Severe Hemophilia A

Primary Objective: - To evaluate the safety of BIVV001 in previously treated pediatric subjects 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

BIVV001/250 IU
BIVV001/500 IU
BIVV001/1000 IU
BIVV001/2000IU

BIVV001
BIVV001
BIVV001
BIVV001

Sterile Water for Injection
Sterile Water for Injection
Sterile Water for Injection
Sterile Water for Injection

50 IU/kg
50 IU/kg
50 IU/kg
50 IU/kg

Primary Endpoints：
The occurrence of inhibitor development (neutralizing antibodies directed against FVIII as determined via the Nijmegen modified Bethesda assay)

Secondary Endpoints：
• Annualized bleeding rate (ABR) (for treated, for untreated, for all bleeding episodes) and by type and location
• Percentage of participants who maintain FVIII activity levels over 1%, 3%, 5%, 10%, 15%, and 20% at Day 7
• Number of injections and dose of BIVV001 to treat a bleeding episode
• Percentage of bleeding episodes treated with a single injection of BIVV001
• Assessment of response to BIVV001 treatment of individual bleeding episodes based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point response scale
• Physician’s global assessment (PGA) of participant’s response to BIVV001 treatment based on a 4-point response scale
• Total annualized BIVV001 consumption per participant
• Annualized joint bleeding rate (AJBR)
• Target joint resolution at Week 52, based on ISTH criteria
• Change from Baseline to Week 52 in total score and domain scores (eg, swelling and strength) assessed by the Hemophilia Joint Health Score (HJHS)
• Changes in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) total score and physical health domain score from baseline to Week 52 (≥4 years old) and via parent proxy version (≥4 years old)
• Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment on the ISTH 4-point response for surgical procedures scale
• Number of injections and dose to maintain hemostasis during perioperative period for major surgery
• Total BIVV001 consumption during perioperative period for major surgery
• Number and type of blood component transfusions used during perioperative period for major surgery
• Estimated blood loss during perioperative period for major surgery
• The occurrence of adverse events (AEs) and serious adverse events (SAEs)
• The occurrence of clinically significant changes from baseline in physical examination, vital signs, and laboratory tests
• The occurrence of embolic and thrombotic events
• PK parameters including, but not limited to, maximum activity (Cmax), elimination half-life (t1/2), total clearance (CL), total clearance at steady state (CLss), volume of distribution at steady state (Vss), areaunder the activity time curve (AUC), dose-normalized area under the activity-time curve (DNAUC), mean residence time (MRT), incremental recovery (IR), trough activity (Ctrough), time above predefined FVIII activity levels

INCLUSION CRITERIA
Participants are eligible to be included in the study onlyif all of the following criteria apply:
Age
I 01.Participant must be younger than 12 years of age, at the time of signing the informed consent. Type of participant and disease characteristics
I 02.Severe hemophilia A defined as <1 IU/dL (<1%) endogenous 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.
I 03.Previous treatment for hemophilia A (prophylaxis or on-demand) with any recombinant and/or plasma-derived FVIII, or cryoprecipitate for at least 150 EDs for patients aged 6-11 years and above 50 EDs for patients aged <6 years.
I 04.For the PK subgroup only: existing PK information with the participant’s pre-study FVIII product (t1/2 and IR) should be available, or alternatively, historic PK assessments deemed adequate for calculating t1/2 and IR PK by the Sanofi PK scientist.
I 05.Platelet count ≥100 000 cells/μL at Screening.
I 06.A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to enrollment.a)CD4 lymphocyte count >200 cells/mm³b)Viral load of <400 copies/mLDocumented results of CD4 lymphocyte count and viral load will be accepted if samples were collected within 26 weeks prior to Screening or if samples were collected during Screening andevaluated by the central laboratory. Participants who have previously tested negative for HIV must have a repeat test by the central laboratory during Screening.
I 07.Willingness and ability of thecaregiver to complete training in the use of the study ePD and to use the ePD throughout the study
Weight
I 08.Weight above or equal to 10 kg.
Sex
I 09.Malea)Male participantsNo contraceptive measures required for this study.InformedConsent
I 10.Ability of the participant or his legally authorized representative (eg, parent or legal guardian) to understand the purpose and risks of the study 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
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01.Serious active bacterial, viral or fungal infection (other than chronic hepatitis or HIV) present within 30 days of Screening.
E 02.Other known coagulation disorder(s) in addition to hemophilia A.
E 03.History of hypersensitivity or anaphylaxis associated with any FVIII product.
E 04.History of a positive inhibitor (to FVIII) test defined as ≥0.6 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 will not exclude the participant.
E 05.Positive inhibitor test result, defined as ≥0.6 BU/mL at Screening.
E 06.Active renal disease (per the discretion of the Investigator and medical records) at Screening.
E 07.Active hepatic disease (per the discretion of the Investigator and medical records) at Screening. Prior/concomitant therapy
E 08.Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) above the maximum dose specified in the regional prescribing information within 2 weeks prior to Screening.
E 09.Treatment with acetylsalicyclic acid (ASA) or other non-NSAIDs anti-platelet therapies within 2 weeks prior to Screening.
E 10.Systemic treatment within 12 weeks prior to Screening with chemotherapy and/or other immunosuppressive drugs (except for the treatment of hepatitis C virus [HCV] or HIV). Use of corticosteroids is allowed, except for systemic corticosteroid treatment given daily or on alternate days for >14 days. Local, topical, and/or inhaled steroid use is permitted.
E 11.Emicizumab use within the 20 weeks prior to Screening.
Prior/concurrent clinical study experience
E 12.Previous enrolment in this study; participants who fail Screening may rescreen (maximum of 2 rescreenings).
E 13.Treatment with an investigational product within 30 days or 5.5 half-lives prior to Screening, whichever is longer. For investigational products with a pharmacodynamic effect that persists longer than the half-life, the maximal pharmacodynamic effect must return to baseline prior to Screening.Other exclusions
E 14.Major surgery within 8 weeks prior to Screening. Major surgery is defined as any surgical procedure (elective or emergent) that usually, but not always, involves general anesthesia and/or respiratory assistance, in which a major body cavity is penetrated and exposed, ora substantial impairment of physical or physiological functions is produced (eg, laparotomy, thoracotomy, craniotomy, joint replacement, or limb amputation).
E 15.Any country-related specific regulation that would prevent the participant from entering the study.
E 16.Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
E 17.Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.
E 18.ASensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.