilgartner MW. Virus safety of solvent/detergent-treated antihaemophilic factor concentrate. Lancet 1988; 02: 186-189
    PubMedGoogle Scholar
  • 38 Morfini M, Longo G, Ferrini PR, Azzi A, Zakrewska C, Ciappi S, Kolum-ban P. Hypoplastic anemia in a hemophiliac first infused with a solvent/ detergent treated factor VIII concentrate: The role of human B19 parvovirus. Am J Hematol 1992; 39: 149 (letter).
    CrossrefPubMedGoogle Scholar
  • 39 Mannucci PM. Outbreak of hepatitis A among Italian patients with haemophilia. Lancet 1992; 339: 819 (letter).
    PubMedGoogle Scholar
  • 40 Gerritzen A, Schneweis KE, Brackmann HH, Oldenburg J, Hanfland P, Gerlich WH, Caspari G. Acute hepatitis A in haemophiliacs. Lancet 1992; 340: 1231 (letter).
    PubMedGoogle Scholar
  • 41 Peerlinck K, Vermylen J. Acute hepatitis A in patients with haemophilia A. Lancet 1993; 341: 179
    PubMedGoogle Scholar
  • 42 Schwartz RS, Abildgaard CF, Aledort LM. et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990; 323: 1800-1805
    CrossrefPubMedGoogle Scholar
  • 43 Schwarzinger I, Pabinger I, Kominger C. et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987; 24: 241-245
    CrossrefPubMedGoogle Scholar
  • 44 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Krackhardt B, Komhuber B. Incidence of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
    CrossrefPubMedGoogle Scholar
  • 45 Addiego J, Kasper C, Abildgaard C, Hilgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-464
    CrossrefPubMedGoogle Scholar
  • 46 Gill FM: The natural history of factor VIII inhibitors in patients with hemophilia A. Prog Clin Biol Res 1984; 150: 19-29
    PubMedGoogle Scholar
  • 47 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao V, Lacerson J. and the Hemophilia Study Group The natural history of factor VIII:c inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:c inhibitors. Blood 1988; 71: 344-348
    PubMedGoogle Scholar
  • 48 Peerlinck K, Amout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost 1993; 69: 115-118
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Rosendaal FR, Nieuwenhuis HK, van denBerg HM, Heijboer H, Mauser-Bunschoten EO, van derMeer J, Smit C, Strengers PFW, Briët E. and the Dutch Hemophilia Study Group A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood 1993; 81: 2180-2186
    PubMedGoogle Scholar