Trial Outcomes & Findings for Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A (NCT NCT01181128)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

165 participants

Primary outcome timeframe

up to 52 weeks ± 2 weeks

Results posted on

2021-01-08

Participant Flow

Participant milestones

Participant milestones
Measure	Arm 1: Individualized (Tailored) Prophylaxis 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Study STARTED	118	24	23
Overall Study Pharmacokinetic (PK) Subgroup	30	0	0
Overall Study Perioperative Management Subgroup	8	1	0
Overall Study COMPLETED	112	19	22
Overall Study NOT COMPLETED	6	5	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1: Individualized (Tailored) Prophylaxis 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Overall Study Withdrawal by Subject	2	2	0
Overall Study Death	1	0	0
Overall Study Physician Decision	2	0	0
Overall Study Adverse Event	0	2	0
Overall Study Other	1	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=118 Participants 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.	Arm 2: Weekly Prophylaxis n=24 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	Total n=165 Participants Total of all reporting groups
Age, Continuous	29.0 years n=5 Participants	31.5 years n=7 Participants	34.0 years n=5 Participants	30.0 years n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Male	118 Participants n=5 Participants	24 Participants n=7 Participants	23 Participants n=5 Participants	165 Participants n=4 Participants

PRIMARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=118 Participants 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.	Arm 2: Weekly Prophylaxis n=24 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total n=165 Participants All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Incidence Rate of FVIII Inhibitor Development Participants with>=50 EDs; n=107, 1, 2, 110	0 percentage of participants Interval 0.0 to 3.4	0 percentage of participants Interval 0.0 to 97.5	0 percentage of participants Interval 0.0 to 84.2	0 percentage of participants Interval 0.0 to 3.3	—
Incidence Rate of FVIII Inhibitor Development All participants; n=117, 24, 23, 164	0 percentage of participants Interval 0.0 to 3.1	0 percentage of participants Interval 0.0 to 14.2	0 percentage of participants Interval 0.0 to 14.8	0 percentage of participants Interval 0.0 to 2.2	—

PRIMARY outcome

Timeframe: up to 52 weeks + 30 days ± 1 week

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=30 Participants 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.	Arm 2: Weekly Prophylaxis n=117 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=24 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total n=23 Participants All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup n=9 Participants Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 TEAE	3 participants	80 participants	18 participants	10 participants	4 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 Related TEAE	0 participants	5 participants	3 participants	2 participants	0 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 TESAE	0 participants	10 participants	2 participants	0 participants	2 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 Related TESAE	0 participants	0 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=118 Participants 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.	Arm 2: Weekly Prophylaxis n=24 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Leukocytes <3.0*10^9/L; n=117, 24, 23	2 participants	0 participants	2 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Leukocytes >=16*10^9/L; n=117, 24, 23	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Lymphocytes <0.8*10^9/L; n=104, 22, 21	3 participants	1 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Lymphocytes >12*10^9/L; n=104, 22, 21	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Neutrophils <1.5*10^9/L; n=104, 22, 21	4 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Neutrophils >13.5*10^9/L; n=104, 22, 21	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Monocytes >2.5*10^9/L; n=104, 22, 21	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Eosinophils >1.6*10^9/L; n=104, 22, 21	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Basophils >1.6*10^9/L; n=104, 22, 21	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Erythrocytes <=3.5*10^12/L; n=117, 24, 23	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Erythrocytes >=6.4*10^12/L; n=117, 24, 23	1 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Hemoglobin <=115 g/L; n=117, 24, 23	3 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Hemoglobin >=190 g/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Hematocrit <=37%; n=117, 24, 23	5 participants	2 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Hematocrit >=60%; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Platelets <=75*10^9/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Platelets >=700*10^9/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Alanine Aminotransferase >=3*ULN; n=117, 24, 23	4 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Aspartate Aminotransferase >=3*ULN; n=117, 24, 23	4 participants	1 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Alkaline Phosphatase >=3*ULN; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Total Bilirubin >=34.2 µmol/L; n=117, 24, 23	3 participants	0 participants	2 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Blood Urea Nitrogen >=10.7 mmol/L; n=117, 24, 23	1 participants	1 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Creatinine >=176.8 µmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Sodium <=126 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Sodium >=156 mmol/L; n=117, 24, 23	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Potassium <=3 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Potassium >=6 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Chloride <=90 mmol/L; n=117, 24, 23	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Chloride >=118 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Phosphate <=0.55 mmol/L n=117, 24, 23	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Phosphate >=1.71 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Glucose <=2.22 mmol/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Glucose >=9.71 mmol/L; n=117, 24, 23	2 participants	1 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Total Protein <=45 g/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline Total Protein >=100 g/L; n=117, 24, 23	0 participants	0 participants	0 participants	—	—

PRIMARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=113 Participants 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.	Arm 2: Weekly Prophylaxis n=24 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs Temperature: >38°C and ≥1°C ↑ from BL	1 participants	0 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs Pulse: >120 bpm or >20 bpm ↑ from BL	11 participants	2 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs Pulse: <50 bpm or >20 bpm ↓ from BL	11 participants	2 participants	1 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs SBP: >180 mm Hg or >40 mm Hg ↑ from BL	0 participants	1 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs SBP: <90 mm Hg or >30 mm Hg ↓ from BL	5 participants	1 participants	1 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs DBP: >105 mm Hg or >30 mm Hg ↑ from BL	1 participants	0 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs DBP: <50 mm Hg or >20 mm Hg ↓ from BL	5 participants	0 participants	1 participants	—	—

PRIMARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=117 Participants 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.	Arm 2: Weekly Prophylaxis n=23 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Annualized Bleeding Rate	1.60 episodes per participant per year Interval 0.0 to 4.69	3.59 episodes per participant per year Interval 1.86 to 8.36	33.57 episodes per participant per year Interval 21.14 to 48.69	—	—

PRIMARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=117 Participants 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.	Arm 2: Weekly Prophylaxis n=23 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3	2.91 episodes per participant per year Interval 2.3 to 3.68	37.25 episodes per participant per year Interval 24.03 to 57.74	—	—	—

PRIMARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay) rFVIIIFc Baseline	51.24 IU*h/dL per IU/kg Interval 44.97 to 58.38	—	—	—	—
Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay) Advate	32.88 IU*h/dL per IU/kg Interval 29.31 to 36.88	—	—	—	—

PRIMARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Elimination Half Life (t1/2; One-stage Clotting Assay) rFVIIIFc Baseline	18.97 hours Interval 17.03 to 21.12	—	—	—	—
Elimination Half Life (t1/2; One-stage Clotting Assay) Advate	12.43 hours Interval 11.14 to 13.86	—	—	—	—

PRIMARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Clearance (CL; One-stage Clotting Assay) rFVIIIFc Baseline	1.952 mL/h/kg Interval 1.713 to 2.224	—	—	—	—
Clearance (CL; One-stage Clotting Assay) Advate	3.041 mL/h/kg Interval 2.711 to 3.412	—	—	—	—

PRIMARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Mean Residence Time (MRT; One-stage Clotting Assay) rFVIIIFc Baseline	25.15 hours Interval 22.65 to 27.91	—	—	—	—
Mean Residence Time (MRT; One-stage Clotting Assay) Advate	16.84 hours Interval 15.22 to 18.63	—	—	—	—

PRIMARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Incremental Recovery (One-stage Clotting Assay) rFVIIIFc Baseline	2.2395 IU/dL per IU/kg Interval 2.1116 to 2.3753	—	—	—	—
Incremental Recovery (One-stage Clotting Assay) Advate	2.3516 IU/dL per IU/kg Interval 2.211 to 2.501	—	—	—	—

SECONDARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with an efficacy assessment.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=23 Participants 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.	Arm 2: Weekly Prophylaxis n=23 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3	8.92 episodes per participant per year Interval 5.48 to 14.51	37.25 episodes per participant per year Interval 24.03 to 57.74	—	—	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=117 Participants 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.	Arm 2: Weekly Prophylaxis n=24 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Annualized rFVIIIFc Consumption Per Participant Overall (n=117, 23, 23)	4631.98 IU/kg rFVIIIFc per participant per year Standard Deviation 1041.608	4003.69 IU/kg rFVIIIFc per participant per year Standard Deviation 652.573	1304.36 IU/kg rFVIIIFc per participant per year Standard Deviation 874.361	—	—
Annualized rFVIIIFc Consumption Per Participant Last 3 months on study (n=112, 16, 18)	4868.35 IU/kg rFVIIIFc per participant per year Standard Deviation 1365.108	3882.89 IU/kg rFVIIIFc per participant per year Standard Deviation 583.344	1225.80 IU/kg rFVIIIFc per participant per year Standard Deviation 848.656	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=202 Bleeding Episodes 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.	Arm 2: Weekly Prophylaxis n=89 Bleeding Episodes 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=454 Bleeding Episodes 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Participant Assessment of Response to Injections to Treat a Bleeding Episode Excellent or Good	79.7 percentage of responses	64.0 percentage of responses	80.2 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Excellent	33.7 percentage of responses	18.0 percentage of responses	30.8 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Good	46.0 percentage of responses	46.1 percentage of responses	49.3 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Moderate	18.8 percentage of responses	34.8 percentage of responses	19.6 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode No Response	1.5 percentage of responses	1.1 percentage of responses	0.2 percentage of responses	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: This supplemental assessment was not summarized because of insufficient data.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with evaluable data.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=117 Participants 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.	Arm 2: Weekly Prophylaxis n=23 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Joint	0.00 episodes per participant per year Interval 0.0 to 3.11	1.93 episodes per participant per year Interval 0.0 to 7.62	22.76 episodes per participant per year Interval 15.07 to 39.02	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Muscle	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 2.01	5.57 episodes per participant per year Interval 1.86 to 10.05	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Internal	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 0.0	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Soft Tissue	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 1.86	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Skin/Mucosa	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 0.0	0.00 episodes per participant per year Interval 0.0 to 0.0	—	—

SECONDARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc with evaluable data.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=117 Participants 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.	Arm 2: Weekly Prophylaxis n=23 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Annualized Joint Bleeding Rate (Spontaneous and Traumatic) Spontaneous	0.00 bleeding episodes per participant per yr Interval 0.0 to 1.73	0.00 bleeding episodes per participant per yr Interval 0.0 to 3.81	18.59 bleeding episodes per participant per yr Interval 7.59 to 29.59	—	—
Annualized Joint Bleeding Rate (Spontaneous and Traumatic) Traumatic	0.00 bleeding episodes per participant per yr Interval 0.0 to 1.16	0.00 bleeding episodes per participant per yr Interval 0.0 to 2.01	3.93 bleeding episodes per participant per yr Interval 0.0 to 8.56	—	—
Annualized Joint Bleeding Rate (Spontaneous and Traumatic) Unknown	0.00 bleeding episodes per participant per yr Interval 0.0 to 0.0	0.00 bleeding episodes per participant per yr Interval 0.0 to 0.0	0.00 bleeding episodes per participant per yr Interval 0.0 to 0.0	—	—

SECONDARY outcome

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

Population: 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.

Number of days from the last injection to treat a bleeding episode to a new bleeding episode, analyzed for per evaluable bleeding episode and per participant. For "per participant" values, number of days from last injection to treat a bleed to a new bleeding episode is averaged across all evaluable bleeding episodes for each participant first, and then descriptive statistics were calculated across participants. A follow-up injection administered \>72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (not evaluable). 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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=149 Evaluable Bleeding Episodes 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.	Arm 2: Weekly Prophylaxis n=76 Evaluable Bleeding Episodes 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=430 Evaluable Bleeding Episodes 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Days From Last Treatment Injection to a New Bleeding Episode Per Bleeding Episode	19.83 days Interval 8.58 to 55.46	8.00 days Interval 5.35 to 15.38	6.55 days Interval 4.46 to 10.27	—	—
Number of Days From Last Treatment Injection to a New Bleeding Episode Per Participant	42.90 days Interval 20.25 to 65.93	40.71 days Interval 11.75 to 52.39	10.12 days Interval 7.42 to 16.37	—	—

