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Clinical Trial Results:
A-LONG: An Open-label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A

Summary
EudraCT number	2010-020558-33
Trial protocol	SE GB FR DE BE ES AT IT PT
Global end of trial date	06 Aug 2012

Results information
Results version number	v1(current)
This version publication date	04 Feb 2016
First version publication date	20 Jun 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

997HA301

ISRCTN number

US NCT number

NCT01181128

WHO universal trial number (UTN)

Sponsor organisation name

Biogen

Sponsor organisation address

225 Binney Street , Cambridge, United States, 02142

Public contact

Biogen Study Medical Director, Biogen , Clinicaltrials@biogen.com

Scientific contact

Biogen Study Medical Director, Biogen , Clinicaltrials@biogen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001114-PIP01-10

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

06 Aug 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Aug 2012

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study are: to evaluate the safety and tolerability of rFVIIIFc administered as a prophylaxis (Arm 1), weekly (Arm 2), on-demand (Arm 3), and surgical treatment regimen; to evaluate the efficacy of the rFVIIIFc tailored prophylaxis regimen (Arm 1); to evaluate the efficacy of rFVIIIFc administered as an on-demand (Arm 3) and surgical treatment regimen. The secondary objectives of this study are: to characterize the pharmacokinetic (PK) profile of rFVIIIFc and compare the PK of rFVIIIFc with the currently marketed product, Advate®; to characterize the range of dose and schedules required to adequately prevent bleeding in a prophylaxis regimen, maintain hemostasis in a surgical setting, or to treat bleeding episodes in an on-demand, weekly treatment, or prophylaxis setting.

Protection of trial subjects

Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent form and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each participant was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Nov 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

Brazil: 3

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Hong Kong: 4

Country: Number of subjects enrolled

India: 15

Country: Number of subjects enrolled

Israel: 4

Country: Number of subjects enrolled

Japan: 14

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

South Africa: 17

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

United States: 54

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

Austria: 5

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 5

Worldwide total number of subjects

165

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

151

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

The screening period to determine subject eligibility was to last for up to 8 weeks and included at least a 96-hour washout from Factor VIII (FVIII) prior to initial study dosing. A 72-hour washout was allowed for adolescent subjects (i.e., 12 to 17 years old).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm 1: Individualized (Tailored) Prophylaxis

Arm description

On rFVIIIFc Day 0, all subjects underwent PK analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

Arm type

Experimental

Investigational medicinal product name

recombinant Factor VIII Fc

Investigational medicinal product code

rFVIIIFc

Other name

BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Study site staff members were instructed to refer to the Directions for Handling and Administration located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment.

Investigational medicinal product name

Advate®

Investigational medicinal product code

Other name

octocog alfa, Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Arm 2: Weekly Prophylaxis

Arm description

65 IU/kg of rFVIIIFc via IV injection every 7 days

Arm type

Experimental

Investigational medicinal product name

recombinant Factor VIII Fc

Investigational medicinal product code

rFVIIIFc

Other name

BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Arm 3: Episodic (On-Demand) Dosing

Arm description

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Arm type

Experimental

Investigational medicinal product name

recombinant Factor VIII Fc

Investigational medicinal product code

rFVIIIFc

Other name

BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Started	118	24	23
Pharmacokinetic (PK) Subgroup	30 ^[1]	0 ^[2]	0 ^[3]
Perioperative Management Subgroup	8 ^[4]	1 ^[5]	0 ^[6]
Completed	112	19	22
Not completed	6	5	1
Adverse event, serious fatal	1	-	-
Consent withdrawn by subject	2	2	-
Physician decision	2	-	-
Adverse event, non-fatal	-	2	-
Not specified	1	1	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.

Baseline characteristics

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Reporting group title

Arm 1: Individualized (Tailored) Prophylaxis

Reporting group description

Reporting group title

Arm 2: Weekly Prophylaxis

Reporting group description

65 IU/kg of rFVIIIFc via IV injection every 7 days

Reporting group title

Arm 3: Episodic (On-Demand) Dosing

Reporting group description

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Reporting group values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing	Total
Number of subjects	118	24	23	165
Age categorical
Units: Subjects
Adolescents (12-17 years)	11	0	2	13
Adults (18-64 years)	106	24	21	151
From 65-84 years	1	0	0	1
Age continuous
Units: years
median (full range (min-max))	29 (12 to 65)	31.5 (18 to 59)	34 (13 to 62)	-
Gender categorical
Units: Subjects
Female	0	0	0	0
Male	118	24	23	165

End points

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Reporting group title

Arm 1: Individualized (Tailored) Prophylaxis

Reporting group description

Reporting group title

Arm 2: Weekly Prophylaxis

Reporting group description

65 IU/kg of rFVIIIFc via IV injection every 7 days

Reporting group title

Arm 3: Episodic (On-Demand) Dosing

Reporting group description

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Subject analysis set title

Arm 1: Individualized (Tailored) Prophylaxis, Advate

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Individualized (Tailored) Prophylaxis arm who received at least 1 dose of Advate.

Subject analysis set title

Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Only

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Individualized (Tailored) Prophylaxis arm who received at least 1 dose of rFVIIIFc.

Subject analysis set title

Any Arm: Perioperative Management (Surgery) Subgroup

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the subject underwent.

Subject analysis set title

Arm 1: Individualized Prophylaxis: Sequential PK Subgroup

Subject analysis set type

Sub-group analysis

Subject analysis set description

On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. Analysis set includes subjects who had evaluable one- or two-stagePK profiles for both Advate and baseline rFVIIIFc.

