Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Abstract

Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (>100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P<0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P<0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

Can B‐domain deletion alter the immunogenicity of recombinant factor VIII? A meta‐analysis of prospective clinical studies

“…Twenty‐nine prospective clinical studies reported from 1990 to 2010 with 3012 total patients at risk for de novo inhibitor development were included in the meta‐analysis [10,14–16,32–60]. All were published.…”

“…In response to inquiries, investigators of the included studies provided data not contained in the published study reports. Such supplementary data concerned study design [39,54], prior ED to FVIII [32,33,39,44], age [53], inhibitor testing frequency [39,44,49,53], patients with an inhibitor history [32,39,44,45,49], ED to rFVIII during study [15,16,44,49,51,53], peak inhibitor titer [55] and ED until inhibitor development [43–45,49,54,55].…”

“…Direct participation and/or sponsorship by the supplier of the evaluated rFVIII product was disclosed for 23 studies [10,15,16,32–38,40–43,45–49,53–60]. Written informed consent was secured in 19 studies [10,15,16,32–38,40–43,46,47,50,51,54,55,58–60], while such consent was not sought in one European study because it was not required [49]. In the remaining 10 studies, written informed consent was unspecified.…”

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

“…Less clinical data are available in adults receiving secondary prophylaxis. One prospective study [42] of 19 evaluable patients has shown that patients with severe haemophilia A (FVIII < 1 IU dL )1 ) and a median age of 36 years, 80% of whom had target joints at study entry, treated with 25 IU kg )1 3 days a week, had a median of 0 bleeds in 6 months compared with a median of 21 bleeds while receiving on-demand treatment. The median (inter-quartile range) FVIII trough levels measured at 48 and 72 h in these patients were 6 (1-11) and 4 (0.5-6) IU dL )1 , respectively.…”

Treatment patterns, health‐related quality of life and adherence to prophylaxis among haemophilia A patients in the United States

“…Prophylaxis has been shown to prevent joint damage and significantly to reduce frequency of bleeds [4][5][6][7][8][9]. However, patients may still receive on-demand treatment for various reasons.…”