Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II).

BACKGROUND: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12­65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS: Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

[The histocompatibility system in schizophrenia]. / O sistema de histocompatibilidade nas esquizofrenias.

Various diseases with a noticeable autoimmune component and frequent occurrence within one family show a statistically significant correlation with specific human leucocyte antigens (HLA). This correlation was also found in studies of HLA in psychiatric disorders. However, results have been contradictory. The phenotype frequencies of HLA specificities were investigated in 100 schizophrenic patients and 472 controls from the same geographic area in Germany. The frequency of HLA-B27 was significantly increased in the patient group as a whole and in the subgroups of paranoid patients, chronic schizophrenics, patients with poor prognosis and in patients with the onset of the disease before the age of 20 years. In the latter three subgroups an elevated incidence of HLA-A9 was also found. The combination A9-B27 was detected in 0,63% of our control group and in 7% of the patients. Of these patients 85,7% were chronic paranoid patients with poor prognostic features. The present study indicates a possible marker of genetic heterogeneity in schizophrenia and gives support to the possibility of using HLA typing in genetic studies of schizophrenia as well as in the differential diagnosis and prognosis. Moreover, in spite of the statistical significance of our findings, the fact that the associations are well below 100% indicates that other factors (presumably environmental) must be involved in the etiology of the disease.

O sistema de histocompatibilidade nas esquizofrenias. / Histocompatibility system in schizophrenia

Varias doencas com importante componente autoimune e com frequente ocorrencia familiar mostraram uma correlacao estatisticamente significante com determidados antigenos de histocompatibilidade (HLA = human leucocyte antigens). Esta correlacao tambem foi encontrada entre HLA e algumas doencas psiquiatricas. No entanto, os resultados de diversos autores tem sido contraditorios. No presente estudo, as frequencias de 31 HLA foram investigadas em 100 pacientes esquizofrenicos e em 472 controles da populacao alema. A frequencia do HLA-B27 estava significativamente aumentada no grupo total de pacientes e nos subgrupos de pacientes paranoides, cronicos, de prgnostico desfavoravel e em pacientes com adoecimento precoce. Nestes ultimos tres grupos encontrou-se tambem um aumento na frequencia do HLA-A9. A combinacao A9-B27 foi dectada em 0,63% dos controles e em 7% dos pacientes. Destes pacientes 85,7% eram esquizofrenicos paranoides cronicos com caracteristicas prognosticas desfavoraveis. Este estudo suporta a possibilidade do uso da tipagem dos antigenos de histocompatibilidade em estudos geneticos das esquizofrenias, assim como no estabelecimente do dignostico diferencial e do prgnostico. Por outro lado, apesar de nossos resultados serem assegurados estatiscamente, o fato de as associacoes estarem bem abaixo de 1,0 indica que outros fatores (presumivelmente ambientais) necessitam estar em jogo na etiologia da doenca