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Trial record 47 of 397 for:    bleeding episodes

Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

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ClinicalTrials.gov Identifier: NCT01181128
Recruitment Status : Completed
First Posted : August 13, 2010
Results First Posted : August 29, 2014
Last Update Posted : August 18, 2017
Sponsor:
Collaborator:
Swedish Orphan Biovitrum
Information provided by (Responsible Party):
Bioverativ Therapeutics Inc.

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Severe Hemophilia A
Interventions Drug: Factor VIII (rFVIIIFc)
Drug: Advate®
Enrollment 165
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Period Title: Overall Study
Started 118 24 23
Pharmacokinetic (PK) Subgroup 30 0 0
Perioperative Management Subgroup 8 [1] 1 [1] 0 [1]
Completed 112 19 22
Not Completed 6 5 1
Reason Not Completed
Withdrawal by Subject             2             2             0
Death             1             0             0
Physician Decision             2             0             0
Adverse Event             0             2             0
Not Specified             1             1             1
[1]
Participants who underwent major surgery.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Total
Hide Arm/Group Description

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode Total of all reporting groups
Overall Number of Baseline Participants 118 24 23 165
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 118 participants 24 participants 23 participants 165 participants
29.0
(12 to 65)
31.5
(18 to 59)
34.0
(13 to 62)
30.0
(12 to 65)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 118 participants 24 participants 23 participants 165 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Male
118
 100.0%
24
 100.0%
23
 100.0%
165
 100.0%
1.Primary Outcome
Title Incidence Rate of FVIII Inhibitor Development
Hide 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 exposure days to rFVIIIFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set: participants who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc; n=number of participants with given number of exposure days who had a valid inhibitor test.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing All Arms: Total
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.
Overall Number of Participants Analyzed 118 24 23 165
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Participants with>=50 EDs; n=107, 1, 2, 110
0
(0.0 to 3.4)
0
(0.0 to 97.5)
0
(0.0 to 84.2)
0
(0.0 to 3.3)
All participants; n=117, 24, 23, 164
0
(0.0 to 3.1)
0
(0.0 to 14.2)
0
(0.0 to 14.8)
0
(0.0 to 2.2)
2.Primary Outcome
Title Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Hide Description AE=any untoward medical occurrence that did not necessarily have a causal relationship with treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. 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. AEs emergent between the first Advate injection and first on-study rFVIIIFc injection (Sequential PK Subgroup) or during the surgical/rehabilitation period (Surgery Subgroup) are presented separately.
Time Frame up to 52 weeks + 30 days ± 1 week
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set: participants who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc. For Arm 1, AEs emergent between 1st on-study Advate dose and 1st rFVIIIFc dose are reported as treatment-emergent to Advate (1st column); AEs emergent after 1st rFVIIIFc injection are reported as treatment-emergent to rFVIIIFc (2nd column).
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis, Advate Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Only Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Any Arm: Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:

Participants underwent pharmacokinetic (PK) analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) and then a single dose of 50 IU/kg rFVIIIFc (rFVIIIFc Day 0) within 8 weeks of the Advate dose. A >= 96 hour washout from Advate or any other FVIII product 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, participants started twice weekly treatment 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, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

On rFVIIIFc Day 0, participants underwent pharmacokinetic (PK) analysis with a single dose of 50 IU/kg rFVIIIFc in order to estimate their PK parameters and guide the appropriate dose or interval of dosing.