Subject analysis set title

Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis

Subject analysis set type

Sub-group analysis

Subject analysis set description

On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

Subject analysis set title

Arm 1: Individualized Prophylaxis, Prestudy On-demand

Subject analysis set type

Sub-group analysis

Subject analysis set description

On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

Subject analysis set title

All Arms: Total

Subject analysis set type

Full analysis

Subject analysis set description

All subjects from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.

Primary: Incidence Rate of FVIII Inhibitor Development

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End point title

Incidence Rate of FVIII Inhibitor Development ^[1]

End point description

An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% confidence interval (CI) were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFVIIIFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their EDs to rFVIIIFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.

End point type

Primary

End point timeframe

up to 52 weeks ± 2 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, descriptive statistics were collected for this endpoint.

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing	All Arms: Total
Number of subjects analysed	118 ^[2]	24 ^[3]	23 ^[4]	165 ^[5]
Units: percentage of subjects
number (confidence interval 95%)
Subjects with>=50 EDs; n=107, 1, 2, 110	0 (0 to 3.4)	0 (0 to 97.5)	0 (0 to 84.2)	0 (0 to 3.3)
All subjects; n=117, 24, 23, 164	0 (0 to 3.1)	0 (0 to 14.2)	0 (0 to 14.8)	0 (0 to 2.2)

Notes
[2] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
[3] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
[4] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
[5] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.

No statistical analyses for this end point

Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) ^[6] ^[7]

End point description

AE=any untoward medical occurrence that did not necessarily have a causal relationship with treatment. TEAE=AE present prior to receiving the first injection of Advate or rFVIIIFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before the last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other medically important event. For Arm 1, AEs emergent between the first on-study Advate dose and 1st rFVIIIFc dose are reported as treatment-emergent to Advate (first column); AEs emergent after the first rFVIIIFc injection are reported as treatment-emergent to rFVIIIFc (2nd column). Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.

End point type

Primary

End point timeframe

up to 52 weeks + 30 days ± 1 week

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, descriptive statistics were collected for this endpoint.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Arm 1, AEs emergent between the first on-study Advate dose and the first rFVIIIFc dose are reported as treatment-emergent to Advate; AEs emergent after the first rFVIIIFc injection are reported as treatment-emergent to rFVIIIFc (2 separate columns).

End point values	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing	Arm 1: Individualized (Tailored) Prophylaxis, Advate	Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Only	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	24	23	30	117	9
Units: subjects
>=1 TEAE	18	10	3	80	4
>=1 Related TEAE	3	2	0	5	0
>=1 TESAE	2	0	0	10	2
>=1 Related TESAE	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

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End point title

Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline ^[8]

End point description

Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. ULN=upper limit of normal. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.

End point type

Primary

End point timeframe

up to 52 weeks ± 2 weeks

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, descriptive statistics were collected for this endpoint.

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	118 ^[9]	24 ^[10]	23 ^[11]
Units: subjects
Leukocytes <3.0*10^9/L; n=117, 24, 23	2	0	2
Leukocytes >=16*10^9/L; n=117, 24, 23	1	0	0
Lymphocytes <0.8*10^9/L; n=104, 22, 21	3	1	1
Lymphocytes >12*10^9/L; n=104, 22, 21	0	0	0
Neutrophils <1.5*10^9/L; n=104, 22, 21	4	0	1
Neutrophils >13.5*10^9/L; n=104, 22, 21	1	0	0
Monocytes >2.5*10^9/L; n=104, 22, 21	0	0	0
Eosinophils >1.6*10^9/L; n=104, 22, 21	0	0	0
Basophils >1.6*10^9/L; n=104, 22, 21	0	0	0
Erythrocytes <=3.5*10^12/L; n=117, 24, 23	1	0	0
Erythrocytes >=6.4*10^12/L; n=117, 24, 23	1	0	1
Hemoglobin <=115 g/L; n=117, 24, 23	3	0	1
Hemoglobin >=190 g/L; n=117, 24, 23	0	0	0
Hematocrit <=37%; n=117, 24, 23	5	2	1
Hematocrit >=60%; n=117, 24, 23	0	0	0
Platelets <=75*10^9/L; n=117, 24, 23	0	0	0
Platelets >=700*10^9/L; n=117, 24, 23	0	0	0
Alanine Aminotransferase >=3*ULN; n=117, 24, 23	4	0	0
Aspartate Aminotransferase >=3*ULN; n=117, 24, 23	4	1	0
Alkaline Phosphatase >=3*ULN; n=117, 24, 23	0	0	0
Total Bilirubin >=34.2 μmol/L; n=117, 24, 23	3	0	2
Blood Urea Nitrogen >=10.7 mmol/L; n=117, 24, 23	1	1	0
Creatinine >=176.8 μmol/L; n=117, 24, 23	0	0	0
Sodium <=126 mmol/L; n=117, 24, 23	0	0	0
Sodium >=156 mmol/L; n=117, 24, 23	1	0	0
Potassium <=3 mmol/L; n=117, 24, 23	0	0	0
Potassium >=6 mmol/L; n=117, 24, 23	0	0	0
Chloride <=90 mmol/L; n=117, 24, 23	1	0	0
Chloride >=118 mmol/L; n=117, 24, 23	0	0	0
Phosphate <=0.55 mmol/L n=117, 24, 23	1	0	0
Phosphate >=1.71 mmol/L; n=117, 24, 23	0	0	0
Glucose <=2.22 mmol/L; n=117, 24, 23	0	0	0
Glucose >=9.71 mmol/L; n=117, 24, 23	2	1	0
Total Protein <=45 g/L; n=117, 24, 23	0	0	0
Total Protein >=100 g/L; n=117, 24, 23	0	0	0

Notes
[9] - n=the number of subjects with at least one postbaseline value.
[10] - n=the number of subjects with at least one postbaseline value.
[11] - n=the number of subjects with at least one postbaseline value.

