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
Authors: Collins Peter , Faradji Albert , Morfini Massimo , Enriquez Monika Maas , Gorina Eduard , Schwartz Lawrence , Lemm Georg 
Published: April 2020

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 (&gt;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&lt;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&lt;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.