Efficacy, Safety and Pharmacokinetic Results of a Phase III, Open-Label, Multicenter Study with a Plasma-Derived Von Willebrand Factor (VWF)/Factor VIII (FVIII) Concentrate in Pediatric Patients <12 Years of Age with Hemophilia A (SWIFTLY-HA Study)

Figures & data

Table 1 Guidelines for Dosage During the Efficacy Component77

Degree of Hemorrhage/Type of Surgical Procedure^a	FVIII Level Required (%)	Dose (IU/kg b.w.)	Frequency of Dosing (Per Day)	Duration of Treatment (Days)
Hemorrhage
Early hemarthrosis, muscle  bleeding, or oral bleeding	20–40	10–20	Repeat every 12–24 h	At least 1 day, until the bleeding episode, as indicated by pain, was resolved or healing was achieved
More extensive  hemarthrosis, muscle  bleeding, or hematoma	30–60	15–30	Repeat infusion every 12–24 h	For 3–4 days or more until pain and acute disability were resolved
Life-threatening  hemorrhages	60–100	30–50	Repeat infusion every 8–24 h	Until threat was resolved
Surgery
Minor, including tooth  extraction	30–60	15–30	Every 24 h	At least 1 day, until healing was achieved
Major	80–100 (pre- and post-operative)	40–50	Repeat infusion every 8–24 h	Until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30–60% (IU/dL)
Prophylaxis^b	–	20–40		At intervals of 2–3 days

Notes: ^aGuidelines were based on the Draft Guideline on Core SPC for Human Plasma Derived and Recombinant Coagulation Factor VIII Products (CPMP/BPWG/1619/1999). ^bIn some cases, especially in younger patients, shorter dosage intervals or higher doses may have been necessary.

Abbreviations: b.w., body weight; FVIII, factor VIII; IU, international unit.

Figure 1 Study design.

Notes: ^aDue to site closure (n=2) and non-compliance with prophylaxis regimen (n=1). ^bDue to FVIII inhibitor development (n=2) and withdrew their consent (n=2).

Abbreviations: N, total number of patients; PK, pharmacokinetics.

Table 2 Patient Characteristics

Variables	Prophylaxis N=18	On-Demand N=17	Total N=35
Age [years]
Mean (SD)	7.3 (2.68)	4.9 (3.43)	6.1 (3.26)
Median (range)	7.5 (2–11)	4.0 (0–11)	6.0 (0–11)
0 to <6 years, n (%)	4 (22.2)	12 (70.6)	16 (45.7)
6 to <12 years, n (%)	14 (77.8)	5 (29.4)	19 (54.3)
Ethnic origin, n (%)
Caucasian	15 (83.3)	17 (100)	32 (91.4)
Hispanic	3 (16.7)	0	3 (8.6)
Weight [kg]
Mean (SD)	29.1 (13.7)	22.6 (11.4)	26.0 (12.9)
Median (range)	25.5 (14.0–66.5)	18.5 (8.5–50.0)	23.0 (8.5–66.5)
Prior treatment regimen, n (%)
Prophylaxis	7 (39)	0	7 (20)
On-demand	7 (39)	17 (100)	24 (69)
Not reported	4 (22)	0	4 (11)

Abbreviations: n, number of patients or events with characteristic; N, total number of patients; SD, standard deviation.

Table 3 PK Parameters of FVIII:C in Patients <6 (N=15) and 6–12 Years of Age (N=16)

	<6 Years			6–12 Years			Overall
Parameter	N	Median	Range	N	Median	Range	N	Median	Range
Dose administered (IU/kg)	15	50.1	47.5–54.5	16	50.0	47.5–54.5	31	50.0	47.5–54.5
Incremental recovery (IU/mL)/(IU/kg)	15	0.015	0.009–0.019	16	0.016	0.010–0.026	31	0.016	0.009–0.026
Half-life (h)	15	9.62	7.75–18.20	16	10.00	8.89–12.50	31	9.78	7.75–18.20
AUC0–48 (h*IU/mL)	15	8.23	3.96–11.04	16	9.90	6.17–17.62	31	8.80	3.96–17.62
Cmax (IU/mL)	15	0.75	0.46–0.94	16	0.84	0.51–1.21	31	0.76	0.46–1.21
Total clearance (mL/(h*kg)	15	6.22	4.22–11.34	16	4.88	2.54–7.74	31	5.44	2.54–11.34
Vss (mL/kg)	15	75.3	63.8–197.2	16	71.9	42.1–109.3	31	73.7	42.1–197.2

Abbreviations: AUC, area under the curve; C_max, maximum plasma concentration; C_min, minimum plasma concentration; FVIII:C, factor VIII: coagulant activity; IU, international unit; MRT, mean residence time; N, number of patients; t_max, time to maximum concentration; V_ss, volume of distribution at steady state.

Figure 2 Mean (SD) concentration profiles (IU/mL) of FVIII:C by age group and overall.

Notes: Solid line with circles: overall population; black dashed line with squares: 0 to <6 years; black dashed line with circles: 6 to <12 years; red dashed line: lower limit of quantitation (0.008 IU/mL).

Abbreviations: FVIII:C, factor VIII: coagulant activity; IU, international unit; PK, pharmacokinetics; SD, standard deviation.