No statistical analyses for this end point

Primary: Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

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End point title

Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs ^[12]

End point description

Number of subjects with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute [bpm]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFVIIIFc dose. ↑signifies increase and ↓ signifies decrease. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc and had a baseline assessment and at least 1 postbaseline assessment for temperature or at least 1 postbaseline assessment for pulse, SBP, and DBP.

End point type

Primary

End point timeframe

up to 52 weeks ± 2 weeks

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, descriptive statistics were collected for this endpoint.

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	113	24	23
Units: subjects
Temperature: >38°C and ≥1°C ↑ from BL	1	0	0
Pulse: >120 bpm or >20 bpm ↑ from BL	11	2	0
Pulse: <50 bpm or >20 bpm ↓ from BL	11	2	1
SBP: >180 mm Hg or >40 mm Hg ↑ from BL	0	1	0
SBP: <90 mm Hg or >30 mm Hg ↓ from BL	5	1	1
DBP: >105 mm Hg or >30 mm Hg ↑ from BL	1	0	0
DBP: <50 mm Hg or >20 mm Hg ↓ from BL	5	0	1

No statistical analyses for this end point

Primary: Annualized Bleeding Rate

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End point title

Annualized Bleeding Rate ^[13]

End point description

Annualized bleeding episodes = (number of bleeding episodes during the efficacy period / number of days during the efficacy period)*365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.

End point type

Primary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: See "Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3" endpoint for statistical analysis.

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	117	23	23
Units: episodes per subject per year
median (inter-quartile range (Q1-Q3))	1.6 (0 to 4.69)	3.59 (1.86 to 8.36)	33.57 (21.14 to 48.69)

No statistical analyses for this end point

Primary: Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

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End point title

Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3 ^[14]

End point description

Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all subjects. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25.The efficacy period in Arm 1 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.

End point type

Primary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, Arm 1 versus Arm 3 only was analyzed as a primary endpoint. Arm 2 versus Arm 3 only was analyzed as a secondary endpoint. Both are included in this record.

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	117	23
Units: episodes per subject per year
number (confidence interval 95%)	2.91 (2.3 to 3.68)	37.25 (24.03 to 57.74)

Statistical Analysis 1

Statistical analysis description

The null hypothesis for the primary endpoint is no difference between the individualized (tailored) prophylaxis regimen and the on-demand regimen. The sample size of this study was mainly based on clinical rather than statistical considerations. However it was projected to have > 90% power at the 2-sided 0.05 level of significance to detect a 60% reduction in annualized bleeding episodes, based upon this hypothesis test.

Comparison groups

Arm 1: Individualized (Tailored) Prophylaxis v Arm 3: Episodic (On-Demand) Dosing

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

negative binomial model

Parameter type

Bleeding Rate Ratio

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.13

Primary: Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

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End point title

Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay) ^[15]

End point description

Dose normalized area under the drug concentration-time curve. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Primary

End point timeframe

See endpoint description for complete time frame.

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[16]
Units: IU*h/dL per IU/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	51.24 (44.97 to 58.38)
Advate	32.88 (29.31 to 36.88)

Notes
[16] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Primary: Elimination Half Life (t1/2; One-stage Clotting Assay)

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End point title

Elimination Half Life (t1/2; One-stage Clotting Assay) ^[17]

End point description

Time required for the activity of the drug to reach half of its original value. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Primary

End point timeframe

See endpoint description for complete time frame.

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[18]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	18.97 (17.03 to 21.12)
Advate	12.43 (11.14 to 13.86)

Notes
[18] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Primary: Clearance (CL; One-stage Clotting Assay)

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End point title

Clearance (CL; One-stage Clotting Assay) ^[19]

End point description

Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Primary

End point timeframe

See endpoint description for complete time frame.

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[20]
Units: mL/h/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	1.952 (1.713 to 2.224)
Advate	3.041 (2.711 to 3.412)

Notes
[20] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Primary: Mean Residence Time (MRT; One-stage Clotting Assay)

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End point title

Mean Residence Time (MRT; One-stage Clotting Assay) ^[21]

End point description

The average time that a drug molecule is present in the systemic circulation. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Primary

End point timeframe

See endpoint description for complete time frame.

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[22]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	25.15 (22.65 to 27.91)
Advate	16.84 (15.22 to 18.63)

Notes
[22] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Primary: Incremental Recovery (One-stage Clotting Assay)

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End point title

Incremental Recovery (One-stage Clotting Assay) ^[23]

End point description

The rise in FVIII activity in IU/dL per unit dose administered in IU/kg. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Primary

End point timeframe

See endpoint description for complete time frame.

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[24]
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	2.2395 (2.1116 to 2.3753)
Advate	2.3516 (2.211 to 2.501)

Notes
[24] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

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End point title

Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3 ^[25]

End point description

Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all subjects. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25.The efficacy period in Arm 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, Arm 1 versus Arm 3 only was analyzed as a primary endpoint. Arm 2 versus Arm 3 only was analyzed as a secondary endpoint. Both are included in this record.

