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

A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients ≥12 Years of Age With Severe Hemophilia A

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04161495

Acronym

XTEND-1

Enrollment

159

Registered

2019-11-13

Start date

2019-11-19

Completion date

2022-02-03

Last updated

2025-09-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Factor VIII Deficiency

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.

Interventions

BIOLOGICALefanesoctocog alfa (BIVV001)

Pharmaceutical form: solution for injection Route of administration: IV injection

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

Inclusion criteria

* Participant, male or female, must be equal to or greater than 12 years of age inclusive, at the time of signing the informed consent. * Severe hemophilia A, defined as less than (\<) 1 international units per deciliter (IU/dL) (\<1 percent \[%\]) endogenous FVIII activity as documented either by central laboratory testing at Screening or in historical medical records from a clinical laboratory demonstrating \<1% FVIII coagulant activity (FVIII:C) or a documented genotype known to produce severe hemophilia A. * Previous treatment for hemophilia A (prophylaxis or on demand) with any recombinant and/or plasma-derived FVIII, or cryoprecipitate for at least 150 exposure days. * Current regimen included one of the following: * Prophylactic treatment regimen with a FVIII product or prophylactic emicizumab therapy for at least 6 months during the previous 12 months. Appropriate washout time needs to be taken into account. * On-demand regimen with a FVIII product with a history of at least 12 bleeding episodes in the previous 12 months or at least 6 bleeding episodes in the previous 6 months prior to study enrollment. * On-demand participant was accepted to move to a prophylaxis treatment regimen after 26-week on-demand period. * Willingness and ability of the participant or surrogate (a caregiver or a family member greater than or equal to \[\>=\] 18 years of age) to complete training in the use of the study electronic Patient Diary (ePD) and to use the ePD throughout the study. * Ability of the participant or his or her legally authorized representative (eg., parent or legal guardian) to understand the purpose and risks of the study, willing and able to comply with study requirements and provide signed and dated informed consent or assent (as applicable) and authorization to use protected health information in accordance with national and local participant privacy regulations.

Exclusion criteria

* Clinically significant liver disease. * Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening. * Other known coagulation disorder(s) in addition to hemophilia A. * History of hypersensitivity or anaphylaxis associated with any FVIII product. * Positive inhibitor results, defined as \>=0.6 Bethesda unit per milliliter (BU/mL) at screening. History of a positive inhibitor test defined as \>=0.6 BU/mL. Family history of inhibitors would not exclude the participant. * Use of Emicizumab within the 20 weeks prior to screening. * Major surgery within 8 weeks prior to screening. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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).
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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).
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).
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.
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.
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 (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: 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: 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.
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: 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: 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.
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).
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.
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.
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.
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).

Countries

Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, France, Germany, Greece, Hungary, Italy, Japan, Mexico, Netherlands, South Korea, Spain, Taiwan, United Kingdom, United States

Participant flow

Recruitment details

Study was conducted at 51 active sites in 19 countries. A total of 170 participants were screened between 19 November 2019 to 19 March 2021, of which 11 had screen failure due to not meeting the eligibility criteria.

Pre-assignment details

A total of 159 participants were enrolled in this current study (EFC16293), of which 92 participants were rolled over from study OBS16221 and then subsequently enrolled and received BIVV001 in current study.

Participants by arm

Arm	Count
Arm A: Prophylaxis 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 IU/kg IV injection 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.	133
Arm B: On-Demand Then Prophylaxis 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.	26
Total Title	159
Total	318

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	Death	0	1
Overall Study	Other - Unspecified	1	0
Overall Study	Prohibited concomitant medication	3	0
Overall Study	Protocol Violation	1	0
Overall Study	Withdrawal by Subject	3	0

Baseline characteristics

Characteristic	Total Title	Arm B: On-Demand Then Prophylaxis	Arm A: Prophylaxis
Age, Continuous	35.4 years STANDARD_DEVIATION 15.1	42.8 years STANDARD_DEVIATION 11.7	33.9 years STANDARD_DEVIATION 15.3
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	29 Participants	0 Participants	29 Participants
Race (NIH/OMB) Black or African American	3 Participants	0 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	30 Participants	0 Participants	30 Participants
Race (NIH/OMB) White	97 Participants	26 Participants	71 Participants
Sex: Female, Male Female	1 Participants	0 Participants	1 Participants
Sex: Female, Male Male	158 Participants	26 Participants	132 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 133	1 / 26	0 / 26	1 / 159
other Total, other adverse events	56 / 133	7 / 26	1 / 26	64 / 159
serious Total, serious adverse events	13 / 133	2 / 26	0 / 26	15 / 159

Outcome results

Primary

Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis

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).