After the PK assessment, participants 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 PK analyses, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 30 117 24 23 9
Measure Type: Number
Unit of Measure: participants
>=1 TEAE 3 80 18 10 4
>=1 Related TEAE 0 5 3 2 0
>=1 TESAE 0 10 2 0 2
>=1 Related TESAE 0 0 0 0 0
3.Primary Outcome
Title Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline
Hide 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.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set: participants who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc n=the number of participants with at least one post-baseline value.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 118 24 23
Measure Type: Number
Unit of Measure: participants
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
4.Primary Outcome
Title Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs
Hide Description Number of participants 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.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set: participants who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc and had a baseline assessment and at least one post-baseline assessment for temperature or at least one post-baseline assessment for pulse, systolic blood pressure, and diastolic blood pressure.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 113 24 23
Measure Type: Number
Unit of Measure: participants
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
5.Primary Outcome
Title Annualized Bleeding Rate
Hide 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 117 23 23
Median (Inter-Quartile Range)
Unit of Measure: episodes per participant per year
1.60
(0.00 to 4.69)
3.59
(1.86 to 8.36)
33.57
(21.14 to 48.69)
6.Primary Outcome
Title Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3
Hide Description Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all participants. 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 117 23
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: episodes per participant per year
2.91
(2.30 to 3.68)
37.25
(24.03 to 57.74)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 1: Individualized (Tailored) Prophylaxis, Arm 3: Episodic (On-Demand) Dosing
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Bleeding Rate Ratio
Estimated Value 0.08
Confidence Interval (2-Sided) 95%
0.05 to 0.13
Estimation Comments [Not Specified]
7.Primary Outcome
Title Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU*h/dL per IU/kg
rFVIIIFc Baseline
51.24
(44.97 to 58.38)
Advate
32.88
(29.31 to 36.88)
8.Primary Outcome
Title Elimination Half Life (t1/2; One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
18.97
(17.03 to 21.12)
Advate
12.43
(11.14 to 13.86)
9.Primary Outcome
Title Clearance (CL; One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/h/kg
rFVIIIFc Baseline
1.952
(1.713 to 2.224)
Advate
3.041
(2.711 to 3.412)
10.Primary Outcome
Title Mean Residence Time (MRT; One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
25.15
(22.65 to 27.91)
Advate
16.84
(15.22 to 18.63)
11.Primary Outcome
Title Incremental Recovery (One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/dL per IU/kg
rFVIIIFc Baseline
2.2395
(2.1116 to 2.3753)
Advate
2.3516
(2.2110 to 2.5010)
12.Secondary Outcome
Title Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3
Hide Description Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all participants. 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.
Arm/Group Title Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:
65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 23 23
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: episodes per participant per year
8.92
(5.48 to 14.51)
37.25
(24.03 to 57.74)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 2: Weekly Prophylaxis, Arm 3: Episodic (On-Demand) Dosing
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Bleeding Rate Ratio
Estimated Value 0.24
Confidence Interval (2-Sided) 95%
0.12 to 0.46
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Annualized rFVIIIFc Consumption Per Participant
Hide 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc. 'Overall' n=participants in the Full Analysis Set with evaluable data in the efficacy period; 'Last 3 Months on Study' n=participants in the Full Analysis Set with evaluable data and >=6 months on study.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 117 24 23
Mean (Standard Deviation)
Unit of Measure: IU/kg rFVIIIFc per participant per year
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) 1225.80  (848.656)
14.Secondary Outcome
Title Participant Assessment of Response to Injections to Treat a Bleeding Episode
Hide Description Participant'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=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants 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.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 63 19 23
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
202 89 454
Measure Type: Number
Unit of Measure: percentage of responses
Excellent or Good 79.7 64.0 80.2
Excellent 33.7 18.0 30.8
Good 46.0 46.1 49.3
Moderate 18.8 34.8 19.6
No Response 1.5 1.1 0.2
15.Secondary Outcome
Title Investigator’s Assessment of Participants’ Bleeding Response to rFVIIIFc Injection
Hide Description The investigator was given the opportunity to record an assessment of a participant’s response to treatment, if the participant was treated in the hospital for a major bleed, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
This supplemental assessment was not summarized because of insufficient data.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
16.Secondary Outcome
Title Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
Hide 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with evaluable data.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 117 23 23
Median (Inter-Quartile Range)