SECONDARY outcome

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

Population: Full Analysis Set: participants who received at least 1 dose of rFVIIIFc and had at least 1 bleeding episode.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=209 Bleeding Episodes 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.	Arm 2: Weekly Prophylaxis n=92 Bleeding Episodes 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=456 Bleeding Episodes 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Injections Required for Resolution of a Bleeding Episode Per Bleeding Episode	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode Per Participant	1.00 injections Interval 1.0 to 1.33	1.00 injections Interval 1.0 to 1.43	1.03 injections Interval 1.0 to 1.17	—	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=64 Participants 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.	Arm 2: Weekly Prophylaxis n=19 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Joint (n=151, 67, 366)	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Muscle (n=35, 23, 82)	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Soft Tissue (n=24, 5, 25)	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 2.0	1.0 injections Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Internal (n=3, 2, 6)	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Skin/Mucosa (n=11, 6, 8)	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	1.0 injections Interval 1.0 to 1.0	—	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=63 Participants 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.	Arm 2: Weekly Prophylaxis n=19 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=23 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Joint (n=151, 67, 366)	29.69 IU/kg Interval 24.1 to 53.44	28.23 IU/kg Interval 20.16 to 40.32	27.35 IU/kg Interval 22.73 to 39.22	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Muscle (n=35, 23, 82)	40.98 IU/kg Interval 26.79 to 53.1	32.12 IU/kg Interval 26.98 to 32.47	27.78 IU/kg Interval 23.47 to 31.01	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Soft Tissue (n=23, 5, 25)	30.60 IU/kg Interval 24.51 to 53.13	51.88 IU/kg Interval 20.16 to 54.88	27.78 IU/kg Interval 23.44 to 31.45	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Internal (n=3, 2, 6)	32.63 IU/kg Interval 23.39 to 51.72	58.40 IU/kg Interval 48.08 to 68.73	32.54 IU/kg Interval 30.0 to 49.18	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Skin/Mucosa (n=11, 6, 8)	33.90 IU/kg Interval 28.23 to 53.19	28.34 IU/kg Interval 21.65 to 44.35	21.37 IU/kg Interval 19.95 to 25.16	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Volume at Steady State (Vss; One-stage Clotting Assay) rFVIIIFc Baseline	49.1 mL/kg Interval 46.6 to 51.7	—	—	—	—
Volume at Steady State (Vss; One-stage Clotting Assay) Advate	51.2 mL/kg Interval 47.2 to 55.5	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Volume at Steady State (Vss; Two-stage Chromogenic Assay) rFVIIIFc Baseline	52.6 mL/kg Interval 47.4 to 58.3	—	—	—	—
Volume at Steady State (Vss; Two-stage Chromogenic Assay) Advate	56.8 mL/kg Interval 51.5 to 62.7	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Time to 1% and 3% FVIII Activity (One-stage Clotting Assay) Advate: Time 1%	3.298 days Interval 2.985 to 3.645	—	—	—	—
Time to 1% and 3% FVIII Activity (One-stage Clotting Assay) Advate: Time 3%	2.478 days Interval 2.242 to 2.738	—	—	—	—
Time to 1% and 3% FVIII Activity (One-stage Clotting Assay) rFVIIIFc Baseline: Time 1%	4.918 days Interval 4.434 to 5.455	—	—	—	—
Time to 1% and 3% FVIII Activity (One-stage Clotting Assay) rFVIIIFc Baseline: Time 3%	3.707 days Interval 3.325 to 4.133	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay) Advate: Time 1%	3.220 days Interval 2.97 to 3.491	—	—	—	—
Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay) Advate: Time 3%	2.306 days Interval 2.12 to 2.509	—	—	—	—
Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay) rFVIIIFc Baseline: Time 1%	5.010 days Interval 4.525 to 5.548	—	—	—	—
Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay) rFVIIIFc Baseline: Time 3%	3.612 days Interval 3.25 to 4.015	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=28 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Time at Maximum Activity (Tmax; One-stage Clotting Assay) rFVIIIFc Baseline	0.49 hours Interval 0.37 to 0.63	—	—	—	—
Time at Maximum Activity (Tmax; One-stage Clotting Assay) Advate	0.48 hours Interval 0.33 to 0.68	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay) rFVIIIFc Baseline	0.55 hours Interval 0.41 to 0.75	—	—	—	—
Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay) Advate	0.46 hours Interval 0.35 to 0.61	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay) rFVIIIFc Baseline	47.45 IU*h/dL per IU/kg Interval 41.55 to 54.18	—	—	—	—
Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay) Advate	28.05 IU*h/dL per IU/kg Interval 24.85 to 31.65	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Elimination Half Life (t1/2; Two-stage Chromogenic Assay) rFVIIIFc Baseline	20.89 hours Interval 18.23 to 23.93	—	—	—	—
Elimination Half Life (t1/2; Two-stage Chromogenic Assay) Advate	13.67 hours Interval 12.31 to 15.18	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Clearance (CL; Two-stage Chromogenic Assay) Advate	3.566 mL/h/kg Interval 3.159 to 4.024	—	—	—	—
Clearance (CL; Two-stage Chromogenic Assay) rFVIIIFc Baseline	2.108 mL/h/kg Interval 1.846 to 2.407	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Mean Residence Time (MRT; Two-stage Chromogenic Assay) rFVIIIFc Baseline	24.96 hours Interval 22.41 to 27.8	—	—	—	—
Mean Residence Time (MRT; Two-stage Chromogenic Assay) Advate	15.94 hours Interval 14.7 to 17.27	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame.