End point values	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	23	23
Units: episodes per subject per year
number (confidence interval 95%)	8.92 (5.48 to 14.51)	37.25 (24.03 to 57.74)

Statistical Analysis 1

Comparison groups

Arm 2: Weekly Prophylaxis v Arm 3: Episodic (On-Demand) Dosing

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

negative binomial model

Parameter type

Bleeding Rate Ratio

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.46

Secondary: Annualized rFVIIIFc Consumption Per Subject

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End point title

Annualized rFVIIIFc Consumption Per Subject

End point description

Consumption is calculated for the efficacy period. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. Overall units (IU/kg) of annualized rFVIIIFc consumption = [Total rFVIIIFc IU/kg received during the efficacy period / number of days in efficacy period] x 365.25. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc. 'Overall' n=subjects in the Full Analysis Set with evaluable data in the efficacy period; 'Last 3 Months on Study' n=subjects in the Full Analysis Set with evaluable data and >=6 months on study.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	117	24	23
Units: IU/kg rFVIIIFc per subject per year
arithmetic mean (standard deviation)
Overall; n=117, 23, 23	4631.98 ( 1041.608 )	4003.69 ( 652.573 )	1304.36 ( 874.361 )
Last 3 months on study; n=112, 16, 18	4868.35 ( 1365.108 )	3882.89 ( 583.344 )	1225.8 ( 848.656 )

No statistical analyses for this end point

Secondary: Subject Assessment of Response to Injections to Treat a Bleeding Episode

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End point title

Subject Assessment of Response to Injections to Treat a Bleeding Episode

End point description

Subject's assessment of the response to the first rFVIIIFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent; good; moderate; no response. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 evaluable bleeding episode; based on the number of injections with an evaluation.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	63 ^[26]	19 ^[27]	23 ^[28]
Units: percentage of responses
number (not applicable)
Excellent or Good	79.7	64	80.2
Excellent	33.7	18	30.8
Good	46	46.1	49.3
Moderate	18.8	34.8	19.6
No Response	1.5	1.1	0.2

Notes
[26] - Number of bleeding episodes analyzed=202
[27] - Number of bleeding episodes analyzed=89
[28] - Number of bleeding episodes analyzed=454

No statistical analyses for this end point

Secondary: Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection

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End point title

Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection

End point description

The investigator was given the opportunity to record an assessment of a subject’s response to treatment, if the subject was treated in the hospital for a major bleed, using the following 4-point scale: excellent; good; moderate; no response.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	0 ^[29]	0 ^[30]	0 ^[31]
Units: percentage of responses
number (not applicable)

Notes
[29] - This supplemental assessment was not summarized because of insufficient data.
[30] - This supplemental assessment was not summarized because of insufficient data.
[31] - This supplemental assessment was not summarized because of insufficient data.

No statistical analyses for this end point

Secondary: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

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End point title

Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

End point description

Annualized bleeding episodes = (Number of bleeding episodes at the specified location / number of days in efficacy period) x 365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation were not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with evaluable data.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	117	23	23
Units: episodes per subject per year
median (inter-quartile range (Q1-Q3))
Joint	0 (0 to 3.11)	1.93 (0 to 7.62)	22.76 (15.07 to 39.02)
Muscle	0 (0 to 0)	0 (0 to 2.01)	5.57 (1.86 to 10.05)
Internal	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)
Soft Tissue	0 (0 to 0)	0 (0 to 0)	0 (0 to 1.86)
Skin/Mucosa	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

No statistical analyses for this end point

Secondary: Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

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End point title

Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

End point description

Annualized bleeding episodes = (Number of bleeding episodes of the specified type / number of days in efficacy period) x 365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation were not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with evaluable data.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	117	23	23
Units: bleeding episodes per subject per year
median (inter-quartile range (Q1-Q3))
Spontaneous	0 (0 to 1.73)	0 (0 to 3.81)	18.59 (7.59 to 29.59)
Traumatic	0 (0 to 1.16)	0 (0 to 2.01)	3.93 (0 to 8.56)
Unknown	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

No statistical analyses for this end point

Secondary: Number of Days From Last Treatment Injection to a New Bleeding Episode

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End point title

Number of Days From Last Treatment Injection to a New Bleeding Episode

End point description

Number of days from the last injection to treat a bleeding episode to a new bleeding episode, analyzed for per evaluable bleeding episode and per subject. For “per subject” values, number of days from last injection to treat a bleed to a new bleeding episode is averaged across all evaluable bleeding episodes for each subject first, and then descriptive statistics were calculated across subjects. A follow-up injection administered >72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (not evaluable). Please see the endpoint "Annualized Bleeding Rate" for a definition of the efficacy period. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 evaluable bleeding episode. The first bleed for each subject could not be included in this analysis since there was no previous bleed from which to measure time.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description).