Unit of Measure: episodes per participant per year
Joint
0.00
(0.00 to 3.11)
1.93
(0.00 to 7.62)
22.76
(15.07 to 39.02)
Muscle
0.00
(0.00 to 0.00)
0.00
(0.00 to 2.01)
5.57
(1.86 to 10.05)
Internal
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
Soft Tissue
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
0.00
(0.00 to 1.86)
Skin/Mucosa
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
17.Secondary Outcome
Title Annualized Joint Bleeding Rate (Spontaneous and Traumatic)
Hide 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with evaluable data.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 117 23 23
Median (Inter-Quartile Range)
Unit of Measure: bleeding episodes per participant per yr
Spontaneous
0.00
(0.00 to 1.73)
0.00
(0.00 to 3.81)
18.59
(7.59 to 29.59)
Traumatic
0.00
(0.00 to 1.16)
0.00
(0.00 to 2.01)
3.93
(0.00 to 8.56)
Unknown
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
18.Secondary Outcome
Title Number of Days From Last Treatment Injection to a New Bleeding Episode
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc and had at least 1 evaluable bleeding episode. The first bleed for each participant could not be included in this analysis since there was no previous bleed from which to measure time.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 48 12 23
Overall Number of Units Analyzed
Type of Units Analyzed: Evaluable Bleeding Episodes
149 76 430
Median (Inter-Quartile Range)
Unit of Measure: days
Per Bleeding Episode
19.83
(8.58 to 55.46)
8.00
(5.35 to 15.38)
6.55
(4.46 to 10.27)
Per Participant
42.90
(20.25 to 65.93)
40.71
(11.75 to 52.39)
10.12
(7.42 to 16.37)
19.Secondary Outcome
Title Number of Injections Required for Resolution of a Bleeding Episode
Hide 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc and had at least 1 bleeding episode.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 64 19 23
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
209 92 456
Median (Inter-Quartile Range)
Unit of Measure: injections
Per Bleeding Episode
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
Per Participant
1.00
(1.00 to 1.33)
1.00
(1.00 to 1.43)
1.03
(1.00 to 1.17)
20.Secondary Outcome
Title Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
Hide Description Please see Outcome Measure 20 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants who received at least 1 dose of rFVIIIFc and had evaluable efficacy assessments; n=total number of bleeds at given location.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 64 19 23
Median (Inter-Quartile Range)
Unit of Measure: injections
Joint (n=151, 67, 366)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
Muscle (n=35, 23, 82)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
Soft Tissue (n=24, 5, 25)
1.0
(1.0 to 1.0)
1.0
(1.0 to 2.0)
1.0
(1.0 to 1.0)
Internal (n=3, 2, 6)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
Skin/Mucosa (n=11, 6, 8)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
21.Secondary Outcome
Title Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
Hide 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 Outcome Measure 20 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.
Time Frame up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants 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.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 63 19 23
Median (Inter-Quartile Range)
Unit of Measure: IU/kg
Joint (n=151, 67, 366)
29.69
(24.10 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 53.10)
32.12
(26.98 to 32.47)
27.78
(23.47 to 31.01)
Soft Tissue (n=23, 5, 25)
30.60
(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)
58.40
(48.08 to 68.73)
32.54
(30.00 to 49.18)
Skin/Mucosa (n=11, 6, 8)
33.90
(28.23 to 53.19)
28.34
(21.65 to 44.35)
21.37
(19.95 to 25.16)
22.Secondary Outcome
Title Volume at Steady State (Vss; One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/kg
rFVIIIFc Baseline
49.1
(46.6 to 51.7)
Advate
51.2
(47.2 to 55.5)
23.Secondary Outcome
Title Volume at Steady State (Vss; Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/kg
rFVIIIFc Baseline
52.6
(47.4 to 58.3)
Advate
56.8
(51.5 to 62.7)
24.Secondary Outcome
Title Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: days
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)
25.Secondary Outcome
Title Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: days
Advate: Time 1%
3.220
(2.970 to 3.491)
Advate: Time 3%
2.306
(2.120 to 2.509)
rFVIIIFc Baseline: Time 1%
5.010
(4.525 to 5.548)
rFVIIIFc Baseline: Time 3%
3.612
(3.250 to 4.015)
26.Secondary Outcome
Title Time at Maximum Activity (Tmax; One-stage Clotting Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 28
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
0.49
(0.37 to 0.63)
Advate
0.48
(0.33 to 0.68)
27.Secondary Outcome
Title Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
0.55
(0.41 to 0.75)
Advate
0.46
(0.35 to 0.61)
28.Secondary Outcome
Title Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU*h/dL per IU/kg
rFVIIIFc Baseline
47.45
(41.55 to 54.18)
Advate
28.05
(24.85 to 31.65)
29.Secondary Outcome
Title Elimination Half Life (t1/2; Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
20.89
(18.23 to 23.93)
Advate
13.67
(12.31 to 15.18)
30.Secondary Outcome
Title Clearance (CL; Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/h/kg
rFVIIIFc Baseline
2.108
(1.846 to 2.407)
Advate
3.566
(3.159 to 4.024)
31.Secondary Outcome
Title Mean Residence Time (MRT; Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
rFVIIIFc Baseline
24.96
(22.41 to 27.80)
Advate
15.94
(14.70 to 17.27)
32.Secondary Outcome
Title Incremental Recovery (Two-stage Chromogenic Assay)
Hide 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.
Time Frame See Measure Description for complete time frame.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
Arm/Group Title Individualized (Tailored) Prophylaxis: Sequential PK Subgroup
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