Time frame: Baseline to Week 52

Population: Analysis was performed on full analysis set (FAS) which included all participants who received at least 1 dose of study drug. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)
Arm A: Prophylaxis	Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis	0.71 episodes per participant per year

Primary

Observed Annualized Bleeding Rate in Arm A: Prophylaxis

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).

Time frame: Baseline to Week 52

Population: Analysis was performed on FAS population. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Observed Annualized Bleeding Rate in Arm A: Prophylaxis	0.71 episodes per participant per year	Standard Deviation 1.43

Secondary

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

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Group	Value (MEDIAN)
Arm A: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Joint	0.00 episodes per participant per year
Arm A: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Muscle	0.00 episodes per participant per year
Arm A: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Internal	0.00 episodes per participant per year
Arm A: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Skin/mucosa	0.00 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Skin/mucosa	0.00 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Joint	18.42 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Internal	0.00 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Muscle	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Skin/mucosa	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Muscle	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Internal	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	Joint	0.00 episodes per participant per year

Secondary

Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Group	Value (MEDIAN)
Arm A: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Traumatic	0.00 episodes per participant per year
Arm A: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Spontaneous	0.00 episodes per participant per year
Arm A: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Unknown type	0.00 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Traumatic	3.95 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Spontaneous	16.69 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Unknown type	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Spontaneous	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Unknown type	0.00 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	Traumatic	0.00 episodes per participant per year

Secondary

Annualized Bleeding Rate for All Bleeding Episodes

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Value (MEDIAN)
Arm A: Prophylaxis	Annualized Bleeding Rate for All Bleeding Episodes	0.00 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate for All Bleeding Episodes	21.13 episodes per participant per year
Arm B: Prophylaxis	Annualized Bleeding Rate for All Bleeding Episodes	0.00 episodes per participant per year

Secondary

Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants

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.

Time frame: Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. In this OM, ABR of Arm B: separately for participants during prophylaxis treatment versus On-Demand treatment was reported.

Arm	Measure	Value (MEDIAN)
Arm A: Prophylaxis	Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants	21.13 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants	0.00 episodes per participant per year

Secondary

Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis

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.

Time frame: Baseline, Week 52

Population: Analysis was performed on FAS population. Here, 'number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Swelling	-0.3 score on scale	Standard Deviation 1.2
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Duration Of Swelling	-0.2 score on scale	Standard Deviation 0.8
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Muscle Atrophy	-0.3 score on scale	Standard Deviation 1.2
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Crepitus On Motion	-0.3 score on scale	Standard Deviation 1.2
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Flexion Loss	-0.3 score on scale	Standard Deviation 1.6
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Extension Loss	-0.2 score on scale	Standard Deviation 1.5
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Joint Pain	-0.1 score on scale	Standard Deviation 1.2
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis	Strength	0.3 score on scale	Standard Deviation 0.6

Secondary

Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis

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.

Time frame: Baseline, Week 52

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this OM. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis	-1.5 score on a scale	Standard Deviation 6.4

Comparison: Testing according to hierarchical testing procedure (only performed if previous OM \[Change From Baseline in PROMIS Pain Intensity 3a First Item at Week 52: Prophylaxis Arm\] was statistically significant for considered dosing regimen). LS mean difference, standard error and 95% confidence interval were estimated by MMRM using visit as fixed effect and Baseline Haem-A-QOL physical health score as covariate.p-value: 0.010195% CI: [-2.7, -0.37]Unstructured covariance matrix

Secondary

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

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.

