A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

dc.contributor.authorPeyvandi, Flora
dc.contributor.authorMannucci, Pier M
dc.contributor.authorGaragiola, Isabella
dc.contributor.authorEl-Beshlawy, Amal
dc.contributor.authorElalfy, Mohsen
dc.contributor.authorRamanan, Vijay
dc.contributor.authorEshghi, Peyman
dc.contributor.authorHanagavadi, Suresh
dc.contributor.authorVaradarajan, Ramabadran
dc.contributor.authorKarimi, Mehran
dc.contributor.authorManglani, Mamta V
dc.contributor.authorRoss, Cecil
dc.contributor.authorYoung, Guy
dc.contributor.authorSeth, Tulika
dc.contributor.authorApte, Shashikant
dc.contributor.authorNayak, Dinesh M
dc.contributor.authorSantagostino, Elena
dc.contributor.authorMancuso, Maria Elisa
dc.contributor.authorSandoval Gonzalez, Adriana C
dc.contributor.authorMahlangu, Johnny N
dc.contributor.authorBonanad Boix, Santiago
dc.contributor.authorCerqueira, Monica
dc.contributor.authorEwing, Nadia P
dc.contributor.authorMale, Christoph
dc.contributor.authorOwaidah, Tarek
dc.contributor.authorSoto Arellano, Veronica
dc.contributor.authorKobrinsky, Nathan L
dc.contributor.authorMajumdar, Suvankar
dc.contributor.authorPerez Garrido, Rosario
dc.contributor.authorSachdeva, Anupam
dc.contributor.authorSimpson, Mindy
dc.contributor.authorThomas, Mathew
dc.contributor.authorZanon, Ezio
dc.contributor.authorAntmen, Bulent
dc.contributor.authorKavakli, Kaan
dc.contributor.authorManco-Johnson, Marilyn J
dc.contributor.authorMartinez, Monica
dc.contributor.authorMarzouka, Esperanza
dc.contributor.authorMazzucconi, Maria G
dc.contributor.authorNeme, Daniela
dc.contributor.authorPalomo Bravo, Angeles
dc.contributor.authorParedes Aguilera, Rogelio
dc.contributor.authorPrezotti, Alessandra
dc.contributor.authorSchmitt, Klaus
dc.contributor.authorWicklund, Brian M
dc.contributor.authorZulfikar, Bulent
dc.contributor.authorRosendaal, Frits R
dc.contributor.authoraffiliation[Peyvandi,F; Mannucci,PM; Santagostino,E; Mancuso,ME] the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Italy. [Peyvandi,F; Mannucci,PM; Garagiola,I] Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy. [Zanon,E] Milan, Clinica Medica II, Azienda Ospedaliera di Padova, Centro Emofilia, Padua. Italy. [Mazzucconi,MG] Ematologia, Unità Operativa Diagnostica Speciale e Terapia delle Malattie dell’Emostasi e della Trombosi, Università Sapienza, Policlinico Umberto I, Rome, Italy. [El-Beshlawy,A] The Pediatric Hematology Department, Cairo University Pediatric Hospital, Cairo. [Elalfy,M] Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo. [Ramanan,V] Jehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises, India. , [Apte,S] Sahyadri Speciality Hospita, l India. [Hanagavadi,S] Pune, Jagadguru Jayadeva Murugarajendra Medical College, Davangere, India. [Baradajaran,P] Center for Blood Disorders, Chennai, India. [Manglani,MV] Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India. [Ross,C] St. John’s Medical College Hospital, Bangalore India. [Seth,T] India Institute of Medical Sciences, Department of Hematology, India. [Sachdeva,A] Pediatric Hematology Oncology and Bone Marrow Transplantation, Institute for Child Health, Sir Ganga Ram Hospital, India. [Nayak,DM] New Delhi, Melaka-Manipal Medical College, Manipal University, Manipal, India. [Thomas,M] Kerala Institute of Medical Science, Trivandrum, India. [Eshghi,P] The Congenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [Karimi,M] Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. [Young,G] Children’s Hospital Los Angeles, Los Angeles,California. [Ewing,NP] City of Hope National Medical Center, Duarte, California. [Sandoval Gonzalez, AC] Hospital de Especialidades Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Monterrey, Mexico. [Paredes Aguilera,R] Instituto Nacional de Pediatria, Mexico City, Mexico. [Mahlangu,JN] Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, National Health Laboratory Service and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg.[Bonanad Boix,S] Hospital Universitario La Fe, Unidad Coagulopatias Congenitas, Valencia, Spain. [Perez Garrido, R] Hospital Universitario Virgen del Rocío, Unidad de Hemofilia, Seville, Spain. [Palomo Bravo,A] Hospital Regional Universitario Carlos Haya, Malaga, Spain. [Cerqueira,M] Centro de Pesquisa Clinica Hemorio–Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brazil. [Prezotti,A] Centro de Hematologia e Hemoterapia do Espírito Santo, Vitoria, Brazil. [Male,C] Medizinische Universität Wien, Department of Pediatrics, Vienna, Austria. [Schmitt,K] Department of Pediatric and Adolescent Medicine, Kepler University Clinic, Linz, Austria. [Owaidah,T] King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. [Soto Arellano,V] Centro de Hemofílicos del Hospital de Niños Dr. Roberto del Río, Chile. [Marzouka,E] Hospital de Niños Dr. Luis Calvo Mackenna, Centro Hemofílico, Santiago, Chile. [Kobrinsky, NL] Sanford Roger Maris Cancer Center, Fargo, ND. [Majundar,S] University of Mississippi Medical Center, Division of Pediatric Hematology–Oncology, Jackson. [Simpson,M] Rush Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago. [Antmen,B] Cukurova Universitesi, Tip Fakultesi Pediatrik Hematoloji Bilim Dali, Adana, Turkey. [Kabakli,K] Ege Universitesi Tip Fakultesi Cocuk Sagligi ve Hastalikari Anabilim Dali, Pediatrik Hematoloji Bilim Dali, Turkey. [Zulfikar,B] Istanbul Universitesi Cerrahpasa Tip Fakultesi, Pediatrik Hematoloji Bilim Dali, Istanbul,Turkey. [Manco-Johnson,MJ] Hemophilia and Thrombosis Center, University of Colorado Denver, Aurora. [Martinez,M] Hospital de Niños Sor María Ludovica La Plata, Servicio de Hematología, Buenos Aires. [Neme,D] Fundación de la Hemofilia, Buenos Aires.[Wicklund,BM] Children’s Mercy Hospital, Kansas City, MO, The Netherlands. [Rosendaal,FR] he Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
dc.descriptionJournal 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]es_ES
dc.description.abstractBACKGROUND 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; number, NCT01064284; EudraCT number, 2009-011186-88.).es_ES
dc.description.sponsorshipSupported by the nonprofit Angelo Bianchi Bonomi Foundation and the Italian Ministry of Health (Progetti Finalizzati and Agenzia Italiana del Farmaco). Grifols, Kedrion Biopharma, and LFB provided unrestricted grants to the Angelo Bianchi Bonomi Foundation.es_ES
dc.identifier.citationPeyvandi 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):2054-64es_ES
dc.journal.titleThe New England Journal of Medicine
dc.publisherMassachusetts Medical Societyes_ES
dc.rights.accessRightsopen access
dc.subjectAnticuerpos neutralizanteses_ES
dc.subjectNiño preescolares_ES
dc.subjectRelación dosis-respuesta de medicamentoses_ES
dc.subjectFarmacoterapia combinadaes_ES
dc.subjectFactor VIIIes_ES
dc.subjectHemofilia Aes_ES
dc.subjectInyecciones subcutáneases_ES
dc.subjectMediana edades_ES
dc.subjectModelos de riesgos proporcionaleses_ES
dc.subjectAdulto jovenes_ES
dc.subjectFactor de von Willebrandes_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Adultes_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Agedes_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::Antibodies, Neutralizinges_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Childes_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Child::Child, Preschooles_ES
dc.subject.meshMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Druges_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Therapy, Combinationes_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::Factor VIIIes_ES
dc.subject.meshMedical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Hemorrhagic Disorders::Hemophilia Aes_ES
dc.subject.meshMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Hemorrhagees_ES
dc.subject.meshMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humanses_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Incidencees_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Infantes_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Administration Routes::Injections::Injections, Subcutaneouses_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::Isoantibodieses_ES
dc.subject.meshMedical Subject Headings::Check Tags::Malees_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle Agedes_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Proportional Hazards Modelses_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young Adultes_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::von Willebrand Factores_ES
dc.subject.meshMedical Subject Headings::Named Groups::Persons::Age Groups::Adolescentes_ES
dc.titleA Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.es_ES
dc.typeresearch article
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