Overall Number of Participants Analyzed 27
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/dL per IU/kg
rFVIIIFc Baseline
2.4912
(2.2762 to 2.7265)
Advate
2.5589
(2.3247 to 2.8168)
33.Secondary Outcome
Title Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14
Hide Description The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (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. Participants in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on-demand).
Time Frame Baseline, Week 14
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants over 17 years of age who received at least 1 dose of rFVIIIFc and had an assessment. n=participants who had specified assessment at given timepoint.
Arm/Group Title Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis Arm 1: Individualized Prophylaxis, Prestudy On-demand Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 69 22 15 17
Median (Full Range)
Unit of Measure: units on a scale
Total Score (n=57, 17, 14, 14)
-2.18
(-25.0 to 20.9)
-1.48
(-28.6 to 5.1)
-4.73
(-30.5 to 3.2)
-2.09
(-25.1 to 5.4)
Physical Health (n=68, 22, 15, 17)
-5.00
(-70.0 to 75.0)
-12.50
(-42.5 to 45.0)
-10.0
(-40.0 to 10.0)
0.00
(-55.0 to 40.0)
Feeling (n=68, 22, 15, 17)
0.00
(-43.8 to 43.8)
-6.25
(-37.5 to 12.5)
-6.25
(-50.0 to 6.3)
-6.25
(-37.5 to 6.3)
View of Yourself (n=68, 22, 15, 17)
0.00
(-70.0 to 25.0)
5.00
(-30.0 to 25.0)
0.00
(-30.0 to 15.0)
-5.00
(-40.0 to 20.0)
Sports and Leisure (n=48, 12, 12, 8)
0.00
(-55.0 to 40.0)
-2.50
(-25.0 to 18.8)
-10.0
(-30.0 to 0.0)
-2.50
(-30.0 to 15.0)
Work and School (n=53, 17,13, 14)
-6.25
(-56.3 to 25.0)
-6.25
(-37.5 to 25.0)
0.00
(-31.3 to 39.6)
0.00
(-58.3 to 12.5)
Dealing with Hemophilia (n=65, 22, 15, 17)
0.00
(-33.3 to 50.0)
0.00
(-25.0 to 16.7)
0.00
(-25.0 to 41.7)
0.00
(-50.0 to 100.0)
Treatment (n=68, 21, 15, 16)
-3.13
(-37.1 to 21.9)
-3.13
(-43.8 to 31.3)
-3.13
(-31.3 to 18.8)
0.00
(-21.9 to 18.8)
Future (n=66, 21, 15, 17)
2.50
(-35.0 to 25.0)
0.00
(-30.0 to 55.0)
-5.00
(-35.0 to 15.0)
-5.00
(-55.0 to 25.0)
Family Planning (n=38, 10, 8, 7)
0.00
(-31.3 to 18.8)
0.00
(-18.8 to 31.3)
0.00
(-50.0 to 8.3)
-2.08
(-31.3 to 0.0)
Partnership and Sexuality (n=62, 20, 15, 17)
0.00
(-25.0 to 41.7)
0.00
(-25.0 to 58.3)
0.00
(-41.7 to 0.0)
0.00
(-100.0 to 25.0)
34.Secondary Outcome
Title Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28
Hide Description The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (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. Participants in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on-demand).
Time Frame Baseline, Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants over 17 years of age who received at least 1 dose of rFVIIIFc and had an assessment. n=participants who had specified assessment at given timepoint.
Arm/Group Title Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis Arm 1: Individualized Prophylaxis, Prestudy On-demand Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 42 17 3 7
Median (Full Range)
Unit of Measure: units on a scale
Total Score (n=34, 12, 3, 5)
-1.03
(-26.7 to 11.5)
-4.31
(-35.6 to 13.9)
-5.81
(-9.8 to 5.4)
-0.56
(-11.2 to 3.4)
Physical Health (n=40, 17, 3, 7)
0.00
(-31.3 to 60.0)
-25.00
(-65.0 to 25.0)
-5.00
(-45.0 to -5.0)
0.00
(-15.0 to 20.0)
Feeling (n=40, 17, 3, 7)
-3.13
(-50.0 to 25.0)
-6.25
(-50.0 to 18.8)
-6.25
(-18.8 to 6.3)
0.00
(-12.5 to 18.8)
View of Yourself (n=42, 17, 3, 7)
0.00
(-40.0 to 35.0)
0.00
(-40.0 to 20.0)
0.00
(-5.0 to 5.0)
0.00
(-5.0 to 15.0)
Sports and Leisure (n=29, 10, 2, 5)
0.00
(-68.8 to 45.0)
-5.00
(-50.0 to 5.0)
-10.0
(-25.0 to 5.0)
5.00
(-8.8 to 5.0)
Work and School (n=34, 15, 2, 6)
0.00
(-50.0 to 37.5)
-6.25
(-56.3 to 25.0)
-9.38
(-18.8 to 0.0)
-3.13
(-25.0 to 6.3)
Dealing with Hemophilia (n=40, 17, 3, 7)
0.00
(-33.3 to 33.3)
0.00
(-25.0 to 58.3)
0.00
(-16.7 to 25.0)
0.00
(-16.7 to 8.3)
Treatment (n=42, 14, 3, 7)
0.00
(-28.1 to 18.8)
-4.69
(-43.8 to 12.5)
6.25
(-12.5 to 28.1)
0.00
(-18.8 to 6.3)
Future (n=40, 17, 3, 6)
0.00
(-45.0 to 35.0)
-5.00
(-45.0 to 60.0)
-5.00
(-20.0 to -5.0)
7.50
(-15.0 to 10.0)
Family Planning (n=19, 10, 2, 2)
0.00
(-25.0 to 16.7)
0.00
(-18.8 to 33.3)
0.00
(0.0 to 0.0)
9.38
(0.0 to 18.8)
Partnership and Sexuality (n=37, 14, 3, 7)
0.00
(-25.0 to 66.7)
0.00
(-25.0 to 91.7)
0.00
(-8.3 to 0.0)
0.00
(-25.0 to 8.3)
35.Secondary Outcome
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
Hide Description The Haemo-QoL III, a quality of life assessment instrument for adolescents with hemophilia, was administered to participants 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 participants 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.
Time Frame Baseline, Week 14, Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: participants 13 to 16 years of age who received at least 1 dose of rFVIIIFc and had an assessment. n=participants who had specified assessment at given timepoint.
Arm/Group Title Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
Hide Arm/Group Description:

On rFVIIIFc Day 0, all participants 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 participants (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 participants 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.

65 IU/kg of rFVIIIFc via IV injection every 7 days
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Number of Participants Analyzed 8 0 2
Median (Full Range)
Unit of Measure: units on a scale
Baseline (n=8, 0, 2)
11.20
(6.5 to 38.3)
26.30
(16.2 to 36.4)
Change from Baseline at Week 14 (n=8, 0, 1)
-3.25
(-21.9 to 2.3)
-5.01
(-5.01 to -5.01)
Change from Baseline at Week 28 (n=4, 0, 0)
-3.73
(-6.2 to -1.3)
NA [1] 
(NA to NA)
[1]
n=0 for this timepoint
36.Secondary Outcome
Title Investigators’/Surgeons’ Assessment of Participants’ Response to rFVIIIFc for Major Surgery
Hide 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.
Time Frame up to 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.
Arm/Group Title Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 9
Overall Number of Units Analyzed
Type of Units Analyzed: Major Surgeries
9
Measure Type: Number
Unit of Measure: responses
Excellent or Good 9
Excellent 8
Good 1
Fair 0
Poor/None 0
37.Secondary Outcome
Title Number of Injections Required to Maintain Hemostasis During Major Surgery
Hide 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.
Time Frame up to 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.
Arm/Group Title Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 9
Overall Number of Units Analyzed
Type of Units Analyzed: Major Surgeries
9
Median (Full Range)
Unit of Measure: injections
1.0
(1 to 1)
38.Secondary Outcome
Title Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
Hide 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.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.
Arm/Group Title Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 9
Overall Number of Units Analyzed
Type of Units Analyzed: Major Surgeries
9
Median (Full Range)
Unit of Measure: IU/kg
Dose per Injection
51.4
(50 to 77)
Total Dose
51.4
(50 to 77)
39.Secondary Outcome
Title Estimated Total Blood Loss During Major Surgery
Hide Description [Not Specified]
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc, underwent major surgery, and had blood loss during surgery information available.
Arm/Group Title Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 9
Overall Number of Units Analyzed
Type of Units Analyzed: Major Surgeries
7
Median (Full Range)
Unit of Measure: mL
15.0
(0 to 600)
40.Secondary Outcome
Title Number of Transfusions Required Per Surgery
Hide Description Number of blood component transfusions during a single surgery.
Time Frame up to 52 weeks ± 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.
Arm/Group Title Perioperative Management (Surgery) Subgroup
Hide Arm/Group Description:
Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Overall Number of Participants Analyzed 9
Overall Number of Units Analyzed
Type of Units Analyzed: Major Surgeries
9
Measure Type: Number
Unit of Measure: surgeries
0 transfusions 8
1 transfusion 0
2 transfusions 1
3 transfusions 0
> 3 transfusions 0
Time Frame up to 52 weeks + 30 days ± 1 week
Adverse Event Reporting Description Based on participants treated with rFVIIIFc in each arm. One participant 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 Outcome Measure 2 for a summary of treatment-emergent events for this subgroup).
 
