Safety, Efficacy and PK of BIVV001 in Pediatric Patients With Hemophilia A (XTEND-Kids)

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 Pediatric Patients <12 Years of Age With Severe Hemophilia A

Primary Objective:

- To evaluate the safety of BIVV001 in previously treated pediatric participants with hemophilia A.

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 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 (QoL) 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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: efanesoctocog alfa (BIVV001)

Detailed Description

Study duration per participants was approximately 60 weeks (maximum 8 weeks for screening and 52 weeks of treatment).

All participants completing or remaining at the end of study were offered participation in the planned extension trial.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Investigational Site Number :0360001
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Investigational Site Number :0360002
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Investigational Site Number :1240004
    • London, Ontario, Canada, N6A 4G5
      • Investigational Site Number :1240003
    • Ottawa, Ontario, Canada, K1H 8L1
      • Investigational Site Number :1240002
    • Toronto, Ontario, Canada, M5G 1X8
      • Investigational Site Number :1240001
• France
  • Bron, France, 69500
    • Investigational Site Number :2500004
  • Kremlin Bicetre, France, 94275
    • Investigational Site Number :2500001
  • Lille, France, 59037
    • Investigational Site Number :2500003
• Germany
  • Frankfurt am Main, Germany, 60590
    • Investigational Site Number :2760001
  • München, Germany, 80337
    • Investigational Site Number :2760002
• Hungary
  • Pécs, Hungary, 7623
    • Investigational Site Number :3480005
• Ireland
  • Dublin, Ireland, D12 N512
    • Investigational Site Number :3720001
• Italy
  • Milano, Italy, 20121
    • Investigational Site Number :3800001
  • Napoli, Italy, 80123
    • Investigational Site Number :3800002
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number :5280002
  • Utrecht, Netherlands, 3584 CX
    • Investigational Site Number :5280001
• Spain
  • Catalunya [Cataluña]
    • Esplugues de Llobregat, Catalunya [Cataluña], Spain, 08950
      • Investigational Site Number :7240002
  • Madrid, Comunidad De
    • Madrid, Madrid, Comunidad De, Spain, 28046
      • Investigational Site Number :7240001
• Sweden
  • Malmö, Sweden, 20502
    • Investigational Site Number :7520001
• Switzerland
  • Zürich, Switzerland, 8032
    • Investigational Site Number :7560001
• Taiwan
  • Taichung, Taiwan, 402
    • Investigational Site Number :1580001
  • Taichung, Taiwan, 407
    • Investigational Site Number :1580003
  • Taipei, Taiwan, 10002
    • Investigational Site Number :1580002
  • Taipei, Taiwan, 11031
    • Investigational Site Number :1580004
• Turkey
  • Antalya, Turkey, 07059
    • Investigational Site Number :7920004
  • Istanbul, Turkey, 34390
    • Investigational Site Number :7920001
  • Izmir, Turkey, TR-35100
    • Investigational Site Number :7920003
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Investigational Site Number :8260003
  • London, United Kingdom, WC1N3JH
    • Investigational Site Number :8260001
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles-Site Number:8400006
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida-Site Number:8400009
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta-Site Number:8400019
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Rush University Medical Center-Site Number:8400001
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics-Site Number:8400002
  • New York
    • New York, New York, United States, 10021
      • NY Presbyterian - Weill Cornell Medical Center-Site Number:8400020
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University/Brody Medical Sciences Building-Site Number:8400015
  • Ohio
    • Cincinnati, Ohio, United States, 45206
      • Cincinnati Children's Hospital Medical Center-Site Number:8400008
    • Columbus, Ohio, United States, 43205
      • Childrens Hospital Of Columbus-Site Number:8400012
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-0509
      • Children's Hospital Of Wisconsin-Site Number:8400005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria :

• Participant must be younger than 12 years of age, at the time of signing the informed consent.
• Severe hemophilia A defined as <1 international units per deciliter (IU/dL) (<1 percent [%]) endogenous Factor VIII (FVIII) 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 (EDs) for participants aged 6 to <12 years and above 50 EDs for participants aged <6 years.
• Weight above or equal to 10 kg.

Exclusion criteria:

