Scientific research question: To systematically review the evidence from Phase III clinical trials evaluating the use of rFIX products for prophylaxis in hemophilia B patients. The outcomes considered were total annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR).
Methodology: A systematic literature search was conducted in both EMBASE and PubMed. Phase III clinical trials of prophylactic rFIX treatment in previously treated, hemophilia B patients aged ≥12 years, with endogenous FIX levels ≤2% were included. Studies which did not meet these criteria, or did not report any of the outcomes mentioned above, were excluded. Relevant data were then extracted from these studies.
Findings: The search identified a total of 1,362 articles, with 35 passing the title and abstract screen. Following full-text review, 9 articles met the inclusion criteria. Data has been extracted from these articles and is summarized in [Table 1] (data marked * was obtained from the clinical study report); information is presented for the weekly infusion regimen where data was available for more than one prophylaxis schedule. ABR reported in the relevant studies ranged from a median of 0-3.0, AsBR ranged from 0-1.0, and AjBR ranged from 0-1.1. The median values reported for rIX-FP were 0 for ABR, AsBR and AjBR. Mean values ranged from 1.24-4.26 for ABR, 0.52-2.6 for AsBR, and 0.89-2.85 for AjBR, with rIX-FP at the lowest end for each value.
Conclusion: This review identified suitable data for an indirect comparison of rFIX products. Within the limitations of potential differences in patient population and study design, a formal meta-analysis may help to understand how these products compare with respect to the parameters of ABR, AsBR, and AjBR.
Table 1
Details of bleeding rates in rFIX studies identified by the systematic review
|
Study and regimen
|
rFIX product
|
No. prophylaxis subjects
|
Age, mean years (range)
|
ABR, median (IQR)
|
ABR, mean (SD)
|
AsBR, median (IQR)
|
AsBR, mean (SD)
|
AjBR, median (IQR)
|
AjBR, mean (SD)
|
|
Santagostino et al. 2016 (35-50 IU/kg weekly prophylaxis)
|
Albutrepenonacog alfa (rIX-FP)
|
40
|
31.6 (SD 15.2)
|
0 (0, 1.87)
|
1.24 (1.780)*
|
0 (0, 0)
|
0.52 (1.116)*
|
0 (0, 1.53)
|
0.89 (1.436)*
|
|
Powell et al. 2013 (50 IU/kg weekly prophylaxis)
|
rFIXFc INN
|
63
|
Median (range): 28 (12-71)
|
3.0 (1.0–4.4)
|
NR
|
1.0 (0.0–2.2)
|
NR
|
1.1 (0.0–4.0)
|
NR
|
|
Lambert et al. 2007 (regimen not reported)
|
Nonacog alfa
|
17
|
28.32 (12–61) [for all 34 patients in study]
|
NR
|
3.11
|
NR
|
0.72
|
NR
|
NR
|
|
Kavakli et al. 2016 (100 IU/kg weekly prophylaxis)
|
Nonacog alfa
|
25
|
31.3 (12.1–53.7)
|
2.0 (0, 13.8)
|
3.6 (4.6)
|
1.0 (0, 13.8)
|
2.6 (4.1)
|
0.0 (0, 9.8)
|
2.1 (3.2)
|
|
Windyga et al. 2014 (40–75 IU/kg twice-weekly prophylaxis)
|
BAX326 INN
|
56
|
Median (range): 33 (12–59) [for all 73 patients in study]
|
1.99 (0, 23.4)
|
4.26 (5.80)
|
0.0 (0, 15.6)
|
1.72 (3.26)
|
0.0 (0, 21.5)
|
2.85 (4.25)
|
|
Collins et al. 2014 (40 IU/kg weekly prophylaxis)
|
Nonacog beta pegol (N9-GP)
|
29
|
30.0 (SD 15.8)
|
1.04 (0.00–4.00)
|
NR
|
0.0 (0.0–0.98)
|
NR
|
NR
|
NR
|
|
Young et al. 2016 (40 IU/kg weekly prophylaxis)
|
Nonacog beta pegol (N9-GP)
|
52
|
32 (SD 14.2)
|
1.00 (0.00–2.03)
|
NR
|
0.00 (0.00–1.00)
|
NR
|
0.00 (0.00–1.97)
|
NR
|
|
Collins et al. 2017 (50–75 IU/kg twice-weekly prophylaxis)
|
Trenonacog alfa (IB1001)
|
58
|
28.8 (SD 14.2)
|
1.52 (0.00–3.46)
|
3.55 (SD 7.15)
|
NR
|
NR
|
NR
|
NR
|
|
Solano Trujillo et al. 2014 (20–40 IU/kg twice-weekly prophylaxis)
|
BAX326 INN
|
32
|
31.9 (14–55)
|
0.9 (0, 11.2)
|
2.3 (3.7)
|
0.0 (0, 10)
|
0.9 (1.95)
|
0.0 (0, 10)
|
1.5 (2.66)
|