Arm/Group Title Individualized (Tailored) Prophylaxis, rFVIIIFc Weekly Prophylaxis Episodic (On-Demand) Dosing
Hide Arm/Group Description

Initial twice weekly dosing 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 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 participants underwent pharmacokinetic (PK) analysis with rFVIIIFc in order to estimate participant'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 participants (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.

65 IU/kg of rFVIIIFc via IV injection every 7 days 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
All-Cause Mortality
Individualized (Tailored) Prophylaxis, rFVIIIFc Weekly Prophylaxis Episodic (On-Demand) Dosing
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Individualized (Tailored) Prophylaxis, rFVIIIFc Weekly Prophylaxis Episodic (On-Demand) Dosing
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/117 (8.55%)   2/24 (8.33%)   0/23 (0.00%) 
Cardiac disorders       
Tachycardia  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Gastrointestinal disorders       
Inguinal hernia  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Tooth disorder  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Injury, poisoning and procedural complications       
Face injury  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Femur fracture  1  0/117 (0.00%)  1/24 (4.17%)  0/23 (0.00%) 
Overdose  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Haemarthrosis  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Lumbar spinal stenosis  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Myalgia  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Nervous system disorders       
Restless legs syndrome  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Syncope  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Psychiatric disorders       
Completed suicide  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Renal and urinary disorders       
Nephrolithiasis  1  0/117 (0.00%)  1/24 (4.17%)  0/23 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Respiratory distress  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Vascular disorders       
Hypertensive emergency  1  1/117 (0.85%)  0/24 (0.00%)  0/23 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Individualized (Tailored) Prophylaxis, rFVIIIFc Weekly Prophylaxis Episodic (On-Demand) Dosing
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   32/117 (27.35%)   8/24 (33.33%)   7/23 (30.43%) 
Infections and infestations       
Nasopharyngitis  1  16/117 (13.68%)  1/24 (4.17%)  3/23 (13.04%) 
Upper respiratory tract infection  1  6/117 (5.13%)  0/24 (0.00%)  3/23 (13.04%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  10/117 (8.55%)  2/24 (8.33%)  1/23 (4.35%) 
Nervous system disorders       
Headache  1  5/117 (4.27%)  6/24 (25.00%)  2/23 (8.70%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Results Point of Contact
Name/Title: Biogen Study Medical Director
Organization: Biogen
Responsible Party: Bioverativ Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT01181128     History of Changes
Other Study ID Numbers: 997HA301
First Submitted: August 12, 2010
First Posted: August 13, 2010
Results First Submitted: June 9, 2014
Results First Posted: August 29, 2014
Last Update Posted: August 18, 2017