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	48 ^[32]	12 ^[33]	23 ^[34]
Units: days
median (inter-quartile range (Q1-Q3))
Per bleeding episode	19.83 (8.58 to 55.46)	8 (5.35 to 15.38)	6.55 (4.46 to 10.27)
Per subject	42.9 (20.25 to 65.93)	40.71 (11.75 to 52.39)	10.12 (7.42 to 16.37)

Notes
[32] - Number of evaluable bleeding episodes analyzed=149
[33] - Number of evaluable bleeding episodes analyzed=76
[34] - Number of evaluable bleeding episodes analyzed=430

No statistical analyses for this end point

Secondary: Number of Injections Required for Resolution of a Bleeding Episode

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End point title

Number of Injections Required for Resolution of a Bleeding Episode

End point description

A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 bleeding episode.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	64 ^[35]	19 ^[36]	23 ^[37]
Units: injections
median (inter-quartile range (Q1-Q3))
Per bleeding episode	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
Per subject	1 (1 to 1.33)	1 (1 to 1.43)	1.03 (1 to 1.17)

Notes
[35] - Number of bleeding episodes analyzed=209
[36] - Number of bleeding episodes analyzed=92
[37] - Number of bleeding episodes analyzed=456

No statistical analyses for this end point

Secondary: Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

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End point title

Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

End point description

Please see previous Endpoint for a definition of the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window were counted. The resolution of a bleed was defined as no sign of bleeding following injection for the bleed. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for the number of injections to resolve that bleeding episode but are included in summaries for each location. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had evaluable efficacy assessments; n=total number of bleeds at given location.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	64	19	23
Units: injections
median (inter-quartile range (Q1-Q3))
Joint; n=151, 67, 366	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
Muscle; n=35, 23, 82	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
Soft Tissue; n=24, 5, 25	1 (1 to 1)	1 (1 to 2)	1 (1 to 1)
Internal; n=3, 2, 6	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
Skin/Mucosa; n=11, 6, 8	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)

No statistical analyses for this end point

Secondary: Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

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End point title

Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

End point description

For each bleeding episode at one location, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. Please see the above Endpoint for a definition of the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for dose administered to resolve that bleeding episode but are included in the individual summaries for each location. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had complete information on the dose administered to treat a bleeding episode; n=total number of bleeding episodes at this location.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	63	19	23
Units: IU/kg
median (inter-quartile range (Q1-Q3))
Joint; n=151, 67, 366	29.69 (24.1 to 53.44)	28.23 (20.16 to 40.32)	27.35 (22.73 to 39.22)
Muscle; n=35, 23, 82	40.98 (26.79 to 53.1)	32.12 (26.98 to 32.47)	27.78 (23.47 to 31.01)
Soft Tissue; n=23, 5, 25	30.6 (24.51 to 53.13)	51.88 (20.16 to 54.88)	27.78 (23.44 to 31.45)
Internal; n=3, 2, 6	32.63 (23.39 to 51.72)	58.4 (48.08 to 68.73)	32.54 (30 to 49.18)
Skin/Mucosa; n=11, 6, 8	33.9 (28.23 to 53.19)	28.34 (21.65 to 44.35)	21.37 (19.95 to 25.16)

No statistical analyses for this end point

Secondary: Volume at Steady State (Vss; One-stage Clotting Assay)

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End point title

Volume at Steady State (Vss; One-stage Clotting Assay)

End point description

Volume of distribution at steady state. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[38]
Units: mL/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	49.1 (46.6 to 51.7)
Advate	51.2 (47.2 to 55.5)

Notes
[38] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Volume at Steady State (Vss; Two-stage Chromogenic Assay)

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End point title

Volume at Steady State (Vss; Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[39]
Units: mL/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	52.6 (47.4 to 58.3)
Advate	56.8 (51.5 to 62.7)

Notes
[39] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

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End point title

Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

End point description

Estimated time after dose (in days) when FVIII activity has declined to approximately 1 or 3 IU/dL (1% or 3%) above baseline, respectively. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[40]
Units: days
geometric mean (confidence interval 95%)
Advate: Time 1%	3.298 (2.985 to 3.645)
Advate: Time 3%	2.478 (2.242 to 2.738)
rFVIIIFc Baseline: Time 1%	4.918 (4.434 to 5.455)
rFVIIIFc Baseline: Time 3%	3.707 (3.325 to 4.133)

Notes
[40] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

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End point title

Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[41]
Units: days
geometric mean (confidence interval 95%)
Advate: Time 1%	3.22 (2.97 to 3.491)
Advate: Time 3%	2.306 (2.12 to 2.509)
rFVIIIFc Baseline: Time 1%	5.01 (4.525 to 5.548)
rFVIIIFc Baseline: Time 3%	3.612 (3.25 to 4.015)

Notes
[41] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Time at Maximum Activity (Tmax; One-stage Clotting Assay)

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End point title

Time at Maximum Activity (Tmax; One-stage Clotting Assay)

End point description

Time at which maximum activity (Cmax) is observed. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	28 ^[42]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	0.49 (0.37 to 0.63)
Advate	0.48 (0.33 to 0.68)

Notes
[42] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

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End point title

Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

End point description

Time at which the maximum activity (Cmax) is observed. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[43]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	0.55 (0.41 to 0.75)
Advate	0.46 (0.35 to 0.61)

Notes
[43] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

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End point title

Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[44]
Units: IU*h/dL per IU/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	47.45 (41.55 to 54.18)
Advate	28.05 (24.85 to 31.65)

Notes
[44] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

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End point title

Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[45]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	20.89 (18.23 to 23.93)
Advate	13.67 (12.31 to 15.18)

Notes
[45] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Clearance (CL; Two-stage Chromogenic Assay)

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End point title

Clearance (CL; Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[46]
Units: mL/h/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	2.108 (1.846 to 2.407)
Advate	3.566 (3.159 to 4.024)

Notes
[46] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Mean Residence Time (MRT; Two-stage Chromogenic Assay)

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End point title

Mean Residence Time (MRT; Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[47]
Units: hours
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	24.96 (22.41 to 27.8)
Advate	15.94 (14.7 to 17.27)

Notes
[47] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Incremental Recovery (Two-stage Chromogenic Assay)

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End point title

Incremental Recovery (Two-stage Chromogenic Assay)

End point description

End point type

Secondary

End point timeframe

See endpoint description for complete time frame.