Time frame: Baseline, Week 52

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	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	-6.79 score on a scale	Standard Deviation 18.59

Comparison: Testing according to hierarchical testing procedure. Only performed if previous OM \[Annualized Bleeding Rate During the Efficacy Period in Prophylaxis Arm - Superiority Analysis\] was statistically significant for considered dosing regimen). Least square (LS) mean difference, standard error and 95% confidence interval were estimated by mixed-effect model with repeated measures (MMRM) using visit as fixed effect and Baseline Haem-A-QOL physical health score as covariate.p-value: 0.000195% CI: [-10.13, -3.36]Unstructured covariance matrix

Secondary

Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis

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.

Time frame: Baseline, Week 52

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis	-4.56 score on scale	Standard Deviation 11.15

Secondary

Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis

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.

Time frame: Baseline, Week 52

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis	-1.97 T-score	Standard Deviation 7.86

Comparison: Testing according to hierarchical testing procedure. Only performed if previous OM \[Change From Baseline in Haem-A-QOL Physical Health Score at Weeks 26 and 52: Prophylaxis Arm\] was statistically significant for considered dosing regimen). LS mean difference, standard error and 95% confidence interval were estimated by MMRM using visit as fixed effect and PROMIS Pain Intensity 3a score as covariate.p-value: 0.004295% CI: [-3.26, -0.63]Unstructured covariance matrix

Secondary

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

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.

Time frame: Baseline, Week 52

Population: Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data for this OM. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	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	0.62 T-score	Standard Deviation 4.77

Secondary

Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis

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).

Time frame: 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

Population: Analysis was performed on per protocol set which included all participants who had received at least one dose of study drug and did not had important protocol deviations potentially impacting efficacy. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)
Arm A: Prophylaxis	Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis	2.99 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis	0.69 episodes per participant per year

Comparison: Hierarchical testing framework: used to control type I error for secondary OM analyses. Statistical testing of Arm A intra-participant comparison non-inferiority continued only when estimation of previous OM was statistically significant at 0.05 level. For Arm A intra-participant comparison, mean difference and 95% confidence interval (CI) were estimated by NB regression model in which treatment (BIVV001 prophylaxis vs historical prophylaxis vs historical prophylaxis) was treated as covariate.95% CI: [-3.49, -1.11]

Secondary

Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis

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).

Time frame: 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

Population: Analysis was performed on FAS population. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)
Arm A: Prophylaxis	Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	2.96 episodes per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	0.69 episodes per participant per year

Comparison: Tested according to hierarchical testing procedure (only performed if the previous OM was statistically significant for the considered dosing regimen). For test about Arm A intra-participant comparison superiority, rate ratio and 95% CI were estimated using NB regression model in which treatment (BIVV001 prophylaxis vs historical prophylaxis) was treated as covariate.p-value: <0.000195% CI: [0.13, 0.42]Negative binomial regression mode

Secondary

Estimated Annualized Joint Bleeding Rate (AJBR)

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Value (MEAN)
Arm A: Prophylaxis	Estimated Annualized Joint Bleeding Rate (AJBR)	0.51 joint BE per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Estimated Annualized Joint Bleeding Rate (AJBR)	17.48 joint BE per participant per year
Arm B: Prophylaxis	Estimated Annualized Joint Bleeding Rate (AJBR)	0.62 joint BE per participant per year

Secondary

Estimated Blood Loss During Major 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).

Time frame: Day 0 (i.e., day of surgery)

Population: Analysis was performed on surgery subgroup population. Here, overall number of participants analyzed = participants with reported blood loss during major surgery and 'overall number of units analyzed' = number of major surgeries with blood loss report during the treatment regimen occurred in participants analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Estimated Blood Loss During Major Surgery	143.33 milliliters	Standard Deviation 189.38

Secondary

Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment

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.

Time frame: Baseline to Week 52

Population: Analyzed on a surgery subgroup population which included all participants who had undergone major surgery after the 1st dose of study drug. Here, 'overall number of participants analyzed' = participants with major surgeries during the treatment regimen and 'overall number of units analyzed' = number of major surgeries during the treatment regimen occurred in participants analyzed.

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Good	0 major surgeries
Arm A: Prophylaxis	Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Excellent or Good	12 major surgeries
Arm A: Prophylaxis	Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Excellent	12 major surgeries
Arm A: Prophylaxis	Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Fair	0 major surgeries
Arm A: Prophylaxis	Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment	Poor/none	0 major surgeries

Secondary

Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery

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).

