@article {117501, title = {A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.}, journal = {The New England journal of medicine}, volume = {374}, year = {2016}, month = {2016 May 26}, pages = {2054-64}, abstract = {

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.).

}, keywords = {Adolescent, Adult, Aged, Antibodies, Neutralizing, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Therapy, Combination, Factor VIII, Hemophilia A, Hemorrhage, Humans, Incidence, Infant, Injections, Subcutaneous, Isoantibodies, Male, Middle Aged, Proportional Hazards Models, von Willebrand factor, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1516437}, author = {Peyvandi, Flora and Mannucci, Pier M and Garagiola, Isabella and Amal El-Beshlawy and Mohsen Elalfy and Ramanan, Vijay and Eshghi, Peyman and Hanagavadi, Suresh and Varadarajan, Ramabadran and Karimi, Mehran and Manglani, Mamta V and Ross, Cecil and Young, Guy and Seth, Tulika and Apte, Shashikant and Nayak, Dinesh M and Santagostino, Elena and Mancuso, Maria Elisa and Sandoval Gonzalez, Adriana C and Mahlangu, Johnny N and Bonanad Boix, Santiago and Cerqueira, Monica and Ewing, Nadia P and Male, Christoph and Owaidah, Tarek and Soto Arellano, Veronica and Kobrinsky, Nathan L and Majumdar, Suvankar and Perez Garrido, Rosario and Sachdeva, Anupam and Simpson, Mindy and Thomas, Mathew and Zanon, Ezio and Antmen, Bulent and Kavakli, Kaan and Manco-Johnson, Marilyn J and Martinez, Monica and Marzouka, Esperanza and Mazzucconi, Maria G and Neme, Daniela and Palomo Bravo, Angeles and Paredes Aguilera, Rogelio and Prezotti, Alessandra and Schmitt, Klaus and Wicklund, Brian M and Zulfikar, Bulent and Rosendaal, Frits R} }