Low Bleeding Rates with Increase or Maintenance of Physical Activity in Patients Treated with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the A-LONG and Kids A-LONG Studies

Background: The phase 3 A-LONG and Kids A-LONG studies demonstrated low annualized bleeding rates (ABRs) with reduced infusion frequency rFVIIIFc prophylaxis 1-2 times/week in adults, adolescents, and children with severe hemophilia A.  Median prestudy and on-study total weekly prophylactic factor consumption was comparable for subjects previously receiving FVIII prophylaxis.

Aims: To evaluate the effect of rFVIIIFc on subjects’ physical activity across age groups using a subject-reported assessment and examine ABRs according to change in physical activity and prestudy treatment regimen (prophylaxis or episodic) in A-LONG and Kids A-LONG.

Methods: Previously treated males with severe haemophilia A (<1 IU/dL endogenous FVIII activity) were eligible for A-LONG (≥ 12 years of age) and Kids A-LONG (<12 years of age).  A-LONG enrolled subjects into 1 of 3 arms: Arm 1, individualized prophylaxis; Arm 2, weekly prophylaxis; or Arm 3, episodic treatment.  All subjects in Kids A-LONG received rFVIIIFc prophylaxis.  There were no restrictions on physical activity in either study.  Physical activity assessments were conducted at Weeks 7, 14, 28, 38, and 52 (A-LONG) and Weeks 2, 7, 12, 17, 22, and 26 (Kids A-LONG).  At each visit after their first rFVIIIFc dose, subjects were asked to report their activity levels relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of activity.  To summarize changes in physical activity throughout the study versus baseline, subjects were classified into 1 of 4 groups: more, same, less, or undetermined.  Within treatment groups, prestudy and on-study ABRs were analyzed according to change in physical activity category and prestudy regimen.  Analyses included all subjects who received ≥ 1 dose of rFVIIIFc during the efficacy period and who completed ≥ 1 physical activity assessment.

Results: This analysis included 163 subjects from A-LONG and 69 subjects from Kids A-LONG.  The majority of subjects in both studies reported more or the same amount of physical activity; few subjects reported less physical activity (more, same, less, undetermined): A-LONG Arm 1 (n = 117), 51%, 36%, 8%, 5%; Arm 2 (n = 23), 39%, 48%, 9%, 4%; Arm 3 (n = 23), 26%, 52%, 9%, 13%; and Kids A-LONG (n = 69), 61%, 26%, 6%, 7%, respectively.  Similar physical activity results were observed in subjects with target joints at baseline.  Median ABRs were lower with rFVIIIFc prophylaxis in A-LONG for all categories of change in physical activity, regardless of prestudy regimen (Table).  In Kids A-LONG subjects on prestudy prophylaxis who reported more or similar physical activity, median ABRs with rFVIIIFc were similar or lower than prestudy ABRs.

Summary/Conclusion: The majority of subjects in A-LONG (86%) and Kids A-LONG (87%) reported maintained or increased physical activity levels on-study, with low ABRs.  These results suggest that people with severe hemophilia A across age groups may maintain or increase physical activity levels with rFVIIIFc while maintaining low bleeding rates with reduced infusion frequency.

 

 

Table.  Prestudy and On-study Median (IQR) ABR by Physical Activity Level in A-LONG and Kids A-LONG

Parent study:	A-LONG			Kids A-LONG
On-study rFVIIIFc prophylaxis:	Arm 1 (Individualized)		Arm 2 (Weekly)	Twice-weekly
Prestudy FVIII regimen:	Prophylaxis (n = 85)a	Episodic (n = 31)	Episodic (n = 23)b	Prophylaxis (n = 62)	Episodic (n = 7)
Median (IQR) ABR by physical activity category
More	n = 38	n = 21	n = 9	n = 35	n = 7
Prestudy	6.0 (3.0, 15.0)	24.0 (17.0, 40.0)	25.0 (20.0, 30.0)	2.0 (1.0, 7.0)	12.0 (10.0, 16.0)
On-study	2.15 (0, 5.42)	0 (0, 1.81)	1.93 (0, 3.59)	2.01 (0, 4.04)	2.05 (0, 3.96)
Same	n = 36	n = 6	n = 11	n = 18	n = 0
Prestudy	6.0 (1.0, 16.5)	33.0 (23.0, 42.0)	33.0 (16.0, 43.0)	2.0 (1.0, 3.0)
On-study	2.76 (0, 6.06)	0.86 (0, 2.03)	4.34 (1.86, 7.62)	0 (0,0)
Less	n = 7	n = 2	n = 2	n = 4	n = 0
Prestudy	2.0 (1.0, 9.0)	66.5 (13.0, 120.0)	37.5 (23.0, 52.0)	1.5 (0.5, 3.5)
On-study	0 (0, 3.78)	0.72 (0, 1.44)	15.04 (8.36, 21.71)	4.07 (1.01, 8.31)
Undetermined	n = 4	n = 2	n = 1	n = 5	n = 0
Prestudy	21.5 (6.0, 40.5)	25.5 (14.0, 37.0)	29.0	3.0 (2.0, 4.0)
On-study	2.80 (1.50, 7.55)	0 (0,0)	4.02	4.18 (2.01, 6.41)

ABR, annualized bleeding rate; IQR, interquartile range.

^aOne subject did not have prestudy ABR data available and was excluded from the analysis.

^bAll subjects in Arm 2 received prior episodic treatment.