Time frame: During the perioperative period (any time during Baseline up to Week 52)

Population: Analysis was performed on surgery subgroup population. Here, overall number of participants analyzed = participants with major surgeries during the treatment regimen and 'overall number of units analyzed' = number of major surgeries during the treatment regimen occurred in participants analyzed.

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Zero	12 transfusions per surgery
Arm A: Prophylaxis	Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	One	0 transfusions per surgery
Arm A: Prophylaxis	Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Two	0 transfusions per surgery
Arm A: Prophylaxis	Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Three	0 transfusions per surgery
Arm A: Prophylaxis	Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery	>Three	0 transfusions per surgery

Secondary

Number of Injections of BIVV001 Required to Treat a Bleeding Episode

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this OM. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Value (MEDIAN)
Arm A: Prophylaxis	Number of Injections of BIVV001 Required to Treat a Bleeding Episode	1.0 injections per participant
Arm A: BIVV001 Prophylaxis in EFC16293	Number of Injections of BIVV001 Required to Treat a Bleeding Episode	1.0 injections per participant
Arm B: Prophylaxis	Number of Injections of BIVV001 Required to Treat a Bleeding Episode	1.0 injections per participant

Secondary

Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery

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).

Time frame: During the perioperative period (any time during Baseline up to Week 52)

Population: Analysis was performed on surgery subgroup population. Here, 'overall number of participants analyzed' = participants with major surgeries during the treatment regimen and 'overall number of units analyzed' = number of major surgeries during the treatment regimen occurred in participants analyzed.

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	Zero injection	1 injections
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	One injection	11 injections
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	Two injection	0 injections
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	Three injection	0 injections
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	Four injection	0 injections
Arm A: Prophylaxis	Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery	>Four injection	0 injections

Secondary

Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on safety population. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Arm A: Prophylaxis	Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII	0 Participants
Arm A: BIVV001 Prophylaxis in EFC16293	Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII	0 Participants
Arm B: Prophylaxis	Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII	0 Participants

Secondary

Number of Participants With Occurrence of Embolic and Thrombotic Events

Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Arm A: Prophylaxis	Number of Participants With Occurrence of Embolic and Thrombotic Events	0 Participants
Arm A: BIVV001 Prophylaxis in EFC16293	Number of Participants With Occurrence of Embolic and Thrombotic Events	0 Participants
Arm B: Prophylaxis	Number of Participants With Occurrence of Embolic and Thrombotic Events	0 Participants

Secondary

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)

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.

Time frame: 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)

Population: Analysis was performed on safety population which included all participants who received at least one dose of study drug. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Arm A: Prophylaxis	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TEAE	108 Participants
Arm A: Prophylaxis	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TESAE	13 Participants
Arm A: BIVV001 Prophylaxis in EFC16293	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TEAE	12 Participants
Arm A: BIVV001 Prophylaxis in EFC16293	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TESAE	2 Participants
Arm B: Prophylaxis	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TEAE	8 Participants
Arm B: Prophylaxis	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	TESAE	0 Participants

Secondary

Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis

Population: Analysis was performed on FAS population. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	2.95 episodes per participant per year	Standard Deviation 5.19
Arm A: BIVV001 Prophylaxis in EFC16293	Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis	0.68 episodes per participant per year	Standard Deviation 1.5

Secondary

Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis

Time frame: 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

Population: Analysis was performed on per protocol set. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis	2.98 episodes per participant per year	Standard Deviation 5.21
Arm A: BIVV001 Prophylaxis in EFC16293	Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis	0.69 episodes per participant per year	Standard Deviation 1.51

Secondary

Observed Annualized Joint Bleeding Rate (AJBR)

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Observed Annualized Joint Bleeding Rate (AJBR)	0.52 joint BE per participant per year	Standard Deviation 1.09
Arm A: BIVV001 Prophylaxis in EFC16293	Observed Annualized Joint Bleeding Rate (AJBR)	17.45 joint BE per participant per year	Standard Deviation 7.31
Arm B: Prophylaxis	Observed Annualized Joint Bleeding Rate (AJBR)	0.61 joint BE per participant per year	Standard Deviation 1.33

Secondary

Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. Here, 'Overall number of participants analyzed' = participants with available data for this OM and 'overall number of units analyzed' = total number of treated bleeding episodes. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Value (NUMBER)
Arm A: Prophylaxis	Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001	94.2 percentage of bleeding episodes
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001	97.4 percentage of bleeding episodes
Arm B: Prophylaxis	Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001	100 percentage of bleeding episodes

Secondary

Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis

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.

