Trial Outcomes & Findings for Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B (NCT NCT01027364)

Results Overview

Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint. ULN=upper limit of normal.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

123 participants

Primary outcome timeframe

up to 52 weeks ± 1 week

Results posted on

2020-12-19

Participant Flow

Participant milestones

Participant milestones
Measure	Arm 1: Weekly Prophylaxis 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Overall Study STARTED	63	29	27	4
Overall Study Enrolled in Sequential PK Subgroup	22	0	0	0
Overall Study Joined Arm 4 for Surgery Then Returned	5	0	1	0
Overall Study Started Arm 4 Then Joined Another Arm	2	0	0	0
Overall Study COMPLETED	59	27	26	3
Overall Study NOT COMPLETED	4	2	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1: Weekly Prophylaxis 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Overall Study Adverse Event	1	0	1	0
Overall Study Lost to Follow-up	1	0	0	0
Overall Study Protocol Violation	1	0	0	1
Overall Study Withdrawal by Subject	1	2	0	0

Baseline Characteristics

Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1: Weekly Prophylaxis n=63 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=29 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management n=4 Participants The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.	Total n=123 Participants Total of all reporting groups
Age, Continuous	28.0 years n=5 Participants	33.0 years n=7 Participants	36.0 years n=5 Participants	40.5 years n=4 Participants	30.0 years n=21 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	0 Participants n=21 Participants
Sex: Female, Male Male	63 Participants n=5 Participants	29 Participants n=7 Participants	27 Participants n=5 Participants	4 Participants n=4 Participants	123 Participants n=21 Participants

PRIMARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc; n=the number of participants with at least one post-baseline value. For this study, a table was not generated for potentially clinically significant laboratory abnormalities for participants in the perioperative management/surgical arm (Arm 4).

Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint. ULN=upper limit of normal.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=63 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=29 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Total Protein >=100 g/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Phosphate >=1.71 mmol/L; n=62, 28, 27	1 participants	1 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Glucose >=9.71 mmol/L; n=62, 28, 27	4 participants	1 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Albumin <=25 g/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Total Protein <=45 g/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities White Blood Cells <3.0*10^9/L; n=62, 28, 27	2 participants	0 participants	2 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities White Blood Cells >=16*10^9/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Lymphocytes >12*10^9/L; n=60, 28, 26	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Monocytes >2.5*10^9/L; n=60, 28, 26	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Eosinophils >1.6*10^9/L; n=60, 28, 26	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Basophils >1.6*10^9/L; n=60, 28, 26	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Red Blood Cells <=3.5*10^12/L; n=62, 28, 27	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hemoglobin >=190 g/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hematocrit <=37%; n=62, 28, 27	4 participants	0 participants	2 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hematocrit >=60%; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Creatinine >=176.8 µmol/L; n=62, 28, 27	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Sodium <=126 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Sodium >=156 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Phosphate <=0.55 mmol/L n=62, 28, 27	0 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Glucose <=2.22 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Potassium <=3 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Potassium >=6 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Platelets <=75*10^9/L; n=62, 28, 27	0 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Platelets >=700*10^9/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Alanine Aminotransferase >=3*ULN; n=62, 28, 27	0 participants	0 participants	2 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Aspartate Aminotransferase >=3*ULN; n=62, 28, 27	2 participants	1 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Alkaline Phosphatase >=3*ULN; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Total Bilirubin >=34.2 µmol/L; n=62, 28, 27	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Blood Urea Nitrogen >=10.7 mmol/L; n=62, 28, 27	1 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Chloride <=90 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Chloride >=118 mmol/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Neutrophils <1.5*10^9/L; n=60, 28, 26	2 participants	0 participants	1 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Lymphocytes <0.8*10^9/L; n=60, 28, 26	1 participants	2 participants	3 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Neutrophils >13.5*10^9/L; n=60, 28, 26	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Red Blood Cells >=6.4*10^12/L; n=62, 28, 27	0 participants	0 participants	0 participants	—	—
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hemoglobin <=115 g/L; n=62, 28, 27	1 participants	0 participants	0 participants	—	—

PRIMARY outcome

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

Population: Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details). Participants with at least one TESAE reported are included in the TEAE count.

AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TE=event present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before 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. Related=related, possibly related, and relationship missing. Data include AEs emergent during the surgical/rehabilitation period; AE data are included in each treatment arm only for the time each participant was enrolled in that arm.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=23 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=63 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=29 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management n=12 Participants The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 TEAE	2 participants	45 participants	23 participants	20 participants	10 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 Related TEAE	0 participants	5 participants	4 participants	1 participants	0 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 TESAE	0 participants	5 participants	4 participants	4 participants	3 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) >=1 Related TESAE	0 participants	0 participants	1 participants	0 participants	0 participants

PRIMARY outcome

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

Population: Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details).

AE=any untoward medical occurrence that did not necessarily have a causal relationship with this 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 BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOCs are abbreviated in the table: Immune System (IS); Injury, Poisoning, and Procedural (IPP); Metabolism and Nutrition (MN); Musculoskeletal and Connective Tissue (MCT); Respiratory, Thoracic and Mediastinal (RTM); Skin and Subcutaneous Tissue (SST).

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=8 Participants With At Least 1 TEAE 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: General Disorders; PT: Infusion Site Pain	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Nervous System Disorders; PT: Dizziness	2 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Nervous System Disorders; PT: Headache	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: RTM Disorders; PT: Dyspnoea	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: SST Disorders; PT: Hyperhidrosis	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Blood/Lymphatic System Disorders; PT: Anaemia	2 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Ear and Labyrinth Disorders; PT: Vertigo	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Gastrointestinal Disorders; PT: Constipation	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Gastrointestinal Disorders; PT: Nausea	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Gastrointestinal Disorders; PT: Vomiting	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: General Disorders; PT: Asthenia	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: IS Disorders; PT: Drug Hypersensitivity	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Infections/Infestations; PT: Cellulitis	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: IPP Complications; PT: Incision Site Pain	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: IPP Complications; PT: Procedural Pain	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: IPP Complications; PT: Wound Complication	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Investigations; PT: Weight Increased	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: MN Disorders; PT: Decreased Appetite	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: MCT Disorders; PT: Muscle Spasms	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Nervous System (NS) Disorders; PT: Neuralgia	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: NS Disorders; PT: Neuropathy Peripheral	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Psychiatric Disorders; PT: Anxiety	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Psychiatric Disorders; PT: Insomnia	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: RTM Disorders; Oropharyngeal Pain	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Vascular Disorders; PT: Hypertension	1 participants	—	—	—	—
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period SOC: Vascular Disorders; PT: Hypotension	1 participants	—	—	—	—

PRIMARY outcome

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

Population: Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details).

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. TESAE=SAE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOC is abbreviated in the table: Injury, Poisoning, and Procedural (IPP).

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=3 Participants With At Least 1 TESAE 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period SOC: Infections/Infestations; PT: Pilondial Cyst	1 participants	—	—	—	—
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period SOC: Cardiac Disorders; PT: Tachycardia	1 participants	—	—	—	—
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period SOC: Infections/Infestations; PT: Bacterial Sepsis	1 participants	—	—	—	—
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period SOC: Infections/Infestations; PT: Tooth Abscess	1 participants	—	—	—	—
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period SOC: IPP Complications; PT: Limb Crushing Injury	1 participants	—	—	—	—

PRIMARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Safety Analysis Set: participants who received at least 1 dose of of rFIXFc and who had a valid inhibitor test; 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% CI were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFIXFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFIXFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=63 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=27 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) n=4 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management n=121 Participants The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Incidence Rate of FIX Inhibitor Development Participants with>=50 EDs to rFIXFc(n=52,2,0,1,55)	0 percentage of participants Interval 0.0 to 6.85	0 percentage of participants Interval 0.0 to 84.19	0 percentage of participants n=0 for this arm	0 percentage of participants Interval 0.0 to 97.5	0 percentage of participants Interval 0.0 to 6.49
Incidence Rate of FIX Inhibitor Development All participants (n=63, 27, 27, 4, 121)	0 percentage of participants Interval 0.0 to 5.69	0 percentage of participants Interval 0.0 to 12.77	0 percentage of participants Interval 0.0 to 12.77	0 percentage of participants Interval 0.0 to 60.24	0 percentage of participants Interval 0.0 to 3.0

PRIMARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc.

Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed pharmacokinetic (PK) sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=26 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Annualized Bleeding Rate	2.95 episodes per participant per year Interval 1.01 to 4.35	1.38 episodes per participant per year Interval 0.0 to 3.43	17.69 episodes per participant per year Interval 10.77 to 23.24	—	—

PRIMARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc.

Estimated with a factor for arm, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 and for all surgical/rehabilitation periods in all 3 arms. 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: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=26 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Comparison of Annualized Bleeding Rates	3.12 episodes per participant per year Interval 2.46 to 3.95	2.40 episodes per participant per year Interval 1.67 to 3.47	18.67 episodes per participant per year Interval 14.01 to 24.89	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc and had a bleeding episode; participants with a non-evaluable bleeding episode are counted in the 'number of participants analyzed,' but not the percentages.

Participant's assessment of the response to the first rFIXFc 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: Weekly Prophylaxis n=156 Bleeding Episodes 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=63 Bleeding Episodes 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=394 Bleeding Episodes 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Participant Assessment of Response to Injections to Treat a Bleeding Episode Excellent	35.3 percentage of responses	31.7 percentage of responses	37.3 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Excellent or Good	78.8 percentage of responses	74.6 percentage of responses	87.1 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Good	43.6 percentage of responses	42.9 percentage of responses	49.7 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode Moderate	18.6 percentage of responses	22.2 percentage of responses	11.9 percentage of responses	—	—
Participant Assessment of Response to Injections to Treat a Bleeding Episode No Response	2.6 percentage of responses	3.2 percentage of responses	1.0 percentage of responses	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc, had evaluable efficacy assessments, and had nonmissing observations at time point.

Physicians assessed each participant's response to rFIXFc using a 4-point scale: excellent=bleeding episodes responded to less than or equal to the usual number of injections or less than or equal to the usual dose of rFIXFc, or the rate of breakthrough bleeding during prophylaxis was less than or equal to that usually observed; effective=most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough bleeding; partially effective=bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; ineffective=routine failure to control hemostasis or hemostatic control required additional agents. Percentage of the total count of scale responses for all participants is presented. Multiple responses per participant are counted.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=267 Responses 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=123 Responses 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=96 Responses 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc Excellent	74.5 percentage of responses	73.2 percentage of responses	58.3 percentage of responses	—	—
Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc Effective	24.3 percentage of responses	26.0 percentage of responses	39.6 percentage of responses	—	—
Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc Partially Effective	1.1 percentage of responses	0.8 percentage of responses	2.1 percentage of responses	—	—
Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc Ineffective	0 percentage of responses	0 percentage of responses	0 percentage of responses	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc with evaluable data in the efficacy period. 'Overall' n=all participants in the Full Analysis Set with evaluable data in the efficacy period; 'Last 3 Months on Study' n=all participants in the Full Analysis Set with evaluable data and \>=6 months on study.

Consumption is calculated for the efficacy period (EP). In Arms 1 and 2, the EP started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. Overall units (IU/kg) of annualized rFIXFc consumption = \[Total rFIXFc IU/kg received during the EP / number of days in EP\]\*365.25.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=26 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Annualized rFIXFc Consumption Per Participant Overall (n=61, 26, 27)	2686.94 IU/kg rFIXFc per participant per year Standard Deviation 825.969	3371.92 IU/kg rFIXFc per participant per year Standard Deviation 649.690	936.70 IU/kg rFIXFc per participant per year Standard Deviation 481.764	—	—
Annualized rFIXFc Consumption Per Participant Last 3 months on study (n=58, 26, 27)	2467.32 IU/kg rFIXFc per participant per year Standard Deviation 978.529	3497.78 IU/kg rFIXFc per participant per year Standard Deviation 957.377	957.73 IU/kg rFIXFc per participant per year Standard Deviation 699.640	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants in Arm 1 who received at least 1 dose of rFIXFc with evaluable data. 'Overall' n=participants with evaluable data; 'Last 3 Months on Study' n=participants with evaluable data and \>=6 months on study.

Average weekly dose = (total IU/kg of all eligible prophylactic doses in the included intervals / total number of days in the included intervals)\*7. Eligible dose = the first of the 2 doses defining the interval. Participants could have multiple prophylactic dose changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 1, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries).

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm Overall (n=61)	46.26 IU/kg Standard Deviation 11.304	—	—	—	—
Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm Last 3 months on study (n=58)	43.10 IU/kg Standard Deviation 15.395	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants in Arm 2 who received at least 1 dose of rFIXFc with \>=6 months on study and evaluable data.

Average dosing interval = sum of days in the included dosing intervals divided by the number of included intervals. Participants could have multiple prophylactic dose interval changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for all surgical/rehabilitation periods (for both major and minor surgeries).

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=26 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Average Dosing Interval For the Individualized Interval Prophylaxis Arm Overall	12.53 days Inter-Quartile Range 2.018 • Interval 10.38 to 13.37	—	—	—	—
Average Dosing Interval For the Individualized Interval Prophylaxis Arm Last 3 months on study	14.00 days Inter-Quartile Range 2.864 • Interval 11.29 to 14.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

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

Annualized bleeding episodes = (number of bleeding episodes/number of days in efficacy period)\*365.25. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=26 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic) Spontaneous	1.04 episodes per participant per year Inter-Quartile Range 2.154 • Interval 0.0 to 2.19	0.88 episodes per participant per year Inter-Quartile Range 1.780 • Interval 0.0 to 2.3	11.78 episodes per participant per year Inter-Quartile Range 11.096 • Interval 2.62 to 19.78	—	—
Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic) Traumatic	0.99 episodes per participant per year Inter-Quartile Range 1.539 • Interval 0.0 to 2.13	0.00 episodes per participant per year Inter-Quartile Range 2.065 • Interval 0.0 to 0.78	2.21 episodes per participant per year Inter-Quartile Range 7.214 • Interval 0.0 to 6.81	—	—
Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic) Unknown	0.00 episodes per participant per year Inter-Quartile Range 0.603 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 0.705 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 1.043 • Interval 0.0 to 1.34	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

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

Annualized bleeding episodes = (number of bleeding episodes/number of days in efficacy period)\*365.25. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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: Weekly Prophylaxis n=61 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=26 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Muscle	0.00 episodes per participant per year Inter-Quartile Range 1.273 • Interval 0.0 to 1.04	0.00 episodes per participant per year Inter-Quartile Range 0.902 • Interval 0.0 to 0.0	3.96 episodes per participant per year Inter-Quartile Range 3.733 • Interval 1.02 to 6.79	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Joint	1.11 episodes per participant per year Inter-Quartile Range 2.678 • Interval 0.0 to 4.01	0.36 episodes per participant per year Inter-Quartile Range 2.498 • Interval 0.0 to 3.24	13.58 episodes per participant per year Inter-Quartile Range 10.418 • Interval 6.13 to 21.61	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Internal	0.00 episodes per participant per year Inter-Quartile Range 0.562 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 0.448 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 0.893 • Interval 0.0 to 1.31	—	—
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) Skin/Mucosa	0.00 episodes per participant per year Inter-Quartile Range 0.668 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 0.472 • Interval 0.0 to 0.0	0.00 episodes per participant per year Inter-Quartile Range 2.968 • Interval 0.0 to 1.14	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

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

Please see the definition of the Efficacy Period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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 (bleeding episodes of this type were not evaluable). The first bleed for each participant could not be included in this analysis since there was no previous bleed from which to measure time. The number of days from the last injection to treat a bleed to a new bleeding episode was analyzed across all evaluable bleeding episodes per participant.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=110 Evaluable Bleeding Episodes 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=45 Evaluable Bleeding Episodes 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=359 Evaluable Bleeding Episodes 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Days From Last Injection to Treat a New Bleeding Episode Per Bleeding Episode	40.78 days Inter-Quartile Range 57.184 • Interval 14.1 to 78.63	39.48 days Inter-Quartile Range 63.228 • Interval 26.05 to 84.82	13.42 days Inter-Quartile Range 21.837 • Interval 8.0 to 22.83	—	—
Number of Days From Last Injection to Treat a New Bleeding Episode Per Participant	59.52 days Inter-Quartile Range 49.610 • Interval 37.39 to 88.78	76.13 days Inter-Quartile Range 37.451 • Interval 51.38 to 98.29	19.67 days Inter-Quartile Range 40.576 • Interval 15.61 to 32.86	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

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

In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 and for all surgical/rehabilitation periods in all 3 arms. 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.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=167 Bleeding Episodes 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=67 Bleeding Episodes 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=402 Bleeding Episodes 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Injections Required for Resolution of a Bleeding Episode Per Bleeding Episode	1.0 injections Inter-Quartile Range 0.56 • Interval 1.0 to 1.0	1.0 injections Inter-Quartile Range 0.53 • Interval 1.0 to 1.0	1.0 injections Inter-Quartile Range 0.31 • Interval 1.0 to 1.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode Per Participant	1.00 injections Inter-Quartile Range 0.50 • Interval 1.0 to 1.25	1.09 injections Inter-Quartile Range 0.30 • Interval 1.0 to 1.33	1.04 injections Inter-Quartile Range 0.32 • Interval 1.0 to 1.08	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc, had a bleeding episode, and had evaluable efficacy assessments; n=total number of bleeds at given location.

Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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: Weekly Prophylaxis n=47 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=15 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Joint (n=125, 52, 314)	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, 10, 90)	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 Internal (n=9, 3, 11)	1.0 injections Interval 1.0 to 2.0	2.0 injections Interval 1.0 to 2.0	1.0 injections Interval 1.0 to 2.0	—	—
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed Skin/Mucosa (n=11, 4, 21)	1.0 injections Interval 1.0 to 2.0	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 ± 1 week (efficacy period as defined in description)

Population: Full Analysis Set: participants who received at least 1 dose of rFIXFc, had a bleeding episode, 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 the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. 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. 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: Weekly Prophylaxis n=47 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=15 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Joint (n=124, 52, 313)	50.14 IU/kg Interval 31.65 to 61.64	45.29 IU/kg Interval 35.71 to 97.41	46.73 IU/kg Interval 33.33 to 60.79	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Muscle (n=35, 10, 90)	55.56 IU/kg Interval 46.89 to 88.16	67.17 IU/kg Interval 33.63 to 87.46	46.57 IU/kg Interval 33.33 to 60.79	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Internal (n=9, 3, 11)	48.72 IU/kg Interval 41.67 to 125.0	70.26 IU/kg Interval 33.63 to 131.72	46.73 IU/kg Interval 33.33 to 61.07	—	—
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed Skin/Mucosa (n=11, 4, 21)	46.89 IU/kg Interval 38.67 to 79.55	48.48 IU/kg Interval 34.5 to 79.69	22.22 IU/kg Interval 20.83 to 36.36	—	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Full Analysis Set: participants in the 2 prophylaxis arms (Arms 1 and 2) over 17 years of age who received at least 1 dose of rFIXFc 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). The areas covered by this instrument are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (all 7 domains, during the last month) and future, family planning, and outlook for the future (all 3 domains, recently). Changes from baseline for the Haem-A-QoL questionnaire are summarized by prestudy treatment regimen (pooled for Arms 1 and 2). 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.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=27 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=31 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Total Score (n=27, 26)	-6.82 units on a scale Interval -22.8 to 6.1	-6.25 units on a scale Interval -25.5 to 12.8	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Physical Health (n=27, 31)	-10.00 units on a scale Interval -45.0 to 20.0	-15.00 units on a scale Interval -60.0 to 15.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Feeling (n=27, 31)	0.00 units on a scale Interval -43.8 to 50.0	0.00 units on a scale Interval -43.8 to 62.5	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 View of Yourself (n=27, 30)	-5.00 units on a scale Interval -25.0 to 15.0	-5.00 units on a scale Interval -35.0 to 25.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Sports and Leisure (n=22, 21)	-7.50 units on a scale Interval -70.0 to 25.0	-20.0 units on a scale Interval -40.0 to 35.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Work and School (n=22, 25)	0.00 units on a scale Interval -31.3 to 52.1	-6.25 units on a scale Interval -31.3 to 18.8	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Dealing with Hemophilia (n=27, 31)	0.00 units on a scale Interval -100.0 to 100.0	-8.33 units on a scale Interval -66.7 to 75.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Treatment (n=27, 31)	-6.25 units on a scale Interval -18.8 to 18.8	0.00 units on a scale Interval -53.1 to 37.5	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Future (n=26, 30)	-5.00 units on a scale Interval -25.0 to 10.0	0.00 units on a scale Interval -30.0 to 20.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Family Planning (n=15, 13)	0.00 units on a scale Interval -29.2 to 12.5	0.00 units on a scale Interval -43.8 to 25.0	—	—	—
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 Partnership and Sexuality (n=26, 30)	0.00 units on a scale Interval -50.0 to 66.7	0.00 units on a scale Interval -25.0 to 25.0	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Full Analysis Set: participants in the 2 prophylaxis arms (Arms 1 and 2) over 17 years of age who received at least 1 dose of rFIXFc 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). The areas covered by this instrument are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (all 7 domains, during the last month) and future, family planning, and outlook for the future (all 3 domains, recently). Changes from baseline for the Haem-A-QoL questionnaire are summarized by prestudy treatment regimen (pooled for Arms 1 and 2). 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.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=27 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=24 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Family Planning (n=14, 11)	0.00 units on a scale Interval -25.0 to 33.3	0.00 units on a scale Interval -12.5 to 12.5	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Physical Health (n=26, 23)	-10.00 units on a scale Interval -45.0 to 20.0	-15.00 units on a scale Interval -60.0 to 0.0	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Feeling (n=26, 23)	0.00 units on a scale Interval -37.5 to 75.0	0.00 units on a scale Interval -50.0 to 18.8	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 View of Yourself (n=26, 24)	-7.50 units on a scale Interval -45.0 to 20.0	-5.00 units on a scale Interval -35.0 to 15.0	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Sports and Leisure (n=20, 16)	-0.62 units on a scale Interval -55.0 to 27.5	-17.50 units on a scale Interval -55.0 to 17.5	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Work and School (n=22, 20)	0.00 units on a scale Interval -31.3 to 25.0	-3.13 units on a scale Interval -41.7 to 25.0	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Dealing with Hemophilia (n=27, 24)	0.00 units on a scale Interval -66.7 to 33.3	4.17 units on a scale Interval -66.7 to 66.7	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Treatment (n=27, 24)	-6.25 units on a scale Interval -30.8 to 15.6	-4.69 units on a scale Interval -34.4 to 34.4	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Future (n=26, 23)	-5.00 units on a scale Interval -40.0 to 20.0	-5.00 units on a scale Interval -40.0 to 15.0	—	—	—
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 Total Score (n=25, 19)	-4.35 units on a scale Interval -24.4 to 9.6	-6.06 units on a scale Interval -31.0 to 1.0	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 26, Week 52

Population: No summary analysis was done for this outcome measure due to the small number of participants completing the questionnaire.

The Haemo-QoL, a quality of life (QoL) assessment instrument for children and adolescents with hemophilia, was administered to participants from 13- to 17-years-old. This instrument assesses domains specific to living with hemophilia. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Participants in Arm 4 who received at least 1 dose of rFIXFc.

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: Weekly Prophylaxis n=14 Major Surgeries 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery Excellent or Good	14 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery Excellent	13 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery Good	1 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery Fair	0 responses	—	—	—	—
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery Poor/None	0 responses	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Participants in Arm 4 who received at least 1 dose of rFIXFc.

The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes including the loading dose to the end date/time of surgery.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=14 Major Surgeries 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Injections Required to Maintain Hemostasis During Major Surgery	1.00 injections Full Range 0.825 • Interval 1.0 to 4.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Participants in Arm 4 who received at least 1 dose of rFIXFc.

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: Weekly Prophylaxis n=14 Major Surgeries 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery Dose per Injection	90.91 IU/kg Full Range 30.869 • Interval 49.4 to 142.3	—	—	—	—
Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery Total Dose	102.59 IU/kg Full Range 60.930 • Interval 49.4 to 264.5	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Participants in Arm 4 who received at least 1 dose of rFIXFc.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=14 Major Surgeries 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Estimated Total Blood Loss During Major Surgery	65.50 mL Full Range 95.161 • Interval 0.0 to 300.0	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Participants in Arm 4 who received at least 1 dose of rFIXFc.

Number of blood component transfusions during a single surgery.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=14 Major Surgeries 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Transfusions Required Per Surgery 0 transfusions	12 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 3 transfusions	0 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery >3 transfusions	1 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 1 transfusion	0 surgeries	—	—	—	—
Number of Transfusions Required Per Surgery 2 transfusions	1 surgeries	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

Maximum concentration during a dosing interval. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Maximum Concentration (Cmax) rFIXFc Baseline	40.81 IU/dL Interval 33.6 to 49.58	—	—	—	—
Maximum Concentration (Cmax) BeneFIX	43.08 IU/dL Interval 36.69 to 50.59	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

Dose normalized area under the drug concentration-time curve. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Area Under the Curve (AUC) Per Dose rFIXFc Baseline	31.32 IU*h/dL per IU/kg Interval 27.88 to 35.18	—	—	—	—
Area Under the Curve (AUC) Per Dose BeneFIX	15.77 IU*h/dL per IU/kg Interval 14.02 to 17.74	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

Time required for the concentration of the drug to reach half of its original value. Alpha and beta half-life indicate distribution and elimination half-life in a two-compartment PK model. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Half Life (t1/2) Alpha and t1/2 Beta rFIXFc Baseline: t1/2 alpha	5.0279 hours Interval 3.2032 to 7.8919	—	—	—	—
Half Life (t1/2) Alpha and t1/2 Beta rFIXFc Baseline: t1/2 beta	82.12 hours Interval 71.39 to 94.46	—	—	—	—
Half Life (t1/2) Alpha and t1/2 Beta BeneFIX: t1/2 alpha	2.4113 hours Interval 1.6183 to 3.593	—	—	—	—
Half Life (t1/2) Alpha and t1/2 Beta BeneFIX: t1/2 beta	33.77 hours Interval 29.13 to 39.15	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Clearance (CL) BeneFIX	6.340 mL/h/kg Interval 5.637 to 7.131	—	—	—	—
Clearance (CL) rFIXFc Baseline	3.193 mL/h/kg Interval 2.843 to 3.587	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

The average time for all the drug molecules to reside in the body. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Mean Residence Time (MRT) BeneFIX	41.19 hours Interval 35.98 to 47.15	—	—	—	—
Mean Residence Time (MRT) rFIXFc Baseline	98.60 hours Interval 88.16 to 110.29	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

Volume of distribution at steady state. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Volume in Steady State (Vss) rFIXFc Baseline	314.8 mL/kg Interval 277.8 to 356.8	—	—	—	—
Volume in Steady State (Vss) BeneFIX	261.1 mL/kg Interval 222.9 to 305.9	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

IU/dL rise in plasma per IU/kg drug administered. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Incremental Recovery rFIXFc Baseline	0.9211 IU/dL per IU/kg Interval 0.771 to 1.1004	—	—	—	—
Incremental Recovery BeneFIX	0.9451 IU/dL per IU/kg Interval 0.8149 to 1.0961	—	—	—	—

SECONDARY outcome

Timeframe: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.

Population: Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.

Time to reach 1 or 3 IU/dL (%) after a single dose. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour \[5-day\] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=22 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Time to 1% and 3% FIX Activity rFIXFc Baseline: 1% Activity	11.224 days Interval 10.2 to 12.35	—	—	—	—
Time to 1% and 3% FIX Activity rFIXFc Baseline: 3% Activity	5.767 days Interval 5.066 to 6.565	—	—	—	—
Time to 1% and 3% FIX Activity BeneFIX: 1% Activity	5.087 days Interval 4.579 to 5.651	—	—	—	—
Time to 1% and 3% FIX Activity BeneFIX: 3% Activity	2.832 days Interval 2.568 to 3.123	—	—	—	—

SECONDARY outcome

Timeframe: up to 52 weeks ± 1 week

Population: Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc; a table was not generated for participants in the perioperative management/surgical arm (Arm 4). n=participants with a baseline assessment and at least one post-baseline assessment for temperature or at least one post-baseline assessment for pulse, SBP, and DBP.

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 rFIXFc dose. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=63 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=29 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs Pulse: >120 bpm or >20 bpm ↑ from BL, n=62,28,24	1 participants	2 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs Pulse: <50 bpm or >20 bpm ↓ from BL, n=62,28,24	2 participants	1 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs Temperature: >38°C and ≥1°C ↑ from BL, n=61,28,24	0 participants	0 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs SBP: >180 mm Hg or >40 mm Hg ↑ from BL, n=62,28,24	0 participants	1 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs SBP: <90 mm Hg or >30 mm Hg ↓ from BL, n=62,28,24	4 participants	1 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs DBP: >105 mm Hg or >30 mm Hg ↑ from BL, n=62,28,24	3 participants	0 participants	0 participants	—	—
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs DBP: <50 mm Hg or >20 mm Hg ↓ from BL, n=62,28,24	5 participants	4 participants	0 participants	—	—

SECONDARY outcome

Timeframe: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)

Population: The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=23 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=23 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) Pre-dosing Value (n=23, 23, 20, 19)	134.1 pmol/L Standard Deviation 64.93	130.0 pmol/L Standard Deviation 57.55	131.6 pmol/L Standard Deviation 42.43	176.7 pmol/L Standard Deviation 112.36	—
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) Change at 1 Hour Post-dosing (n=23, 22, 20, 0)	73.4 pmol/L Standard Deviation 171.68	8.6 pmol/L Standard Deviation 39.14	1.3 pmol/L Standard Deviation 51.64	NA pmol/L Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) Change at 6 Hours Post-dosing (n=23, 22, 20, 0)	7.8 pmol/L Standard Deviation 55.45	8.3 pmol/L Standard Deviation 38.66	-4.4 pmol/L Standard Deviation 45.95	NA pmol/L Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) Change at 24 Hours Post-dosing (n=23, 22, 18, 0)	-3.7 pmol/L Standard Deviation 34.39	9.8 pmol/L Standard Deviation 45.62	1.7 pmol/L Standard Deviation 27.14	NA pmol/L Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) Maximum Post-dosing Change (n=23, 23, 19, 0)	83.0 pmol/L Standard Deviation 168.71	30.9 pmol/L Standard Deviation 48.52	20.4 pmol/L Standard Deviation 49.38	NA pmol/L Standard Deviation NA assessment was not done at this time point	—

SECONDARY outcome

Timeframe: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)

Population: The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=23 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=23 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex Change at 1 Hour Post-dosing (n=23, 22, 20, 0)	6.67 ng/mL Standard Deviation 15.491	1.05 ng/mL Standard Deviation 4.019	0.11 ng/mL Standard Deviation 5.813	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex Change at 6 Hours Post-dosing (n=23, 22, 20, 0)	1.91 ng/mL Standard Deviation 7.303	1.07 ng/mL Standard Deviation 4.686	-0.09 ng/mL Standard Deviation 5.763	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex Maximum Post-dosing Change (n=23, 23, 19, 0)	7.42 ng/mL Standard Deviation 15.416	3.63 ng/mL Standard Deviation 7.000	0.32 ng/mL Standard Deviation 5.969	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex Pre-dosing Value (n=23, 23, 20, 19)	2.87 ng/mL Standard Deviation 2.891	2.87 ng/mL Standard Deviation 2.230	3.11 ng/mL Standard Deviation 4.075	4.28 ng/mL Standard Deviation 7.588	—
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex Change at 24 Hours Post-dosing (n=23, 22, 18, 0)	-0.58 ng/mL Standard Deviation 2.968	0.81 ng/mL Standard Deviation 6.095	-1.10 ng/mL Standard Deviation 4.308	NA ng/mL Standard Deviation NA assessment was not done at this time point	—