End point values	Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
Number of subjects analysed	27 ^[48]
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)
rFVIIIFc Baseline	2.4912 (2.2762 to 2.7265)
Advate	2.5589 (2.3247 to 2.8168)

Notes
[48] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

No statistical analyses for this end point

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

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End point title

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 ^[49]

End point description

The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult subjects (17 years and older). The 10 domains are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (time frame for all 7 domains, during the last month) and future, family planning, and outlook for the future (time frame for all 3 domains, recently). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100. Subjects in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on demand). Full Analysis Set: subjects over 17 years of age who received at least 1 dose of rFVIIIFc and had an assessment; n=subjects who had specified assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 14

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For this endpoint, the Individualized Prophylaxis arm (Arm 1) is broken down by the subject's prestudy treatment regimen (either Prestudy Prophylaxis or Prestudy On-demand). Both are presented here.

End point values	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing	Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis	Arm 1: Individualized Prophylaxis, Prestudy On-demand
Number of subjects analysed	15	17	69	22
Units: units on a scale
median (full range (min-max))
Total Score; n=57, 17, 14, 14	-4.73 (-30.5 to 3.2)	-2.09 (-25.1 to 5.4)	-2.18 (-25 to 20.9)	-1.48 (-28.6 to 5.1)
Physical Health; n=68, 22, 15, 17	-10 (-40 to 10)	0 (-55 to 40)	-5 (-70 to 75)	-12.5 (-42.5 to 45)
Feeling; n=68, 22, 15, 17	-6.25 (-50 to 6.3)	-6.25 (-37.5 to 6.3)	0 (-43.8 to 43.8)	-6.25 (-37.5 to 12.5)
View of Yourself; n=68, 22, 15, 17	0 (-30 to 15)	-5 (-40 to 20)	0 (-70 to 25)	5 (-30 to 25)
Sports and Leisure; n=48, 12, 12, 8	-10 (-30 to 0)	-2.5 (-30 to 15)	0 (-55 to 40)	-2.5 (-25 to 18.8)
Work and School; n=53, 17,13, 14	0 (-31.3 to 39.6)	0 (-58.3 to 12.5)	-6.25 (-56.3 to 25)	-6.25 (-37.5 to 25)
Dealing with Hemophilia; n=65, 22, 15, 17	0 (-25 to 41.7)	0 (-50 to 100)	0 (-33.3 to 50)	0 (-25 to 16.7)
Treatment; n=68, 21, 15, 16	-3.13 (-31.3 to 18.8)	0 (-21.9 to 18.8)	-3.13 (-37.1 to 21.9)	-3.13 (-43.8 to 31.3)
Future; n=66, 21, 15, 17	-5 (-35 to 15)	-5 (-55 to 25)	2.5 (-35 to 25)	0 (-30 to 55)
Family Planning; n=38, 10, 8, 7	0 (-50 to 8.3)	-2.08 (-31.3 to 0)	0 (-31.3 to 18.8)	0 (-18.8 to 31.3)
Partnership and Sexuality; n=62, 20, 15, 17	0 (-41.7 to 0)	0 (-100 to 25)	0 (-25 to 41.7)	0 (-25 to 58.3)

No statistical analyses for this end point

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28

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End point title

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 ^[50]

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For this endpoint, the Individualized Prophylaxis arm (Arm 1) is broken down by the subject's prestudy treatment regimen (either Prestudy Prophylaxis or Prestudy On-demand). Both are presented here.

End point values	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing	Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis	Arm 1: Individualized Prophylaxis, Prestudy On-demand
Number of subjects analysed	3	7	42	17
Units: units on a scale
median (full range (min-max))
Total Score; n=34, 12, 3, 5	-5.81 (-9.8 to 5.4)	-0.56 (-11.2 to 3.4)	-1.03 (-26.7 to 11.5)	-4.31 (-35.6 to 13.9)
Physical Health; n=40, 17, 3, 7	-5 (-45 to -5)	0 (-15 to 20)	0 (-31.3 to 60)	-25 (-65 to 25)
Feeling; n=40, 17, 3, 7	-6.25 (-18.8 to 6.3)	0 (-12.5 to 18.8)	-3.13 (-50 to 25)	-6.25 (-50 to 18.8)
View of Yourself; n=42, 17, 3, 7	0 (-5 to 5)	0 (-5 to 15)	0 (-40 to 35)	0 (-40 to 20)
Sports and Leisure; n=29, 10, 2, 5	-10 (-25 to 5)	5 (-8.8 to 5)	0 (-68.8 to 45)	-5 (-50 to 5)
Work and School; n=34, 15, 2, 6	-9.38 (-18.8 to 0)	-3.13 (-25 to 6.3)	0 (-50 to 37.5)	-6.25 (-56.3 to 25)
Dealing with Hemophilia; n=40, 17, 3, 7	0 (-16.7 to 25)	0 (-16.7 to 8.3)	0 (-33.3 to 33.3)	0 (-25 to 58.3)
Treatment; n=42, 14, 3, 7	6.25 (-12.5 to 28.1)	0 (-18.8 to 6.3)	0 (-28.1 to 18.8)	-4.69 (-43.8 to 12.5)
Future; n=40, 17, 3, 6	-5 (-20 to -5)	7.5 (-15 to 10)	0 (-45 to 35)	-5 (-45 to 60)
Family Planning; n=19, 10, 2, 2	0 (0 to 0)	9.38 (0 to 18.8)	0 (-25 to 16.7)	0 (-18.8 to 33.3)
Partnership and Sexuality; n=37, 14, 3, 7	0 (-8.3 to 0)	0 (-25 to 8.3)	0 (-25 to 66.7)	0 (-25 to 91.7)

