A randomized comparison of two prophylaxis regimens and a paired comparison of on‐demand and prophylaxis treatments in hemophilia A management

Abstract

Background: Prophylaxis with factor (F)VIII is considered the optimal treatment for managing hemophilia A patients without inhibitors. Objectives: To compare the efficacy of two prophylaxis regimens (primary outcome) and of on-demand and prophylaxis treatments (secondary outcome), and to continue the evaluation of immunogenicity and overall safety of the ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM). Patients/Methods: Previously on-demand-treated patients aged 7–59 years (n = 66) with FVIII levels ≤ 2% received 6 months of on-demand treatment and then were randomized to 12 months of either standard (20–40 IU kg−1 every other day) or pharmacokinetic (PK)-tailored (20–80 IU kg−1 every third day) prophylaxis, both regimens intended to maintain FVIII trough levels at or above 1%. Efficacy was evaluated in terms of annualized bleeding rates (ABRs). As subjects were first treated on-demand and then on prophylaxis, statistical comparisons between these treatments were paired. Results: Twenty-two (33.3%) subjects on prophylaxis experienced no bleeding episodes, whereas none treated on-demand were free from an episode of bleeding. ABRs for the two prophylaxis regimens were comparable, whereas differences between on-demand and either prophylaxis were statistically significant (P < 0.0001): median (interquartile range [IQR]) ABRs were 43.9 (21.9), 1.0 (3.5), 2.0 (6.9) and 1.1 (4.9) during on-demand treatment, standard, PK-tailored and any prophylaxis, respectively. There were no differences in FVIII consumption or adverse event rates between prophylaxis regimens. No subject developed FVIII inhibitors. Conclusions: The present study demonstrates comparable safety and effectiveness for two prophylaxis regimens and that prophylaxis significantly reduces bleeding compared with on-demand treatment. PK-tailored prophylaxis offers an alternative to standard prophylaxis for the prevention of bleeding.

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

“…The median ABR in the individualized prophylaxis arm was consistent with ABRs reported for other prophylactic regimens, [15][16][17] and 45.3% of subjects experienced no bleeding episodes on study. The majority of subjects *The median dosing interval among subjects on study for at least 6 months was 3.5 (range, 2.9-5.7) days when averaged over all dosing intervals during the respective time intervals for the last 3 months on the study.…”

“…For subjects randomized to arm 2, there was a statistically significant reduction in ABR relative to their prior episodic regimen, and most subjects achieved an ABR in the range reported for existing prophylactic regimens. [15][16][17] The low median ABR and observation that some subjects (4/23, 17.4%) had no breakthrough bleeding episodes indicate that once-weekly prophylaxis can provide positive clinical outcomes for some patients. However, 3 subjects (13.0%) in this arm experienced .5 bleeding episodes on the study.…”

Extended half‐life pegylated, full‐length recombinant factor VIII for prophylaxis in children with severe haemophilia A

“…Efficacy of BAX 855 in bleeding treatment in terms of ratings of 'excellent' or 'good' and in terms of infusions administered per bleeding event was comparable with results reported for other FVIII preparations in children [19,29,32], adolescents and adults [14,18,30,31,33].…”

“…Prophylactic regimens with standard FVIII products require infusions every other day or three times weekly to effectively prevent or reduce spontaneous bleeds [6,[14][15][16].…”

BAY 81‐8973, a full‐length recombinant factor VIII: manufacturing processes and product characteristics

“…Twice-weekly BAY 81-8973 prophylaxis may be appropriate for patients whose bleeding episodes currently are well-controlled on a twice-weekly regimen and for patients with severe haemophilia A who have a mild bleeding phenotype. In the LEOPOLD clinical trial program, a mild bleeding phenotype and good Haemophilia (2017), 23, e67--e78 SPINART [40] Valentino et al [41] Recht et al [42] Guardian 1 [43] GENA-08 [44] AFFINITY [45] A-LONG [46] PROLONG-ATE response to twice-weekly prophylaxis was associated with older age (≥30 years), few target joints, low number of joint bleeds, high von Willebrand factor levels (≥120%) and high FVIII trough levels at 72 hours postinfusion [16,24,25]. Other considerations in determining the appropriateness of a twiceweekly regimen include the patient's activity level, level of adherence to prophylaxis and FVIII pharmacokinetic profile.…”