Time frame: Baseline to Week 52

Population: Analysis was performed on pharmacokinetic (PK) analysis set which included participants who had completed adequate blood sample collection to assess key PK parameters. Here, 'overall number of participants analyzed' = participants with available data for this OM. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	>1%	100 percentage of participants
Arm A: Prophylaxis	Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	>5%	99.0 percentage of participants
Arm A: Prophylaxis	Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	>10%	83.5 percentage of participants
Arm A: Prophylaxis	Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	>15%	40.8 percentage of participants
Arm A: Prophylaxis	Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis	>20%	17.5 percentage of participants

Secondary

Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. Here, 'Overall number of participants analyzed' = participants with available data for this OM. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Moderate	13.7 percentage of participants
Arm A: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Good	28.8 percentage of participants
Arm A: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent or Good	82.2 percentage of participants
Arm A: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent	53.4 percentage of participants
Arm A: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	None	4.1 percentage of participants
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Good	22.0 percentage of participants
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent or Good	98.4 percentage of participants
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent	76.5 percentage of participants
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Moderate	1.6 percentage of participants
Arm A: BIVV001 Prophylaxis in EFC16293	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	None	0 percentage of participants
Arm B: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	None	0 percentage of participants
Arm B: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Moderate	0 percentage of participants
Arm B: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent or Good	100 percentage of participants
Arm B: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Good	16.7 percentage of participants
Arm B: Prophylaxis	Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Excellent	83.3 percentage of participants

Secondary

Pharmacokinetics: Accumulation Index (AI)

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.

Time frame: Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26

Population: Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this OM. Data for this OM was planned to be collected and analyzed for combined population of Arm A and B. For Week 26, PK samples were collected and analyzed for arm A only as per protocol.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Accumulation Index (AI)	1.17 ratio	Standard Deviation 0.16

Secondary

Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)

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.

Time frame: 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)

Population: Analysis was performed on PK population. Here, 'number analyzed' = participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined population of Arm A and B. For Week 26, PK samples were collected and analyzed for arm A only as per protocol.

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)	Baseline	9600 hour*IU/deciliter	Standard Deviation 2010
Arm A: Prophylaxis	Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)	Week 26	11800 hour*IU/deciliter	Standard Deviation 2720

Secondary

Pharmacokinetics: Clearance (CL)

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.

Time frame: Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Clearance (CL)	0.508 milliliter per hour per kilogram	Standard Deviation 0.124

Secondary

Pharmacokinetics: Elimination Half-life (t1/2z)

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.

Time frame: 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

Arm	Measure	Group	Value (MEDIAN)
Arm A: Prophylaxis	Pharmacokinetics: Elimination Half-life (t1/2z)	Baseline	46.5 hours
Arm A: Prophylaxis	Pharmacokinetics: Elimination Half-life (t1/2z)	Week 26	46.7 hours

Secondary

Pharmacokinetics: Incremental Recovery (IR)

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.

Time frame: Pre-dose, 0.25 hours post-dose on Day 1 (Baseline); pre-dose, 0.25 hours post-dose on Week 26 (Day 183)

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Incremental Recovery (IR)	Baseline	2.60 IU/dL per IU/kg	Standard Deviation 0.648
Arm A: Prophylaxis	Pharmacokinetics: Incremental Recovery (IR)	Week 26	3.05 IU/dL per IU/kg	Standard Deviation 0.592

Secondary

Pharmacokinetics: Mean Residence Time (MRT)

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.

Time frame: 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)

Arm	Measure	Group	Value (MEDIAN)
Arm A: Prophylaxis	Pharmacokinetics: Mean Residence Time (MRT)	Baseline	61.9 hours
Arm A: Prophylaxis	Pharmacokinetics: Mean Residence Time (MRT)	Week 26	66.1 hours

Secondary

Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)

Cmax was defined as the maximum observed plasma FVIII Activity.