No statistical analyses for this end point

Secondary: Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score

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End point title

Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score

End point description

The Haemo-QoL III, a quality of life assessment instrument for adolescents with hemophilia, was administered to subjects from 13 to 16 years old. This instrument assesses domains specific to living with hemophilia and consists of 12 domains: physical health, feeling, view of yourself, family, friends, others, sports and school, treatment, perceived support, dealing with hemophilia, future, and relationships. Total HAEMO-QoL score is the sum of all raw scores for all subscales for subjects for whom at least the minimum number of required questions have been answered. Total scores are presented as the Transformed Scale Score (TSS) from 0-100%, with lower scores indicating a better quality of life. A negative change indicates improvement. Full Analysis Set: subjects 13 to 16 years of age who received at least 1 dose of rFVIIIFc and had an assessment; n=subjects who had specified assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 14, Week 28

End point values	Arm 1: Individualized (Tailored) Prophylaxis	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Number of subjects analysed	8	0 ^[51]	2 ^[52]
Units: units on a scale
median (full range (min-max))
Baseline; n=8, 0, 2	11.2 (-6.2 to -1.3)	( to )	26.3 (16.2 to 36.4)
Change from Baseline at Week 14; n=8, 0, 1	-3.25 (6.5 to 38.3)	( to )	-5.01 (-5.01 to -5.01)
Change from Baseline at Week 28; n=4, 0, 0	-3.73 (-21.9 to 2.3)	( to )	0 (0 to 0)

Notes
[51] - No subjects had an assessment for this reporting group.
[52] - All values of '0' for Week 28 are actually 'NA', since there were no subjects analyzed.

No statistical analyses for this end point

Secondary: Investigators'/Surgeons' Assessment of Subjects' Response to rFVIIIFc for Major Surgery

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End point title

Investigators'/Surgeons' Assessment of Subjects' Response to rFVIIIFc for Major Surgery

End point description

Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.

End point type

Secondary

End point timeframe

up to 52 weeks

End point values	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	9 ^[53]
Units: responses
Excellent or Good	9
Excellent	8
Good	1
Fair	0
Poor/None	0

Notes
[53] - Number of major surgeries analyzed=9

No statistical analyses for this end point

Secondary: Number of Injections Required to Maintain Hemostasis During Major Surgery

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End point title

Number of Injections Required to Maintain Hemostasis During Major Surgery

End point description

The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes, including from the loading dose to the end date/time of surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.

End point type

Secondary

End point timeframe

up to 52 weeks

End point values	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	9 ^[54]
Units: injections
median (full range (min-max))	1 (1 to 1)

Notes
[54] - Number of major surgeries analyzed=9

No statistical analyses for this end point

Secondary: Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery

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End point title

Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery

End point description

Mean dose per injection is the average dose for all injections (including loading dose) needed to maintain hemostasis during surgery. Total dose is the sum across all injections (including loading dose) needed to maintain hemostasis during surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks

End point values	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	9 ^[55]
Units: IU/kg
median (full range (min-max))
Dose per Injection	51.4 (50 to 77)
Total Dose	51.4 (50 to 77)

Notes
[55] - Number of major surgeries analyzed=9

No statistical analyses for this end point

Secondary: Estimated Total Blood Loss During Major Surgery

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End point title

Estimated Total Blood Loss During Major Surgery

End point description

Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc, underwent major surgery, and had blood loss during surgery information available.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks

End point values	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	9 ^[56]
Units: mL
median (full range (min-max))	15 (0 to 600)

Notes
[56] - Number of major surgeries analyzed=7

No statistical analyses for this end point

Secondary: Number of Transfusions Required Per Surgery

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End point title

Number of Transfusions Required Per Surgery

End point description

Number of blood component transfusions during a single surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.

End point type

Secondary

End point timeframe

up to 52 weeks ± 2 weeks

End point values	Any Arm: Perioperative Management (Surgery) Subgroup
Number of subjects analysed	9 ^[57]
Units: surgeries
0 transfusions	8
1 transfusion	0
2 transfusions	1
3 transfusions	0
> 3 transfusions	0

Notes
[57] - Number of major surgeries analyzed=9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

up to 52 weeks + 30 days ± 1 week

Adverse event reporting additional description

Based on subjects treated with rFVIIIFc in each arm. One subject in Individualized (Tailored) Prophylaxis arm received only Advate and was not included in the treatment-emergent AE table. Does not include SAEs emergent during surgical/rehabilitation period (see Endpoint 2 for a summary of treatment-emergent events for this subgroup).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc

Reporting group description

Initial twice weekly dosing with 25 IU/kg of rFVIIIFc via IV injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days to maintain a trough level of 1% to 3% (or higher, as clinically indicated) rFVIIIFc activity. Prior to rFVIIIFc treatment, on rFVIIIFc Day 0, all subjects underwent PK analysis with rFVIIIFc in order to estimate subject's PK parameters and guide the appropriate dose or interval of dosing. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. A subset of subjects (Sequential PK Subgroup) also had PK profiling performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout from Advate or any other FVIII product was performed before the first PK dose of rFVIIIFc was administered.