Population: Participants who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=27 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Incremental Recovery (Two-stage Chromogenic Assay) rFVIIIFc Baseline	2.4912 IU/dL per IU/kg Interval 2.2762 to 2.7265	—	—	—	—
Incremental Recovery (Two-stage Chromogenic Assay) Advate	2.5589 IU/dL per IU/kg Interval 2.3247 to 2.8168	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 14

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=69 Participants 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.	Arm 2: Weekly Prophylaxis n=22 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=15 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total n=17 Participants All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Work and School (n=53, 17,13, 14)	-6.25 units on a scale Interval -56.3 to 25.0	-6.25 units on a scale Interval -37.5 to 25.0	0.00 units on a scale Interval -31.3 to 39.6	0.00 units on a scale Interval -58.3 to 12.5	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 View of Yourself (n=68, 22, 15, 17)	0.00 units on a scale Interval -70.0 to 25.0	5.00 units on a scale Interval -30.0 to 25.0	0.00 units on a scale Interval -30.0 to 15.0	-5.00 units on a scale Interval -40.0 to 20.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Sports and Leisure (n=48, 12, 12, 8)	0.00 units on a scale Interval -55.0 to 40.0	-2.50 units on a scale Interval -25.0 to 18.8	-10.0 units on a scale Interval -30.0 to 0.0	-2.50 units on a scale Interval -30.0 to 15.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Dealing with Hemophilia (n=65, 22, 15, 17)	0.00 units on a scale Interval -33.3 to 50.0	0.00 units on a scale Interval -25.0 to 16.7	0.00 units on a scale Interval -25.0 to 41.7	0.00 units on a scale Interval -50.0 to 100.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Treatment (n=68, 21, 15, 16)	-3.13 units on a scale Interval -37.1 to 21.9	-3.13 units on a scale Interval -43.8 to 31.3	-3.13 units on a scale Interval -31.3 to 18.8	0.00 units on a scale Interval -21.9 to 18.8	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Future (n=66, 21, 15, 17)	2.50 units on a scale Interval -35.0 to 25.0	0.00 units on a scale Interval -30.0 to 55.0	-5.00 units on a scale Interval -35.0 to 15.0	-5.00 units on a scale Interval -55.0 to 25.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Partnership and Sexuality (n=62, 20, 15, 17)	0.00 units on a scale Interval -25.0 to 41.7	0.00 units on a scale Interval -25.0 to 58.3	0.00 units on a scale Interval -41.7 to 0.0	0.00 units on a scale Interval -100.0 to 25.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Total Score (n=57, 17, 14, 14)	-2.18 units on a scale Interval -25.0 to 20.9	-1.48 units on a scale Interval -28.6 to 5.1	-4.73 units on a scale Interval -30.5 to 3.2	-2.09 units on a scale Interval -25.1 to 5.4	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Physical Health (n=68, 22, 15, 17)	-5.00 units on a scale Interval -70.0 to 75.0	-12.50 units on a scale Interval -42.5 to 45.0	-10.0 units on a scale Interval -40.0 to 10.0	0.00 units on a scale Interval -55.0 to 40.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Feeling (n=68, 22, 15, 17)	0.00 units on a scale Interval -43.8 to 43.8	-6.25 units on a scale Interval -37.5 to 12.5	-6.25 units on a scale Interval -50.0 to 6.3	-6.25 units on a scale Interval -37.5 to 6.3	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 Family Planning (n=38, 10, 8, 7)	0.00 units on a scale Interval -31.3 to 18.8	0.00 units on a scale Interval -18.8 to 31.3	0.00 units on a scale Interval -50.0 to 8.3	-2.08 units on a scale Interval -31.3 to 0.0	—

SECONDARY outcome

Timeframe: Baseline, Week 28

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=42 Participants 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.	Arm 2: Weekly Prophylaxis n=17 Participants 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=3 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total n=7 Participants All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Total Score (n=34, 12, 3, 5)	-1.03 units on a scale Interval -26.7 to 11.5	-4.31 units on a scale Interval -35.6 to 13.9	-5.81 units on a scale Interval -9.8 to 5.4	-0.56 units on a scale Interval -11.2 to 3.4	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Physical Health (n=40, 17, 3, 7)	0.00 units on a scale Interval -31.3 to 60.0	-25.00 units on a scale Interval -65.0 to 25.0	-5.00 units on a scale Interval -45.0 to -5.0	0.00 units on a scale Interval -15.0 to 20.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Feeling (n=40, 17, 3, 7)	-3.13 units on a scale Interval -50.0 to 25.0	-6.25 units on a scale Interval -50.0 to 18.8	-6.25 units on a scale Interval -18.8 to 6.3	0.00 units on a scale Interval -12.5 to 18.8	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 View of Yourself (n=42, 17, 3, 7)	0.00 units on a scale Interval -40.0 to 35.0	0.00 units on a scale Interval -40.0 to 20.0	0.00 units on a scale Interval -5.0 to 5.0	0.00 units on a scale Interval -5.0 to 15.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Sports and Leisure (n=29, 10, 2, 5)	0.00 units on a scale Interval -68.8 to 45.0	-5.00 units on a scale Interval -50.0 to 5.0	-10.0 units on a scale Interval -25.0 to 5.0	5.00 units on a scale Interval -8.8 to 5.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Dealing with Hemophilia (n=40, 17, 3, 7)	0.00 units on a scale Interval -33.3 to 33.3	0.00 units on a scale Interval -25.0 to 58.3	0.00 units on a scale Interval -16.7 to 25.0	0.00 units on a scale Interval -16.7 to 8.3	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Treatment (n=42, 14, 3, 7)	0.00 units on a scale Interval -28.1 to 18.8	-4.69 units on a scale Interval -43.8 to 12.5	6.25 units on a scale Interval -12.5 to 28.1	0.00 units on a scale Interval -18.8 to 6.3	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Work and School (n=34, 15, 2, 6)	0.00 units on a scale Interval -50.0 to 37.5	-6.25 units on a scale Interval -56.3 to 25.0	-9.38 units on a scale Interval -18.8 to 0.0	-3.13 units on a scale Interval -25.0 to 6.3	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Future (n=40, 17, 3, 6)	0.00 units on a scale Interval -45.0 to 35.0	-5.00 units on a scale Interval -45.0 to 60.0	-5.00 units on a scale Interval -20.0 to -5.0	7.50 units on a scale Interval -15.0 to 10.0	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Family Planning (n=19, 10, 2, 2)	0.00 units on a scale Interval -25.0 to 16.7	0.00 units on a scale Interval -18.8 to 33.3	0.00 units on a scale Interval 0.0 to 0.0	9.38 units on a scale Interval 0.0 to 18.8	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 Partnership and Sexuality (n=37, 14, 3, 7)	0.00 units on a scale Interval -25.0 to 66.7	0.00 units on a scale Interval -25.0 to 91.7	0.00 units on a scale Interval -8.3 to 0.0	0.00 units on a scale Interval -25.0 to 8.3	—

