Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

BackgroundBAY 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.ObjectivesTo demonstrate superiority of prophylaxis vs. on-demand therapy with BAY 81-8973 in patients with severe hemophilia A.Patients/MethodsIn this multinational, randomized, open-label crossover study (LEOPOLD II; ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 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.ResultsEighty 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.ConclusionsTwice-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.

In patients with beta-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with beta-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (UP/Cr), urinary N-acetyl-beta-D-glucosaminidase to creatinine (UNAG/Cr), and urinary malondialdehyde to creatinine, (UMDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high UP/cr, UNAG/Cr and UMDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload.

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Summary. Background: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept TM 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. Objectives: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. Methods/patients: This was a post hoc analysis of adept TM 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Results: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Conclusions: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

Development of inhibitors to infused factor concentrates represents a major clinical and economic challenge in the treatment of haemophilic patients. It has been shown that a delay in initiation of treatment leads to requirement of a larger number of injections to stop the bleeding but this has never been formally linked to costs associated with the bleeding. The objectives of this study were to assess the relationship between time to initiation of NovoSeven and total costs, number of doses administered and time to bleeding resolution in mild to moderate bleeding episodes. Data on time to treatment initiation, time to bleeding resolution and on all resource use related to the bleeding were extracted from medical records in Turkey for 129 bleeding episodes. Regression analysis was used to assess the impact of time to treatment on outcomes. Longer time to treatment initiation increased both total costs associated with the bleeding, the number of doses needed and the time to bleeding resolution. Treatment in hospital was associated with significantly longer time to treatment, higher costs and longer time to bleeding resolution as compared with home treatment or outpatient treatment. When controlling for other bleeding characteristics, the cost of bleedings treated in hospital was more than 150% higher. This study shows that treatment with NovoSeven should be initiated as soon as possible after the onset of bleeding in order to minimize costs and optimize outcomes. Home treatment reduces time to treatment initiation and also reduces costs related to the bleeding.

Circumcision is the oldest and most frequent surgical procedure in the world and especially in Turkey as is seen in the other Islamic countries because of religious and traditional pressures. In this study, we aim to report the experience of circumcision at Çukurova University in a total of 76 patients with haemophilia between 1990 and 2011. We retrospectively reviewed medical records of 69 haemophilia patients without inhibitors and seven haemophilia patients with inhibitors who had been circumcised. Before the year 2000, factor concentrates were given before and after circumcision for 6-7 days. After 2000, we used fibrin glue together with factor concentrates for only 3 days. By-passing agents were used for circumcision in haemophilia patients with inhibitors. Twelve of 69 patients without inhibitors were referred to our centre with bleeding after the circumcision before diagnosis of haemophilia. Nine of these twelve patients had severe life threatening bleeding and three of them had moderate bleeding. Sixty-four patients with haemophilia were circumcised in our centre under general anaesthesia except for three patients who were given local anaesthesia. Thirteen of 57 haemophilia patients (22.8%) without inhibitors had seven mild and six moderate bleeding complications. A few patients had significant bleeding, despite adequate factor replacement. Five of seven haemophilia patients with inhibitors had two moderate and three mild bleeding complications. Our experience showed that circumcision for patients with haemophilia should be carefully performed by surgeons together with paediatric haematologist, under appropriate conditions in haemophilia centres which has comprehensive coagulation lab.

Remifentanil, alfentanil, remifentanil-midazolam, and alfentanil-midazolam combinations are effective in children and can be used safely in bone marrow aspiration which is a brief but painful procedure performed in the pediatric patient group.