Reporting group title

Arm 2: Weekly Prophylaxis

Reporting group description

65 IU/kg of rFVIIIFc via IV injection every 7 days

Reporting group title

Arm 3: Episodic (On-Demand) Dosing

Reporting group description

Initial single dose of 50 IU/kg of rFVIIIFc via IV injection followed by 10 to 50 IU/kg rFVIIIFc, as required to treat a bleeding episode.

Serious adverse events	Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 117 (8.55%)	2 / 24 (8.33%)	0 / 23 (0.00%)
number of deaths (all causes)	1	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Face injury
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 117 (0.00%)	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Vascular disorders
Hypertensive emergency
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Restless legs syndrome
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth disorder
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory distress
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 117 (0.00%)	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 117 (0.85%)	0 / 24 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc	Arm 2: Weekly Prophylaxis	Arm 3: Episodic (On-Demand) Dosing
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 117 (27.35%)	8 / 24 (33.33%)	7 / 23 (30.43%)
Nervous system disorders
Headache
subjects affected / exposed	5 / 117 (4.27%)	6 / 24 (25.00%)	2 / 23 (8.70%)
occurrences all number	6	7	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	10 / 117 (8.55%)	2 / 24 (8.33%)	1 / 23 (4.35%)
occurrences all number	11	3	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	16 / 117 (13.68%)	1 / 24 (4.17%)	3 / 23 (13.04%)
occurrences all number	24	1	3
Upper respiratory tract infection
subjects affected / exposed	6 / 117 (5.13%)	0 / 24 (0.00%)	3 / 23 (13.04%)
occurrences all number	7	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

13 Jun 2011

- The required washout period from any FVIII product before collecting blood samples for PK assessment was reduced from 96 hours to 72 hours for adolescent subjects. - The inclusion criteria defining the cut-off value in international normalized ratio (INR) was removed. - Exclusion Criterion #1 was amended to define a positive inhibitor value.

02 Apr 2012

- The end-of-study definition was further clarified. - The criteria for recommending a modification of dose or dosing interval for subjects in Arm 1 were clarified.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/25196897
http://www.ncbi.nlm.nih.gov/pubmed/24227821

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Clinical trials

Clinical Trial Results: A-LONG: An Open-label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence Rate of FVIII Inhibitor Development

Primary: Incidence Rate of FVIII Inhibitor Development

Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Primary: Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

Primary: Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

Primary: Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

Primary: Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

Primary: Annualized Bleeding Rate

Primary: Annualized Bleeding Rate

Primary: Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

Primary: Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

Primary: Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

Primary: Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

Primary: Elimination Half Life (t1/2; One-stage Clotting Assay)

Primary: Elimination Half Life (t1/2; One-stage Clotting Assay)

Primary: Clearance (CL; One-stage Clotting Assay)

Primary: Clearance (CL; One-stage Clotting Assay)

Primary: Mean Residence Time (MRT; One-stage Clotting Assay)

Primary: Mean Residence Time (MRT; One-stage Clotting Assay)

Primary: Incremental Recovery (One-stage Clotting Assay)

Primary: Incremental Recovery (One-stage Clotting Assay)

Secondary: Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

Secondary: Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

Secondary: Annualized rFVIIIFc Consumption Per Subject

Secondary: Annualized rFVIIIFc Consumption Per Subject

Secondary: Subject Assessment of Response to Injections to Treat a Bleeding Episode

Secondary: Subject Assessment of Response to Injections to Treat a Bleeding Episode

Secondary: Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection

Secondary: Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection

Secondary: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

Secondary: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

Secondary: Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

Secondary: Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

Secondary: Number of Days From Last Treatment Injection to a New Bleeding Episode

Secondary: Number of Days From Last Treatment Injection to a New Bleeding Episode

Secondary: Number of Injections Required for Resolution of a Bleeding Episode

Secondary: Number of Injections Required for Resolution of a Bleeding Episode

Secondary: Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

Secondary: Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

Secondary: Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

Secondary: Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

Secondary: Volume at Steady State (Vss; One-stage Clotting Assay)

Secondary: Volume at Steady State (Vss; One-stage Clotting Assay)

Secondary: Volume at Steady State (Vss; Two-stage Chromogenic Assay)

Secondary: Volume at Steady State (Vss; Two-stage Chromogenic Assay)

Secondary: Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

Secondary: Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

Secondary: Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

Secondary: Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

Secondary: Time at Maximum Activity (Tmax; One-stage Clotting Assay)

Secondary: Time at Maximum Activity (Tmax; One-stage Clotting Assay)

Secondary: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

Secondary: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

Secondary: Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

Secondary: Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

Secondary: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

Secondary: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

Secondary: Clearance (CL; Two-stage Chromogenic Assay)

Secondary: Clearance (CL; Two-stage Chromogenic Assay)

Secondary: Mean Residence Time (MRT; Two-stage Chromogenic Assay)

Secondary: Mean Residence Time (MRT; Two-stage Chromogenic Assay)

Secondary: Incremental Recovery (Two-stage Chromogenic Assay)

Secondary: Incremental Recovery (Two-stage Chromogenic Assay)

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28

Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28

Secondary: Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score

Secondary: Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score

Clinical Trial Results:
A-LONG: An Open-label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A