• History of hypersensitivity or anaphylaxis associated with any FVIII product.
• History of a positive inhibitor (to FVIII) test defined as greater than or equal to (>=) 0.6 Bethesda units (BU/mL), or any value greater than or equal to the lower sensitivity cut-off for laboratories with cut-offs for inhibitor detection between 0.7 and 1.0 BU/mL, or clinical signs or symptoms of decreased response to FVIII administrations. Family history of inhibitors would not exclude the participant.
• Positive inhibitor test result, defined as >=0.6 BU/mL at Screening.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BIVV001: Participants aged <6 Years; Participants aged less than (<) 6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks.	Drug: efanesoctocog alfa (BIVV001); Pharmaceutical form: solution for injection Route of administration: IV
Experimental: BIVV001: Participants aged 6 to <12 Years; Participants aged 6 to <12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.	Drug: efanesoctocog alfa (BIVV001); Pharmaceutical form: solution for injection Route of administration: IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Neutralising Antibodies (Development of Inhibitors) Directed Against Factor VIII	Inhibitor development was defined as an inhibitor result of greater than or equal to (>=0.6) Bethesda units (BU/mL) that was confirmed by a second test result 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.	Baseline up to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	During the perioperative period (any time during Baseline up to Week 52)
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).	During the perioperative period (any time during Baseline up to Week 52)
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).	Day 0 (i.e., day of surgery)
Annualized Bleeding Rate (ABR): For Treated Bleeds	ABR: annualized number of treated bleeding episodes (BE) per participant per year. ABR=number of treated BE during efficacy period (EP)/total number of days during EP*365.25. Treated BE:any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered less than or equal to (<=) 72 hours apart from previous injection were considered same BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location:considered as separate BE, regardless of time from last injection. EP=sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. ABR:by negative binomial model with total number of treated BE during EP as response variable and log transformed EP duration (years) as offset variable.	Baseline up to Week 52
Sensitivity Analysis: Annualized Bleeding Rate: For Treated Bleeds	ABR: annualized number of treated BE per participant per year. ABR = number of treated BE during EP/total number of days during EP*365.25. Treated BE: 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 BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new bleeding episode in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. ABR: using negative binomial (NB) model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable.	Baseline up to Week 52
Annualized Bleeding Rate for All Bleeding Episodes	ABR:annualized number of all BE (treated and untreated)/participant/year. ABR=number of all BE during EP/total number of days during EP*365.25. BE:any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP:sum of all intervals of time during which participants treated with BIVV001 according to study arms & treatment regimens. ABR:NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous:bleeding without contributing factor, Traumatic:bleeding with known reason.	Baseline up to Week 52
Sensitivity Analysis: Annualized Bleeding Rate for All Bleeding Episodes	ABR: annualized number of all BE (treated & untreated)/participant/year. ABR=number of all BE during EP/total number of days during EP*365.25. BE: any hemorrhage occurrence required administration of BIVV001. It started from 1st sign of bleed & ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 according to study arms and treatment regimens. ABR: estimated by NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous: bleeding without contributing factor (definite trauma/antecedent strenuous activity). Traumatic: bleeding with known/believed reason.	Baseline up to Week 52
Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated BE: 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 injection to treat bleed, taken >72 hours after preceding one was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.	Baseline up to Week 52
Sensitivity Analysis: Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)	ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated BE: 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 injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.	Baseline up to Week 52
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP*365.25. 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 injection >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.	Baseline up to Week 52
Sensitivity Analysis: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)	ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms & treatment regimens. Treated BE: 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 injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.	Baseline up to Week 52
Percentage of Participants Achieving FVIII Activity Levels Above 1%, 3%, 5%, 10%, 15%, and 20%	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%, 3%, 5%, 10%, 15%, and 20% were reported in this outcome measure. Participants were counted in more than one category, as applicable.	Baseline up to Week 52
Number of Injections of BIVV001 Required to Treat a Bleeding Episode	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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection.	Baseline up to Week 52
Sensitivity Analysis: Number of Injections of BIVV001 Required to Treat a Bleeding Episode	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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection.	Baseline up to Week 52
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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this outcome measure.	Baseline up to Week 52
Sensitivity Analysis: 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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this outcome measure.	Baseline up to Week 52
Total Dose of BIVV001 Required to Treat a Bleeding Episode	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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: International units per kilogram (IU/kg).	Baseline up to Week 52
Sensitivity Analysis: Total Dose of BIVV001 Required to Treat a Bleeding Episode	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. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any injection after >72 hours post preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: IU/kg.	Baseline up to Week 52
Physicians' Global Assessment (PGA) of Participant's Response to BIVV001 Treatment Based on a 4-point Response Scale	Physicians assessed participant's response to BIVV001 treatment using 4-point response scale categorized as: Excellent= 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.	Week 13 and Week 52/End of study (EOS)/Early termination (ET)
Participant's Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale	Participant's response to the 1st injection of BIVV001 treatment for treating a bleed was evaluated by 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). Assessed approximately 72 hours after initial treatment for BE. Bleeding episode: an episode that started from 1st 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 BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Participants were counted in more than one category, as applicable.	Baseline up to Week 52
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.	Baseline up to Week 52
Annualized Joint Bleeding Rate (AJBR)	AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint BE during EP divided by total number of days during EP*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed & ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart considered same BE. Any injection after >72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 per study arms and treatment regimens. ABR:NB model with total number of treated BE during EP (response variable) & log-transformed EP duration (offset variable).	Baseline up to Week 52
