Peyvandi, FloraMannucci, Pier MGaragiola, IsabellaEl-Beshlawy, AmalElalfy, MohsenRamanan, VijayEshghi, PeymanHanagavadi, SureshVaradarajan, RamabadranKarimi, MehranManglani, Mamta VRoss, CecilYoung, GuySeth, TulikaApte, ShashikantNayak, Dinesh MSantagostino, ElenaMancuso, Maria ElisaSandoval Gonzalez, Adriana CMahlangu, Johnny NBonanad Boix, SantiagoCerqueira, MonicaEwing, Nadia PMale, ChristophOwaidah, TarekSoto Arellano, VeronicaKobrinsky, Nathan LMajumdar, SuvankarPerez Garrido, RosarioSachdeva, AnupamSimpson, MindyThomas, MathewZanon, EzioAntmen, BulentKavakli, KaanManco-Johnson, Marilyn JMartinez, MonicaMarzouka, EsperanzaMazzucconi, Maria GNeme, DanielaPalomo Bravo, AngelesParedes Aguilera, RogelioPrezotti, AlessandraSchmitt, KlausWicklund, Brian MZulfikar, BulentRosendaal, Frits R2017-05-262017-05-262016-05-26Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016; 374(21):2054-640028-4793http://hdl.handle.net/10668/2671Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't;Comment in: Hemophilia Therapy--Navigating Speed Bumps on the Innovation Highway. [N Engl J Med. 2016]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.).enAdultoAncianoAnticuerpos neutralizantesNiñoAdolescenteNiño preescolarRelación dosis-respuesta de medicamentosFarmacoterapia combinadaFactor VIIIHemofilia AHemorragiaHumanosIncidenciaLactanteInyecciones subcutáneasIsoanticuerposMasculinoMediana edadModelos de riesgos proporcionalesAdulto jovenFactor de von WillebrandMedical Subject Headings::Named Groups::Persons::Age Groups::AdultMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::Antibodies, NeutralizingMedical Subject Headings::Named Groups::Persons::Age Groups::ChildMedical Subject Headings::Named Groups::Persons::Age Groups::Child::Child, PreschoolMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, DrugMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Therapy, CombinationMedical Subject Headings::Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::Factor VIIIMedical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Hemorrhagic Disorders::Hemophilia AMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::HemorrhageMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::IncidenceMedical Subject Headings::Named Groups::Persons::Age Groups::InfantMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Administration Routes::Injections::Injections, SubcutaneousMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::IsoantibodiesMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Proportional Hazards ModelsMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young AdultMedical Subject Headings::Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::von Willebrand FactorMedical Subject Headings::Named Groups::Persons::Age Groups::Adolescentresearch article27223147open access10.1056/NEJMoa15164371533-4406