To cite this article: Konkle BA, Ebbesen LS, Erhardtsen E, Bianco RP, Lissitchkov T, Rusen L, Serban MA. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5: 1904-13. Summary. Background: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. Objectives: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. Methods: Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean ‡ 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 lg kg )1 for 3 months, followed by a 3-month postprophylaxis period. Results: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 lg kg , respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. Conclusion: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on-demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.

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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.

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.

Children with haemophilia often experience limitations in activities of daily life. Recently the Paediatric Haemophilia Activities List (PedHAL) has been developed and tested in Dutch children with intensive replacement therapy. The psychometric properties of the PedHAL in children not receiving intensive replacement therapy are not known. The objective was to gain further insight into the psychometric properties of the PedHAL and to study the functional health status of Romanian children and adolescents with haemophilia. Children attending to the rehabilitation centre of Buzias in Romania were sampled consecutively. Construct validity of the PedHAL was evaluated by concurrent testing with objective and subjective measures of physical function and functional ability. Reproducibility was tested by a 3-day test-retest by intraclass correlation coefficient (ICC) and limits of agreement (LOA). Responsiveness to rehabilitation was assessed by Haemophilia Joint Health Score (HJHS) and PedHAL. Twenty-nine children with severe (n = 25) or moderate (n = 4) haemophilia participated. Mean age was 13.2 years (SD 4.0). Median score of the PedHAL was 83.5 (IQR 47.9-90.5). The PedHAL correlated moderately with HJHS (rho = -0.59), Functional Independence Score in& Haemophilia (rho = 0.65) and Child Health Questionnaire-physical function (rho = 0.40) and not with Child Health Questionnaire-mental health, Child Health Questionnaire-behaviour and 6MWT. Test-retest reliability was good (ICC = 0.95). LOA was 17.4 points for the sum score. HJHS scores improved slightly after rehabilitation, whereas PedHAL scores did not change. In general, construct validity and test-retest reliability were good, test-retest agreement showed some variability. Therefore, currently the PedHAL may be more appropriate for research purposes than for individual patient monitoring in clinical practice.

Introduction: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. Aim: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. Methods: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri-and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg À1. Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg À1, repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. Results: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra-or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. Conclusions: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal periand postoperative concentrate consumption and infrequent injections as reported with standard FIX products.

Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra® for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra® is an effective and well-tolerated treatment for pediatric patients.

The aim of this study was to determine the clinical conditions of patients with haemophilia within Europe as recommended by the European Commission. In this multicentre, cross-sectional, ambispective study, conducted within 21 European countries patients' clinical data were collected, amongst others haemophilia type, severity, treatment pattern, use of factor products, bleeding, orthopaedic joint scores and infections. A total of 1400 patients, 84.3% with haemophilia A and 15.7% with haemophilia B were enrolled by 42 centres between 2004 and 2006. Thereof, 417 were children (30.0%) and 983 were adults (70.0%). About 70% of patients had severe factor deficiency (<1%). More than half of the adults were carriers of chronic infections (12.6% HIV, 55.8% HCV), compared to only 3.8% children (no HIV, 2.9% HCV). Patients were grouped according to per capita amount of clotting factor used in patients' region of residence in 2005: region 1: >5 IU; region 2: 2-5 IU; region 3: <2 IU. Paediatric and adult patients in region 3 had median numbers of three and eight joint bleeds, respectively, with worse joint scores compared to region 1 with zero and one bleed. Prophylactic therapy was used in only 31.3% children and 8.9% adults with severe haemophilia in region 3 compared to 93.7% and 54.1%, respectively, in region 1. Statistical analysis revealed that residence in areas with low factor consumption/availability is the most prominent risk factor for joint disease. Access of European patients with haemophilia to optimal care with safe factor VIII concentrates is limited and depends on the region of residence.