Time frame: Baseline (15 minutes post-dose on Day 1) and 15 minutes post-dose on Week 52

Population: Analysis was performed on PK population which included all participants who had completed adequate blood sample collection to assess key PK parameters. Here, 'number analyzed' = participants with available data for each specified category.

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Baseline	125.05 IU per deciliter	Standard Deviation 31.72
Arm A: Prophylaxis	Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Week 52	144.72 IU per deciliter	Standard Deviation 36.65
Arm A: BIVV001 Prophylaxis in EFC16293	Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Baseline	138.36 IU per deciliter	Standard Deviation 48.66
Arm A: BIVV001 Prophylaxis in EFC16293	Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Week 52	149.42 IU per deciliter	Standard Deviation 29.63

Secondary

Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels

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.

Time frame: Pre-dose and 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)

Population: Analysis was performed on PK population. Data for this OM was planned to be collected and analyzed for combined population of Arm A and B.

Arm	Measure	Group	Value (MEDIAN)
Arm A: Prophylaxis	Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels	Time to 10 IU/dL	185 hours
Arm A: Prophylaxis	Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels	Time to 40 IU/dL	85.1 hours

Secondary

Pharmacokinetics: Total Clearance at Steady State (CLss)

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.

Time frame: Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Total Clearance at Steady State (CLss)	0.449 milliliter per hour per kilogram	Standard Deviation 0.101

Secondary

Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)

Ctrough is the pre-dose concentration of a drug.

Time frame: Pre-dose at Baseline (Day 1) and Week 52

Population: Analysis was performed on PK population. Here, 'number analyzed' = participants with available data for each specified category.

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Baseline	0.00 IU/dL	Standard Deviation 0
Arm A: Prophylaxis	Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Week 52	15.70 IU/dL	Standard Deviation 10.72
Arm A: BIVV001 Prophylaxis in EFC16293	Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Baseline	0.00 IU/dL	Standard Deviation 0
Arm A: BIVV001 Prophylaxis in EFC16293	Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Week 52	21.14 IU/dL	Standard Deviation 29.59

Secondary

Pharmacokinetics: Volume of Distribution at Steady State (Vss)

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.

Time frame: 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)

Arm	Measure	Group	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Pharmacokinetics: Volume of Distribution at Steady State (Vss)	Baseline	31.7 milliliters per kilogram	Standard Deviation 7.44
Arm A: Prophylaxis	Pharmacokinetics: Volume of Distribution at Steady State (Vss)	Week 26	29.6 milliliters per kilogram	Standard Deviation 8.26

Secondary

Physicians' Global Assessment of Participant's Response to BIVV001 Treatment

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Excellent	95.7 percentage of responses
Arm A: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Effective	4.3 percentage of responses
Arm A: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Partially effective	0 percentage of responses
Arm A: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Ineffective	0 percentage of responses
Arm A: BIVV001 Prophylaxis in EFC16293	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Ineffective	0 percentage of responses
Arm A: BIVV001 Prophylaxis in EFC16293	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Excellent	96.1 percentage of responses
Arm A: BIVV001 Prophylaxis in EFC16293	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Partially effective	0 percentage of responses
Arm A: BIVV001 Prophylaxis in EFC16293	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Effective	3.9 percentage of responses
Arm B: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Ineffective	0 percentage of responses
Arm B: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Effective	6.8 percentage of responses
Arm B: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Partially effective	0 percentage of responses
Arm B: Prophylaxis	Physicians' Global Assessment of Participant's Response to BIVV001 Treatment	Excellent	93.2 percentage of responses

Secondary

Total Annualized BIVV001 Consumption Per Participant

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Arm	Measure	Value (MEDIAN)
Arm A: Prophylaxis	Total Annualized BIVV001 Consumption Per Participant	2756.99 IU/kg per participant per year
Arm A: BIVV001 Prophylaxis in EFC16293	Total Annualized BIVV001 Consumption Per Participant	1212.27 IU/kg per participant per year
Arm B: Prophylaxis	Total Annualized BIVV001 Consumption Per Participant	2737.53 IU/kg per participant per year

Secondary

Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery

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.

