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

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.


Study Design
A summary of the study procedures and assessments is provided in Supporting Info. Table 1.
Dosing for the on-demand treatment of hemorrhages was dependent on the severity and type of bleeding (Supporting Info. Table 2). The hemostatic efficacy of treatment was rated by the subject or site staff using a 4-point ordinal scale (Supporting Info. Table 3).
Subject compliance with treatment was monitored by regularly scheduled telephone calls, an electronic compliance tool provided to the subject and direct review of the subject's source data at the sites and evaluation against the protocol requirements. Drug accountability was evaluated at each interval study visit and at study termination by comparing the infusions recorded in the subject diary, empty vials returned by each subject to the site, and the site's dispensing record.

Efficacy results
The mean (range) treatment period of the per-protocol (PP) analysis set was 185 days (137 to 254) for the on-demand regimen, 362 days (283 to 397) for standard prophylaxis, and 361 days (287 to 382) for PK-tailored prophylaxis. Over these periods, a total of 1351 hemorrhages VALENTINO et al.

Supporting Information: Comparisons of treatment in hemophilia A management
Page 2 of 5 occurred in 53 subjects who were treated on-demand, 77 hemorrhages in 17 of 30 subjects treated by standard prophylaxis, and 75 hemorrhages in 14 of 23 subjects treated by PK-tailored prophylaxis. No subject treated on-demand was hemorrhage-free during the 6-month treatment period, whereas 13 of 30 and 9 of 23 subjects treated with standard and PK-tailored prophylaxis, respectively (overall 41.5%) experienced no bleeding during the 12-month prophylaxis period.
ABRs for all etiologies (spontaneous and traumatic) and types of bleeding (joint and non-joint) for standard and PK-tailored prophylaxis were similar, and reductions in ABRs compared to ondemand treatment were also similar (Supporting Info. Table 4).
VALENTINO et al. Minor hemarthrosis 20 to 40 IU/kg Repeat infusions every 12 to 24 hours for 3 days or more until the pain and moderate disability/incapacity are resolved.
Moderate hemarthrosis and deep muscle bleed 30 to 60 IU/kg Repeat infusions every 12 to 24 hours for 3 days or more until the pain and moderate disability/incapacity are resolved.
Major hemarthrosis or lifethreatening hemorrhage 60 to 100 IU/kg Repeat infusions every 8 to 12 hours until the bleed is resolved.
Genitourinary, gastrointestinal and intracranial episode 60 to 100 IU/kg Repeat infusions every 8 to 12 hours until the bleed is resolved.

Supporting Info. Table 3 Hemostatic efficacy rating scale for treatment of bleeding
Excellent Full relief of pain and cessation of objective signs of bleeding (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) within approximately 8 hours of a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring.

Good
Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after the infusion. Possibly requires more than 1 infusion for complete resolution.

Fair
Probable or slight relief of pain and slight improvement in signs of bleeding within approximately 8 hours after the infusion. Requires more than 1 infusion for complete resolution.

None
No improvement or condition worsens.
VALENTINO et al. % Reduction difference with on _ demand † P<.0001 P<.0001 * Intention-to-treat analysis set † Paired difference between on-demand and prophylaxis (Wilcoxon signed-rank test) ‡ Median % reduction in ABRs between on-demand and any prophylaxis