Sensitivity Analysis: Annualized Joint Bleeding Rate (AJBR)	AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint BE during EP divided by total number of days during EP*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed & ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart considered same BE. Any injection after >72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 per study arms and treatment regimens. ABR: NB model with total number of treated BE during EP (response variable) & log-transformed EP duration (offset variable).	Baseline up to Week 52
Change From Baseline in Hemophilia Joint Health Score Domain Score at 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), for each item 0 = no damage and higher score = severe damage.	Baseline, Week 52
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haemo-QoL) Kids Short Version Total Score at Week 52 for Children Participants (Aged 4 to 7 and 8 to <12 Years)	Haemo-QoL kids short version: used to measure physical and emotional impacts on quality of life in children & adolescent with hemophilia. It was administered to children & their caregivers. Short version for children containing 16 items (4 to 7 years) and 35 items (8 to <12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia & treatment). Items were rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. Haem- A-QoL total score=average of all domain scores and ranged from 0 to 100, where lower scores=better QoL.	Baseline, Week 52
Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Total Score at Week 52 for Children Participants (Aged 4 to 7 and 8 to <12 Years): Parent's Evaluation	Haemo-QoL parent proxy short version: used to measure physical and emotional impacts on quality of life in children and adolescent with hemophilia. It was administered to children & their caregivers. Short version for children's caregivers containing 16 items (participants 4 to 7 years) and 35 items (participants 8 to <12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain: transformed to scale ranged between 0 to 100, lower score=better HRQoL. Haem-A-QoL total score=average of all domain scores and ranged from 0 to 100, lower scores=better quality of life. Haemo-QoL Total Score as per parent's evaluation was reported in this outcome measure.	Baseline, Week 52
Change From Baseline in Hemophilia Quality of Life Questionnaire Kids Short Version Physical Health Domain Score at Week 52 for Children Participants (Aged 8 to <12 Years)	Haemo-QoL kids short version: used to measure physical and emotional impacts on quality of life in children and adolescent with hemophilia. It was administered to children and their caregivers. Short version for children containing 35 items (8 to <12 years) were selected in this study. This version covers 9 dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. Change from baseline in physical Health domain score was reported in this outcome measure.	Baseline, Week 52
Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Physical Health Domain Score at Week 52 for Children Participants (Aged 8 to <12 Years): Parent's Evaluation	Haemo-QoL parent proxy short version: used to measure physical & emotional impacts on quality of life in children & adolescent with hemophilia. It was administered to children & their caregivers. Short version for children's caregivers containing 35 items (participants 8 to <12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia & treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 and 100, where lower score=better HRQoL. Change from baseline in physical health domain score as per parent's evaluation was reported in this outcome measure.	Baseline, Week 52
Total Number of Target Joints Resolved in Participants at 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 (defined as treatment regimen period >=52 weeks). Total number of target joints resolved at Week 52 were reported.	Week 52
Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at 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 to 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.	Baseline, Week 52
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: 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. As pre-specified, this outcome measure was planned to be analyzed combinedly for both the cohorts (participants <6 years and participants 6 to <12 years) and presented under a single reporting group.	Baseline up to Week 52
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 (process to prevent and stop bleeding from 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 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).	During the perioperative period (any time during Baseline up to Week 52)
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 outcome measure.	Day -1 to Day 14
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 surgery) and post-operative (24-hour post-surgery). Total dose (IU/kg) was sum across all injections per major surgery (including loading dose) needed to maintain hemostasis (process to prevent and stop bleeding from 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 joint; removal of organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of mesenchymal barrier (e.g., pleura, peritoneum, dura). Day 0=surgery day. Loading dose for given surgery was preoperative injection, administered either on day of surgery or one day prior to surgery (i.e., Day -1).	Day -1 to Day 0 (day of surgery)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse (TESAEs)	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.	From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55)
Number of Participants With Occurrence of Embolic and Thrombotic Events	Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging.	Baseline up to Week 52
Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)	Cmax was defined as the maximum observed plasma FVIII Activity.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
Pharmacokinetics: Clearance (CL)	CL is defined as the rate at which the drug is removed from the body.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
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.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
Pharmacokinetics: Elimination Half-life (t1/2z)	Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
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.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
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.	0 hour - 168 hour at week 26, 39 or 52
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.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)	Ctrough is the pre-dose concentration of a drug. Ctrough was measured by apTT-Baseline-one-stage clotting assay.	Pre-dose at Baseline (Day 1) and Week 52
Pharmacokinetics: Mean Residence Time (MRT)	MRT is the average total time a drug molecule spends in the body.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
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 doses of 50 IU/kg.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
Pharmacokinetics: Dose-normalized Area Under the Activity-time Curve (DNAUC0-tau)	AUC0-tau was defined as the area under the activity-time curve over the dosing interval. AUC was normalized by dose.	Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1

Collaborators and Investigators

• Sponsor: Bioverativ, a Sanofi company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2021
• Primary Completion (Actual): January 18, 2023
• Study Completion (Actual): January 18, 2023

Study Registration Dates

• First Submitted: February 13, 2021
• First Submitted That Met QC Criteria: February 13, 2021
• First Posted (Actual): February 18, 2021

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: EFC16295; 2020-000769-18 (EudraCT Number); U1111-1244-0558 (Other Identifier: UTN); 017464 (Other Identifier: IND)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No