r surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg).
The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient).
14.3 Routine Prophylaxis
Adolescents and Adults
A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase], and 153 EDs (103-187) in Study 2 (see TABLE 11). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 100% of the prescribed number of prophylaxis infusions.
Table 11: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure
Study 1
(N=62)* Study 2
(N=59)
* Study 1 included PK, safety and efficacy of prophylaxis and hemostasis during surgeries. Prophylaxis phase data are presented.
Median nominal prophylaxis dose/ infusion (range)
All
Prophylaxis 2 times per week
Prophylaxis 3 times per week
31.2 IU/kg (21-43 IU/kg)
35.0 IU/kg (21-42 IU/kg)
31.1 IU/kg (24-43 IU/kg)
31.7 IU/kg (21-42 IU/kg)
30.4 IU/kg (21-34 IU/kg)
37.4 IU/kg (30-42 IU/kg)
Treatment duration
1 year main study
1 year
Study 1: 2 times per week (n=18); 3 times per week (n=44)
Study 2: 2 times per week (n=28); 3 times per week (n=31)
The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p<0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis.
Table 12: ABR in Adolescent and Adult Subjects
* IQR = Interquartile Range † Month 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six months of the treatment period ‡ Observation of one-year treatment period § n=total number of subjects with zero bleeds ¶ n=total number of subjects randomized to treatment arms
Study 1
(N=62)
Study 2
(N=59)
2 times per week
(n=18)
3 times per week
(n=44)
2 times per week
(n=28)
3 times per week
(n=31)
ABR Median (IQR*Q1; Q3)
All Bleeds
1.0 (0.0; 8.0)
2.0 (0.5; 5.
