Multicentre, randomized, open‐label study of on‐demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects

Abstract

Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6-65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg(-1) twice-weekly period, and the 100 IU kg(-1) once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg(-1) twice weekly or 100 IU kg(-1) once weekly reduced ABR by 89.4% relative to on-demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.

Albutrepenonacog alfa (Idelvion®) for the treatment of Italian patients with hemophilia B: a budget impact model

“…Both prophylaxis regimes had significantly reduced ABR compared to on-demand therapy (p < 0.0001), while no significant differences were observed between prophylaxis regimens (p = 0.22) [5]. In order to better assess the efficacy and safety of once-weekly prophylaxis with BeneFIX ® compared with on-demand, 25 male patients (age 12-65 years) with moderately severe to severe hemophilia B (FIX:C ≤ 2%), ≥ 12 bleeding episodes in the previous 12-months and ≥ 100 exposure days to FIX, were enrolled in a pivotal, multicenter, open-label trial [6].…”

“…Currently in Italy, three rFIX are available for treatment of hemophilia B: nonacog alfa (BeneFIX BeneFIX ® (nonacog alfa) was the first rFIX to get marketing authorization in 1997. Efficacy and safety of two prophylaxis regimens (50 IU/kg twice weekly and 100 IU/kg once weekly) vs on-demand therapy were evaluated in a multicenter, randomized, open-label trial conducted on patients with moderately severe to severe hemophilia B (FIX:C ≤ 2%) [5]. Fifteen male subjects (age 6-65 years) with ≥ 12 bleeding episodes within 12 months of study participation were enrolled; the study included four periods: 1) a 16-week on-demand treatment; 2) randomization and 16-week prophylactic treatment with BeneFIX ® 50 IU/kg twice weekly or 100 IU/kg once weekly, 3) a 8-week on-demand treatment, 4) cross-over and 16 weeks receiving the alternate study prophylactic regimen.…”

“…Clinical and cost inputs 1 Weighted average extrapolated from phase 3 extension study [19] 2 Mean value between 40 IU/kg twice a week indicated in adult population and 63.7 IU/kg every 3-7 days indicated in child < 6 years 3 Due to the lack of specific value, a mean value between BeneFIX ® 50 IU/kg twice a week (ABR = 2.6 [5]) and Idelvion ® 75 IU/kg every 14 days (ABR = 1.96 [23]) was assumed 4 Dose/infusion was calculated as: weigh (kg) x increase FIX/IR, where increase FIX is the FIX level required to stop bleeding (50% [29]). 5 Due to lack of specific value, according to a conservative approach, the same number of infusion was assumed both for adults and children ABR = Annualized Bleeding Ratio; IR = Incremental Recovery prophylaxis treatment and the management of bleeding events. The consumption of each FIX is calculated taking into account an average weight of 25 kg for the pediatric population (< 12 years), and of 70 kg for patients adolescents/adults (≥ 12 years).…”

Nonacog alfa

“…Study 304 (N ¼ 34) compared the bioequivalence of original and reformulated nonacog alfa and evaluated the efficacy and safety of the new formulation during 6-12 months of open-label on-demand treatment or prophylaxis of previously treated patients at least 12 years of age with moderately severe or severe haemophilia B [26]. Study 400 (N ¼ 50) was a phase 4, randomized, open-label, four-period crossover study that compared prophylactic and on-demand treatment with nonacog alfa in previously treated patients aged 6-65 years with moderately severe or severe haemophilia B [32]. The four periods included 16 weeks of on-demand treatment, randomization to a prophylactic regimen (50 IU/kg twice weekly or 100 IU/kg once weekly) for 16 weeks, a subsequent 8-week, on-demand treatment period and a final crossover to the alternative prophylactic regimen for 16 weeks.…”

Lack of seasonal variation in bleeding and patient‐assessed pain patterns in patients with haemophilia B receiving on‐demand therapy

“…The design and primary results of this study have been reported previously 11. In brief, patients received on-demand treatment with nonacog alfa for 16 weeks, with dosing adjusted based on the investigator's judgment, according to body weight and bleeding severity (Period 1).…”