SECONDARY outcome

Timeframe: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)

Population: The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

Outcome measures

Outcome measures
Measure	Arm 1: Weekly Prophylaxis n=23 Participants 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=23 Participants 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 3: Episodic (On Demand) n=23 Participants 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes	Arm 4: Perioperative Management The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
Coagulation Parameter: Change From Pre-dose Values in D-dimer Pre-dosing Value (n=23, 22, 20, 19)	153.0 ng/mL Standard Deviation 119.37	176.2 ng/mL Standard Deviation 165.48	120.5 ng/mL Standard Deviation 73.38	134.7 ng/mL Standard Deviation 151.36	—
Coagulation Parameter: Change From Pre-dose Values in D-dimer Change at 1 Hour Post-dosing (n=23, 21, 20, 0)	35.9 ng/mL Standard Deviation 101.80	89.6 ng/mL Standard Deviation 509.24	-5.9 ng/mL Standard Deviation 28.18	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in D-dimer Change at 6 Hours Post-dosing (n=23, 21, 20, 0)	47.6 ng/mL Standard Deviation 259.70	-39.6 ng/mL Standard Deviation 134.42	-9.4 ng/mL Standard Deviation 16.84	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in D-dimer Change at 24 Hours Post-dosing (n=23, 21, 18, 0)	20.0 ng/mL Standard Deviation 85.93	-31.0 ng/mL Standard Deviation 138.22	-8.2 ng/mL Standard Deviation 26.06	NA ng/mL Standard Deviation NA assessment was not done at this time point	—
Coagulation Parameter: Change From Pre-dose Values in D-dimer Maximum Post-dosing Change (n=23, 22, 19, 0)	95.7 ng/mL Standard Deviation 266.98	100.6 ng/mL Standard Deviation 494.70	4.8 ng/mL Standard Deviation 16.10	NA ng/mL Standard Deviation NA assessment was not done at this time point	—

Adverse Events

Arm 1: Weekly Prophylaxis

Serious events: 5 serious events

Other events: 29 other events

Deaths: 0 deaths

Arm 2: Individualized Interval Prophylaxis

Serious events: 4 serious events

Other events: 17 other events

Deaths: 0 deaths

Arm 3: Episodic (On Demand)

Serious events: 4 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm 1: Weekly Prophylaxis n=63 participants at risk 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=29 participants at risk 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 participants at risk 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
Cardiac disorders Angina pectoris	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Abdominal adhesions	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Inguinal hernia	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.4% 1/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Cellulitis	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Device related infection	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Peritonsillar abscess	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.4% 1/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Musculoskeletal and connective tissue disorders Arthralgia	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.4% 1/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Renal and urinary disorders Obstructive uropathy	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.4% 1/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.

Other adverse events

Additional Information

Bioverativ Study Medical Director

Bioverativ

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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Arm 1: Weekly Prophylaxis n=63 participants at risk 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.	Arm 2: Individualized Interval Prophylaxis n=29 participants at risk 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.	Arm 3: Episodic (On Demand) n=27 participants at risk 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
Infections and infestations Nasopharyngitis	20.6% 13/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	13.8% 4/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Influenza	7.9% 5/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	14.8% 4/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Upper respiratory tract infection	6.3% 4/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Infections and infestations Sinusitis	4.8% 3/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Musculoskeletal and connective tissue disorders Arthralgia	9.5% 6/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.2% 2/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.4% 1/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	7.4% 2/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Gastrointestinal disorders Nausea	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Injury, poisoning and procedural complications Laceration	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Nervous system disorders Headache	3.2% 2/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	7.4% 2/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Nervous system disorders Dizziness	4.8% 3/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Investigations Weight increased	1.6% 1/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	7.4% 2/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Vascular disorders Hypertension	4.8% 3/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	3.7% 1/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	11.1% 3/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
Immune system disorders Allergy to arthropod bite	0.00% 0/63 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	6.9% 2/29 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.	0.00% 0/27 • up to 52 weeks + 30 days ± 1 week As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.