SECONDARY outcome

Timeframe: Baseline, Week 14, Week 28

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=8 Participants 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing n=2 Participants 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
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 Baseline (n=8, 0, 2)	11.20 units on a scale Interval 6.5 to 38.3	—	26.30 units on a scale Interval 16.2 to 36.4	—	—
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 Change from Baseline at Week 14 (n=8, 0, 1)	-3.25 units on a scale Interval -21.9 to 2.3	—	-5.01 units on a scale Interval -5.01 to -5.01	—	—
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 Change from Baseline at Week 28 (n=4, 0, 0)	-3.73 units on a scale Interval -6.2 to -1.3	—	NA units on a scale n=0 for this timepoint	—	—

SECONDARY outcome

Timeframe: up to 52 weeks

Population: Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=9 Major Surgeries 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery Excellent or Good	9 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery Excellent	8 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery Good	1 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery Fair	0 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery Poor/None	0 responses	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks

Population: Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=9 Major Surgeries 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Injections Required to Maintain Hemostasis During Major Surgery	1.0 injections Interval 1.0 to 1.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.

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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=9 Major Surgeries 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery Dose per Injection	51.4 IU/kg Interval 50.0 to 77.0	—	—	—	—
Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery Total Dose	51.4 IU/kg Interval 50.0 to 77.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=7 Major Surgeries 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Estimated Total Blood Loss During Major Surgery	15.0 mL Interval 0.0 to 600.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 2 weeks

Population: Participants in the Full Analysis Set (FAS) who received at least 1 dose of rFVIIIFc and underwent major surgery.

Number of blood component transfusions during a single surgery.

Outcome measures

Outcome measures
Measure	Arm 1: Individualized (Tailored) Prophylaxis n=9 Major Surgeries 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.	Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days	Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode	All Arms: Total All participants from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.	Any Arm: Perioperative Management (Surgery) Subgroup Participants from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the participant underwent.
Number of Transfusions Required Per Surgery 0 transfusions	8 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 1 transfusion	0 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 2 transfusions	1 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 3 transfusions	0 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery > 3 transfusions	0 surgeries	—	—	—	—

Adverse Events

Individualized (Tailored) Prophylaxis, rFVIIIFc

Serious events: 10 serious events

Other events: 32 other events

Deaths: 0 deaths

Weekly Prophylaxis

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Episodic (On-Demand) Dosing

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Individualized (Tailored) Prophylaxis, rFVIIIFc n=117 participants at risk 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.	Weekly Prophylaxis n=24 participants at risk 65 IU/kg of rFVIIIFc via IV injection every 7 days	Episodic (On-Demand) Dosing n=23 participants at risk 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
Infections and infestations Nasopharyngitis	13.7% 16/117 • up to 52 weeks + 30 days ± 1 week 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).	4.2% 1/24 • up to 52 weeks + 30 days ± 1 week 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).	13.0% 3/23 • up to 52 weeks + 30 days ± 1 week 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).
Infections and infestations Upper respiratory tract infection	5.1% 6/117 • up to 52 weeks + 30 days ± 1 week 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).	0.00% 0/24 • up to 52 weeks + 30 days ± 1 week 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).	13.0% 3/23 • up to 52 weeks + 30 days ± 1 week 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).
Musculoskeletal and connective tissue disorders Arthralgia	8.5% 10/117 • up to 52 weeks + 30 days ± 1 week 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).	8.3% 2/24 • up to 52 weeks + 30 days ± 1 week 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).	4.3% 1/23 • up to 52 weeks + 30 days ± 1 week 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).
Nervous system disorders Headache	4.3% 5/117 • up to 52 weeks + 30 days ± 1 week 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).	25.0% 6/24 • up to 52 weeks + 30 days ± 1 week 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).	8.7% 2/23 • up to 52 weeks + 30 days ± 1 week 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).

Additional Information

Biogen Study Medical Director

Biogen

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
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Restriction type: OTHER