Time frame: Day -1 to Day 14

Population: Analysis was performed on surgery subgroup population. Here, overall number of participants analyzed = participants with major surgeries during the treatment regimen and 'overall number of units analyzed' field = number of major surgeries with BIVV001 administration within Day -1 to Day 14.

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery	166.71 IU/kg per major surgery	Standard Deviation 72.48

Secondary

Total Dose of BIVV001 Required to Treat Bleeding Episode

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.

Time frame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this OM and 'overall number of units analyzed' = total number of treated bleeding episodes. Data for this OM was planned to be collected and analyzed separately in Arm B for participants during on-demand treatment and during prophylaxis treatment post switch.

Arm	Measure	Value (MEDIAN)
Arm A: Prophylaxis	Total Dose of BIVV001 Required to Treat Bleeding Episode	50.85 IU/kg
Arm A: BIVV001 Prophylaxis in EFC16293	Total Dose of BIVV001 Required to Treat Bleeding Episode	50.96 IU/kg
Arm B: Prophylaxis	Total Dose of BIVV001 Required to Treat Bleeding Episode	49.79 IU/kg

Secondary

Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major 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).

Time frame: Day -1 to Day 0 (day of surgery)

Population: Analysis was performed on surgery subgroup population. Here, 'overall number of participants analyzed' = participants with major surgeries during the treatment regimen and 'overall number of units analyzed' = number of major surgeries for which a loading dose was given on the day of surgery or one day prior to surgery (i.e. Day -1).

Arm	Measure	Value (MEAN)	Dispersion
Arm A: Prophylaxis	Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery	41.65 IU/kg	Standard Deviation 15.21

Secondary

Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis

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.

Time frame: Week 52

Population: Analysis was performed on FAS population. Here, 'overall number of participants analyzed' = participants with available data for this OM and 'overall number of units analyzed' = total number of evaluable target joints with \>=3 spontaneous bleeding at Baseline and with 12 months continuous exposure. Data for this OM was not planned to be collected and analyzed for Arm B.

Arm	Measure	Value (NUMBER)
Arm A: Prophylaxis	Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis	45 Target joints resolved

Secondary

Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery

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).

Time frame: During the perioperative period (any time during Baseline up to Week 52)

Arm	Measure	Group	Value (NUMBER)
Arm A: Prophylaxis	Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Red Blood Cell	0 transfusions per surgery
Arm A: Prophylaxis	Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Platelet	0 transfusions per surgery
Arm A: Prophylaxis	Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Fresh Frozen Plasma	0 transfusions per surgery
Arm A: Prophylaxis	Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Whole Blood	0 transfusions per surgery
Arm A: Prophylaxis	Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery	Other	0 transfusions per surgery

Source: ClinicalTrials.gov · Data processed: Mar 7, 2026

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

Conditions

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis

Observed Annualized Bleeding Rate in Arm A: Prophylaxis

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

Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)

Annualized Bleeding Rate for All Bleeding Episodes

Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants

Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis

Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis

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

Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis

Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis

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

Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis

Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis

Estimated Annualized Joint Bleeding Rate (AJBR)

Estimated Blood Loss During Major Surgery

Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment

Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery

Number of Injections of BIVV001 Required to Treat a Bleeding Episode

Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery

Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII

Number of Participants With Occurrence of Embolic and Thrombotic Events

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)

Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis

Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis

Observed Annualized Joint Bleeding Rate (AJBR)

Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001

Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis

Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale

Pharmacokinetics: Accumulation Index (AI)

Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)

Pharmacokinetics: Clearance (CL)

Pharmacokinetics: Elimination Half-life (t1/2z)

Pharmacokinetics: Incremental Recovery (IR)

Pharmacokinetics: Mean Residence Time (MRT)

Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)

Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels

Pharmacokinetics: Total Clearance at Steady State (CLss)

Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)

Pharmacokinetics: Volume of Distribution at Steady State (Vss)

Physicians' Global Assessment of Participant's Response to BIVV001 Treatment

Total Annualized BIVV001 Consumption Per Participant

Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery

Total Dose of BIVV001 Required to Treat Bleeding Episode

Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery

Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis

Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery