A Phase 3 Open-label Interventional Study of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein, Efanesoctocog Alfa (BIVV001), in Patients With Severe Hemophilia A

Phase 3

Completed

Conditions: Factor VIII Deficiency

Interventions: Biological: efanesoctocog alfa (BIVV001)

Registration Number: NCT04161495

Lead Sponsor: Bioverativ, a Sanofi company

Brief Summary: Primary Objective:

- To evaluate the efficacy of BIVV001 as a prophylaxis treatment in prophylaxis treatment arm.

Secondary Objectives:

* To evaluate the efficacy of BIVV001 as a prophylaxis treatment.

* To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes.

* To evaluate BIVV001 consumption for the prevention and treatment of bleeding episodes.

* To evaluate the effect of BIVV001 prophylaxis on joint health outcomes.

* To evaluate the effect of BIVV001 prophylaxis on Quality of Life outcomes.

* To evaluate the efficacy of BIVV001 for perioperative management.

* To evaluate the safety and tolerability of BIVV001 treatment.

* To assess the pharmacokinetics (PK) of BIVV001 based on the 1-stage activated partial thromboplastin time (aPTT) and 2-stage chromogenic coagulation factor VIII (FVIII) activity assays.

Detailed Description: Participants in prophylaxis arm received a weekly prophylactic dose of BIVV001 for 52 weeks. Participants in on-demand arm received BIVV001 on demand for 26 weeks followed by a switch to weekly prophylaxis for another 26 weeks.

The Sponsor planned to perform a long-term safety trial. Enrollment in this open-label extension study would be offered to participants completing the treatment period based on eligibility criteria.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 159

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: On-Demand Then Prophylaxis	efanesoctocog alfa (BIVV001)	Participants who were on an on-demand treatment regimen with a FVIII product prior to study EFC16293, including participants who rolled over from study OBS16221, received BIVV001 50 IU/kg IV injection as an on-demand treatment (as needed for the treatment of bleeding episodes) from Week 1 to Week 26 in current study. At Week 26, participants in Arm B were switched to prophylaxis treatment, and received BIVV001 50 IU/kg, IV injection QW until Week 52.
Arm A: Prophylaxis	efanesoctocog alfa (BIVV001)	Participants who were on a prophylaxis treatment with a FVIII product prior to study EFC16293 including participants who rolled over from study OBS16221, received BIVV001 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) for 52 weeks in the current study. Study OBS16221 participants with 6 months historical data on prophylaxis treatment with a marketed FVIII product prior to enrollment were analyzed as a subgroup (named as: Arm A: Historical Prophylaxis \[OBS16221\]) in the outcome measure analysis.

Primary Outcome Measures

Name	Time	Method
Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis	Baseline to Week 52	ABR is annualized number of treated bleeding episodes (BE) per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered less than or equal to (\<=) 72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated BE during efficacy period (EP)/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This outcome measure (OM) presents estimated results (i.e., results estimated by fitting negative binomial \[NB\] regression model on data collected during EP).
Observed Annualized Bleeding Rate in Arm A: Prophylaxis	Baseline to Week 52	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

Secondary Outcome Measures

Name	Time	Method
Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis	Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 prophylaxis: Baseline up to Week 52 of current study EFC16293	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents estimated results (i.e., results received estimated by fitting NB regression model on data collected during EP).
Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis	Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).
Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents estimated results (i.e., results received estimated by fitting NB regression model on data collected during EP).
Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. Following domains were assessed for elbows, knee and ankle joints: swelling (score 0 = no swelling to 3=severe), duration of swelling (score 0 = no swelling and 1 = \>=6 months), muscle atrophy (score 0 = none to 2 = severe), crepitus on motion (score 0 = none to 2=severe), flexion loss (score 0 = \<5' to 3 = \>20'), extension loss (score 0 = \<5' to 3 = \>20'), joint pain (score 0 = no pain through active range of motion to 2 = pain through active range) and strength (score 0 = holds test position with maximum resistance to 4 = trace/no muscle contraction), in each item 0 = none and higher score = severe damage.
Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants	Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR = (Number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens.
Number of Injections of BIVV001 Required to Treat a Bleeding Episode	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	The number of injections required to resolve each bleeding episode was averaged across all bleeding episodes per participant. A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode.
Total Dose of BIVV001 Required to Treat Bleeding Episode	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	The total dose (IU/kg) used to resolve each bleeding episode was averaged across all bleeding episodes per participant. A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode.
Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	Baseline to Week 52	FVIII activity level was measured using activated partial thromboplastin time (aPTT)-based one stage clotting assay. Percentage of participants who achieved steady-state trough FVIII activity levels above (\>) 1%, 5%, 10%, 15%, and 20% were reported for Arm A: Prophylaxis in this OM. Participants were counted in more than one row, as applicable.
Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	During the perioperative period (any time during Baseline up to Week 52)	The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The type of blood component (Red blood cell, platelet, fresh frozen plasma, whole blood and other) transfusions used were summarized for all major surgeries. Post-operative referred to the day following the end of surgery to the date of hospital discharge. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Number of Participants With Occurrence of Embolic and Thrombotic Events	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging.
Pharmacokinetics: Clearance (CL)	Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)	CL is defined as the rate at which the drug is removed from the body. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)	Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)	AUC0-tau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to dosing interval. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels	Pre-dose and 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)	Time above predefined (10 and 40%) FVIII activity levels mean time which BIVV001 maintains above 10 IU/dL and 40 IU/dL with single dose of 50 IU/kg. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline; however, participants did not receive BIVV001 dose in week 2 and week 27.
Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this OM.
Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	The participant's response related to each injection of BIVV001 treatment for treating a bleed was evaluated using ISTH 4-point response scale categorized as: Excellent (complete pain relief/complete resolution of signs of bleeding), Good (significant pain relief/improvement in signs of bleeding), Moderate (modest pain relief/improvement in signs of bleeding) and none (no or minimal improvement/condition worsened). Assessment was performed approximately 72 hours after the initial treatment for the bleeding episode. Bleeding episode was defined as an episode that started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections \<=72 hours apart were considered same bleeding episode. Participants were counted in more than one row, as applicable.
Total Annualized BIVV001 Consumption Per Participant	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	Total annualized BIVV001 consumption (in IU/kg) was calculated for each participant as: Total IU/kg of BIVV001 during EP divided by total number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens.
Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery	Day -1 to Day 14	Perioperative period: time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total BIVV001 consumption were summarized from the loading dose (the day before surgery, i.e, on Day -1) up to 2 weeks following the surgery (i.e., Day 14) and were reported in this OM.
Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	Haem-A-QoL: participant-reported questionnaire designed for adult participants (\>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health \[5 items\], feelings \[4 items\], view of self \[5 items\], sports and leisure \[5 items\], work and school \[4 items\], dealing with hemophilia \[3 items\], treatment \[8 items\], future \[5 items\], family planning \[4 items\], partnership and sexuality \[3 items\]). Items were rated along 5 response options: 1=never, 2=rarely, 3=sometimes,4=often, and 5=all the time and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better physical health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores = better quality of life.
Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	During the perioperative period (any time during Baseline up to Week 52)	The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of blood component transfusions used during perioperative period were summarized categorically (0, 1, 2, 3 and \>3) for all major surgeries for the surgery subgroup. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Estimated Blood Loss During Major Surgery	Day 0 (i.e., day of surgery)	The estimated total blood loss (in milliliters) during major surgeries were summarized. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	Arm A: From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55); Arm B: On-demand: Baseline to Week 26 and Arm B: Prophylaxis: From Week 26 up to 3 weeks post last dose of BIVV001 in Week 52 (i.e., up to Week 55)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. Treatment-emergent AEs were AEs that developed, worsened or became serious from Baseline (Day 1) up to 3 weeks post last dose.
Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293	ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).
Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	Haem-A-QoL is a participant-reported questionnaire designed for adult participants (greater than or equal to \[\>=\] 17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health \[5 items\], feelings \[4 items\], view of self \[5 items\], sports and leisure \[5 items\], work and school \[4 items\], dealing with hemophilia \[3 items\], treatment \[8 items\], future \[5 items\], family planning \[4 items\], partnership and sexuality \[3 items\]). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health. Change from baseline in physical Health domain score was reported in this OM.
Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	PROMIS is a system of reliable and precise measures of participant-reported heath status. PROMIS measures cover physical, mental and social health and can be used for many chronic conditions. PROMIS - Pain Intensity - Short Form 3a consisted of 3 questions, participants reported for the intensity of pain experienced in the past 7 days. Each question had 5 responses scored between 1 (had no pain) to 5 (very severe pain). Total PROMIS pain intensity 3a score range was from 3 (no pain) to 15 (very severe pain), where higher score indicated more intense pain. Total raw score was converted into a T-score which rescaled raw score into standardized score with mean of 50 and standard deviation (SD) of 10. Higher PROMIS T-score represented worst outcome. For PROMIS pain intensity 3a, T-score of 60 was one SD worse than average.
Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 and 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage.
Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	ABR: annualized number of treated bleeding episodes per participant per year. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: bleeding episode without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: bleeding episode with known/believed reason for bleed.
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	ABR: annualized number of treated bleeding episodes per participant per year. Efficacy period reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: bleeding episode without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: bleeding episode with known/believed reason for bleed.
Annualized Bleeding Rate for All Bleeding Episodes	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	ABR: annualized number of all bleeding (treated and untreated) episodes/participant/year. ABR = number of all bleeding episodes during EP/number of days in EP\*365.25. EP reflects sum of all time intervals during which participants were treated with BIVV001 according to study arms and treatment regimens. Bleeding episode: episode started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location: considered as separate bleeding episode, regardless of time from last injection. Spontaneous: bleeding without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic: bleeding with known/believed reason.
Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	Physicians assessed participant's response to BIVV001 treatment using 4-point response scale: Excellent=bleeding episodes (BE) responded to fewer than/usual number of injections/less than/usual dose of FVIII/rate of breakthrough bleeding during prophylaxis was \<= that usually observed; Effective = most BE responded to same number of injections and dose, but some required more injections/higher doses/there was minor increase in rate of breakthrough bleeding; partially effective = BE most often required more injections and/or higher doses than expected/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. Percentages were based on total number of responses.
Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Baseline (15 minutes post-dose on Day 1) and 15 minutes post-dose on Week 52	Cmax was defined as the maximum observed plasma FVIII Activity.
Pharmacokinetics: Elimination Half-life (t1/2z)	pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26	Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Total Clearance at Steady State (CLss)	Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26	CLss is defined as the rate at which the drug is removed from the body at steady state. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Change From Baseline in Patient Reported Outcomes Measurements Information Systems Short Form (PROMIS-SF) Physical Function (PF) 6b at Week 52 in Arm A: Prophylaxis	Baseline, Week 52	PROMIS-SF v2.0 PF 6b consisted of 2-items from item-improved Health Assessment Questionnaire (HAQ) and 4-items from item-improved Physical Function-10 (PF-10) instruments. Both of these instruments assessed participant's present abilities and had 5-response options: HAQ: 1=without any difficulty, 2=with little difficulty, 3=with some difficulty, 4=with much difficulty,5=unable to do and PF-10: 1=not at all, 2=very little, 3=somewhat, 4=quite a lot, 5=cannot do. Total score of PROMIS-SF PF 6b: average scores of component items, which ranged from 0 (no disability) to 100 (worst disability). T-score rescales raw scale score (sum of scores from all questions answered) into a standardized score with a mean of 50 and standard deviation of 10, based on scoring tables provided in PROMIS Scoring Manuals. Higher PROMIS T-score=more of concept being measured.
Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Baseline to Week 52	The Investigators/Surgeons who complete the surgical procedures assess the participant's response to surgery with BIVV001 treatment using a 4-point scale, where responses were categorized as worst response: 1 = Excellent, 2 = Good, 3 = Fair, and 4 = Poor/none. Higher score indicated worst response. This assessment was performed 24 hours after the surgery. A surgery can be counted in more than one response category.
Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	During the perioperative period (any time during Baseline up to Week 52)	Perioperative period was time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of injections to maintain hemostasis (a process to prevent and stop bleeding from a blood vessel) per surgery included all injections from loading dose (i.e., the preoperative injection, administered either on the day of surgery or one day prior to the surgery), to the end of surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery	Day -1 to Day 0 (day of surgery)	Perioperative period was time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total dose (IU/kg) was the sum across all injections per major surgery (including loading dose) needed to maintain hemostasis (a process to prevent and stop bleeding from a blood vessel) during surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Day 0 was defined as the surgery day. The loading dose for a given surgery was the preoperative injection, administered either on the day of surgery or one day prior to the surgery (i.e., Day -1).
Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	Development of inhibitors was defined as an inhibitor result of \>=0.6 bethesda unit per milliliter (BU/mL) that was confirmed by a second test result of \>=0.6 BU/mL from a separate sample, drawn 2 to 4 weeks following the date when the original sample was drawn. Both tests must have been performed by the central laboratory using the Nijmegen-modified Bethesda assay.
Estimated Annualized Joint Bleeding Rate (AJBR)	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint bleeding episodes during EP divided by total number of days during EP\*365.25. Joint bleeding episode: an unusual sensation in joint ('aura') in combination with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. Bleeding episode (BE): episode that started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections \<=72 hours apart were considered same bleeding episode. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens.
Observed Annualized Joint Bleeding Rate (AJBR)	Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52	AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint bleeding episodes during EP divided by total number of days during EP\*365.25. Joint bleeding episode: unusual sensation in joint ('aura') with 1) in combination with increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. BE: episode that started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections \<= 72 hours apart were considered same bleeding episode. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens.
Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis	Week 52	A target joint at baseline was defined as a major joint with \>=3 spontaneous bleeding episodes in a consecutive 6 month period prior to entry to the study, captured at Baseline. A target joint resolved was defined as \<=2 spontaneous bleeds into that joint during 12 months of continuous exposure. Total number of target joints resolved at Week 52 were reported.
Pharmacokinetics: Accumulation Index (AI)	Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26	AI is the ratio of accumulation of a drug under steady state conditions (i.e., after repeated administration) as compared to a single dose. AI was calculated as ratio of area under the curve (AUC) at Week 26 (Day 183) divided by AUC at Day 1, where AUC is the area under the plasma concentration versus time curve from time 0 to infinity. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Volume of Distribution at Steady State (Vss)	Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)	Volume of distribution (Vd) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Mean Residence Time (MRT)	Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)	MRT is the average total time a drug molecule spends in the body. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.
Pharmacokinetics: Incremental Recovery (IR)	Pre-dose, 0.25 hours post-dose on Day 1 (Baseline); pre-dose, 0.25 hours post-dose on Week 26 (Day 183)	IR was calculated as (Peak activity \[in IU/dL\] - Trough activity \[in IU/dL\])/Actual Dose (in IU/kg), and peak activity at each visit was the highest activity level after the dosing, and trough activity at each visit was the activity level prior to the dosing.
Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Pre-dose at Baseline (Day 1) and Week 52	Ctrough is the pre-dose concentration of a drug.

Trial Locations

Locations (46): Investigational Site Number 532
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Taipei, Taiwan
Investigational Site Number 205
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Hamilton, Canada
Investigational Site Number 121
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Perth, Australia
Investigational Site Number 171
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Plovdiv, Bulgaria
Investigational Site Number 161
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Brussels, Belgium
Investigational Site Number 302
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Bonn, Germany
Investigational Site Number 304
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Berlin, Germany
Investigational Site Number 321
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Athens, Greece
Investigational Site Number 312
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Budapest, Hungary
Investigational Site Number 303
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Frankfurt, Germany
Investigational Site Number 603
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Daegu, Korea, Republic of
Investigational Site Number 902
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Seattle, Washington, United States
Investigational Site Number 920
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Los Angeles, California, United States
Investigational Site Number 921
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Los Angeles, California, United States
Investigational Site Number 136
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Buenos Aires, Argentina
Investigational Site Number 137
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Buenos Aires, Argentina
Investigational Site Number 908
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Lansing, Michigan, United States
Investigational Site Number 122
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Sydney, Australia
Investigational Site Number 139
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Mendoza, Argentina
Investigational Site Number 202
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Hamilton, Canada
Investigational Site Number 181
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Campinas, Brazil
Investigational Site Number 172
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Sofia, Bulgaria
Investigational Site Number 283
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Lille, France
Investigational Site Number 281
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Brest, France
Investigational Site Number 282
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Lyon, France
Investigational Site Number 284
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Marseille, France
Investigational Site Number 314
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Debrecen, Hungary
Investigational Site Number 402
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Milan, Italy
Investigational Site Number 426
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Kawasaki, Japan
Investigational Site Number 401
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Vicenza, Italy
Investigational Site Number 422
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Nara, Japan
Investigational Site Number 423
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Kitakyushu, Japan
Investigational Site Number 425
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Nagoya, Japan
Investigational Site Number 421
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Tokyo, Japan
Investigational Site Number 424
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Tokyo, Japan
Investigational Site Number 531
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Chang Hua, Taiwan
Investigational Site Number 435
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Durango, Mexico
Investigational Site Number 521
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Madrid, Spain
Investigational Site Number 641
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Utrecht, Netherlands
Investigational Site Number 601
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Seoul, Korea, Republic of
Investigational Site Number 600
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Seoul, Korea, Republic of
Investigational Site Number 581
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London, United Kingdom
Investigational Site Number 911
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San Diego, California, United States
Investigational Site Number 917
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Gainesville, Florida, United States
Investigational Site Number 919
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Ann Arbor, Michigan, United States
Investigational Site Number 906
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Las Vegas, Nevada, United States