Table 4 Investigator’s Assessment of Hemostatic Efficacy per Bleeding Event in the On-Demand and Prophylaxis Arms

	On-Demand Arm					Prophylaxis Arm
		Number (%) of NSB Events					Number (%) of NSB Events
Bleeding Type	Number of NSB Events	Excellent	Good	Moderate	None	Number of NSB Events	Excellent	Good	Moderate	None
All NSB events	318	77 (24.2)	241 (75.8)	0	0	172	148 (86.0)	23 (13.4)	1 (0.6)	0
Spontaneous	123	26 (21.1)	97 (78.9)	0	0	54	42 (77.8)	11 (20.4)	1 (1.9)	0
Trauma	194	51 (26.3)	143 (73.7)	0	0	118	106 (89.8)	12 (10.2)	0	0
Post-surgery	1	0	1 (100.0)	0	0	0	0	0	0	0
Major	98	4 (4.1)	94 (95.9)	0	0	85	70 (82.4)	15 (17.6)	0	0
Minor	220	73 (33.2)	147 (66.8)	0	0	87	78 (89.7)	8 (9.2)	1 (1.1)	0
Joint	176	31 (17.6)	145 (82.4)	0	0	143	122 (85.3)	20 (14.0)	1 (0.7)	0
Mucosal	73	24 (32.9)	49 (67.1)	0	0	13	12 (92.3)	1 (7.7)	0	0
Muscle	67	21 (31.3)	46 (68.7)	0	0	14	12 (85.7)	2 (14.3)	0	0
Other	2	1 (50.0)	1 (50.0)	0	0	2	2 (100.0)	0	0	0

Notes: Percentages were based on the number of bleeding events of the considered type with available investigator’s assessment. Bleeding events for which no treatment was needed (on-demand arm, n=2; prophylaxis arm, n=1) were not considered for this table.

Abbreviations: N, number of patients; NSB, non-surgical bleeding.

Table 5 Annualized Spontaneous Bleeding Rate and Prophylaxis Schedule (Number of Doses per Week per Individual Patient Who Completed the Study)

	Study Month	1	2	3	4	5	6	7	8	9	10	11	12	AsBR
Age (Years)
2	Spontaneous NSB	0	0	0	0	0	0							0.00
	Prophylaxis/week	3.7	3.3	2.8	3.0	2.8	3.0
3	Spontaneous NSB	0	0	0	0	1	1	2	0	0	0	0		4.35
	Prophylaxis/week	1.9	1.4	1.9	2.3	1.6	1.2	1.6	1.9	1.4	2.6	1.4
4	Spontaneous NSB	1	0	0	0	0	0	0	0	0	1			2.32
	Prophylaxis/week	1.2	2.3	1.6	2.3	2.3	2.8	1.6	2.3	1.6	2.6
5	Spontaneous NSB	0	1	0	1	0	1	0	0	1	0	0		4.24
	Prophylaxis/week	1.2	1.6	1.6	2.1	2.1	1.6	1.9	0.9	1.9	1.4	1.2
6	Spontaneous NSB	0	0	0	0	0	0							0.00
	Prophylaxis/week	3.3	3.0	2.6	2.6	3.3	4.2
7	Spontaneous NSB	0	0	0	0	0	0							0.00
	Prophylaxis/week	2.1	2.6	2.3	2.6	2.3	2.8
7	Spontaneous NSB	0	0	0	0	0	0	0	0					0.00
	Prophylaxis/week	2.8	3.3	3.3	3.0	2.3	1.9	3.3	0.2
8	Spontaneous NSB	0	0	0	0	0	0							0.00
	Prophylaxis/week	3.7	3.3	3.5	3.7	3.5	4.0
8	Spontaneous NSB	0	0	0	0	0	0	0	1	1				2.64
	Prophylaxis/week	2.3	3.3	4.4	1.9	1.9	5.1	2.3	2.8	1.2
9	Spontaneous NSB	2	1	0	0	1	1	4	0	3	5	2	7	24.91*
	Prophylaxis/week	0.9	0.7	2.3	3.0	0.2	0.9	1.4	1.2	0.0	0.2	0.2	0.2
10	Spontaneous NSB	0	0	0	0	0	0							0.00
	Prophylaxis/week	2.1	2.6	2.3	2.6	1.9	2.3
10	Spontaneous NSB	2	1	3	0	0	0	0						9.36*
	Prophylaxis/week	3.0	2.8	2.1	3.0	3.0	2.6	3.3
10	Spontaneous NSB	0	0	0	0	0	0	0						0.00
	Prophylaxis/week	3.3	3.3	3.0	3.5	2.6	2.1	0.9
10	Spontaneous NSB	0	0	0	0	0	0	0	0	1	0	0		1.15
	Prophylaxis/week	1.9	1.6	1.6	1.6	1.9	2.3	0.9	2.1	2.3	2.6	0.5
11	Spontaneous NSB	0	2	3	0	0	0	1	0	0				8.05*
	Prophylaxis/week	3.0	1.9	2.8	2.3	2.1	1.9	3.3	1.9	1.9

Notes: Spontaneous NSB events are highlighted in grey; *More than half of the reported NSB events (56%) were reported by these three patients.

Abbreviations: AsBR, annualized spontaneous bleeding rate; NSB, non-surgical bleeding.