A Study of PEGylated Recombinant Factor VIII (BAX855) in Previously Untreated Young Children With Severe Hemophilia A

Study Overview
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Brief Summary
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This study is for young children with severe hemophilia A who have previously not been treated with BAX855 or other FVIII concentrates. The main aim of the study is to check for side effects from treatment with BAX855. This includes the buildup of antibodies against FVIII which may stop BAX855 from working properly. Another aim is to learn how well BAX855 controls bleeding. In this study, the children can receive BAX855 either as preventative treatment (prophylaxis), or as needed to treat bleeding (on-demand). In case a participant develops antibodies, treatment will be provided as part of the study.

Official Title
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Phase 3, Prospective, Multi-center, Open Label Study to Investigate Safety, Immunogenicity and Hemostatic Efficacy of PEGylated Factor VIII (BAX 855) in Previously Untreated Patients (PUPs) < 6 Years With Severe Hemophilia A (FVIII < 1%)

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: PEGylated Recombinant Factor VIII
* Biological: ITI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participant is <6 years old at the time of screening. Participant is previously untreated with <3 exposure days (EDs) to ADVATE, BAX 855 or plasma transfusion at any time prior to screening. Participant has severe hemophilia A (Factor VIII (FVIII) <1%) as determined by the central laboratory, or a historical FVIII level <1% as determined at any local laboratory, optionally supported by an additional FVIII gene mutation consistent with severe hemophilia A. Participant is immune competent with a cluster of differentiation 4 (CD4+) count > 200 cells per cubic millimeter (mm^3), as confirmed by the central laboratory at screening. Parent or legally authorized representative is willing and able to comply with the requirements of the protocol. Additional inclusion criteria for Part B (immune tolerance induction [ITI]). Parent or legal representative has/have voluntarily provided signed informed consent for ITI portion. Participant has a confirmed positive high titer inhibitor (> 5.00 Bethesda unit (BU)) or has a positive confirmed low titer inhibitor (greater than or equal to [>=] 0.6 BU) as determined by the central laboratory based on a second repeat blood sample with poorly controlled bleeding despite increased BAX 855 doses, or requires bypassing agents to treat bleeding. Exclusion Criteria Participant has detectable FVIII inhibitory antibodies (>=0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening. Participant has a history of FVIII inhibitory antibodies (>=0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to screening. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease). Participant has been previously treated with any type of FVIII concentrate other than ADVATE or BAX 855, or was administered ADVATE, BAX 855 or plasma transfusion for >=3 EDs at any time prior to screening. Participant receives > two EDs of ADVATE in total during the periods prior to enrollment and during the screening period, until the baseline infusion. The participant's weight is anticipated to be <5 kilogram (kg) at the baseline visit. Participant's platelet count is <100,000 per milliliter (mL). Participant has known hypersensitivity towards mouse or hamster proteins, polyethylene glycol (PEG) or Tween 80. Participant has severe chronic hepatic dysfunction (eg, >5 times upper limit of normal alanine aminotransferase [ALT], aspartate aminotransferase [AST], or a documented international normalized ratio [INR] >1.5) in his medical history or at the time of screening. Participant has severe renal impairment (serum creatinine >1.5 times the upper limit of normal). Participant has current or recent (<30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation. Participant is scheduled to receive during the course of the study a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day or α-interferon) other than anti-retroviral chemotherapy. Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study. Parent or legally authorized representative has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance. Parent, legally authorized representative or participant are a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study. Additional exclusion criteria for Part B (ITI) Spontaneous disappearance of the inhibitor prior to ITI. FVIII inhibitor titer >=0.6 BU is not confirmed by a second new blood sample and determined at the central laboratory. Inability or unwillingness to comply with the protocol.

Ages Eligible for Study
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Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Previously untreated patients (PUPs)<br>Part A (Main Study): Participants age <3 years and not experienced two joint bleeds will receive on- demand treatment of 10-80 international unit per kilogram (IU/kg) of BAX 855 intravenously depending on the severity of the bleeding episode and age <3 years or after a maximum of two joint bleeds will receive prophylaxis treatment with dose of 25-80 IU/kg of BAX855 IV (based on investigator discretion) once weekly for up to 100 EDs. Part A (Surgery): In participants, the administration of BAX 855 will be individualized based on the participants IR and half-life. For major surgery to achieve the target level of 80-100% FVIII in plasma of normal FVIII level and for minor surgery >=30-60% FVIII levels for dental or other invasive surgery. Part B (Immune tolerance induction [ITI]): Participants will receive prophylaxis treatment of 100-200 IU/kg BAX 855 IV daily or 50 IU/kg three time in a week and will be reduced to twice weekly to maintain FVIII trough level of 1% for further 3 months. | Biological: PEGylated Recombinant Factor VIII<br>* Polyethylene glycol (PEG)-ylated full-length recombinant FVIII (rFVIII).<br>* Other names: TAK-660;Biological: ITI<br>* Immune tolerance induction therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With FVIII Inhibitor Development | Number of participants who develop an inhibitor (at any time) confirmed by a central laboratory based on a second repeat blood sample draw within 2 weeks of site notification of an inhibitor and all participants who not developed an inhibitor and has greater than or equal to (>=) 100 exposure doses (EDs) when the sample for the last valid inhibitor test will be drawn. | Throughout Part A of the study, approximately 5 years | 
| Success Rate of Immune Tolerance Induction (ITI) | Success is defined as 1) a persistently negative inhibitor titer less than (<) 0.6 Bethesda unit (BU), 2) FVIII IR >=66% of the baseline value following a wash-out period of 84-96 hours, and 3) a FVIII half-life of >=6 hours. | Up to 33 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies | Binding IgG and IgM antibodies to Factor VIII (FVIII), Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG). | Throughout Part A of the study, approximately 5 years | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A SAE is any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which results in death, is life-threatening, requires inpatient hospitalization, prolongation of hospitalization, is an important medical event. Number of participants with AEs and SAEs in both part A and part B will be assessed. | Throughout Part A and Part B of the study, approximately 7 years | 
| Number of Participants With Clinically Significant Changes in Vital Signs | Vital signs will be assessed based on body temperature, respiratory rate, blood pressure, and heart rate. | Throughout Part A and Part B of the study, approximately 7 years | 
| Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters | Clinical laboratory parameters includes hematology and clinical chemistry. Changes in laboratory values may be considered as AE if they are judged to be clinically significant. | Throughout Part A and Part B of the study, approximately 7 years | 
| Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment | ABR is assessed based upon each individual bleeding episode. A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding occurring at multiple locations related to the same injury (example, knee and ankle bleed following a fall) will be counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) will be reported. | Throughout Part A of the study, approximately 5 years | 
| Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes | A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. The number of BAX 855 infusions needed for each bleeding episode is determined by the participant, caregiver, clinician treating the participant, and is based upon the participant's response to treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes. | Throughout Part A of the study, approximately 5 years | 
| Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Initiation of Treatment | The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens | 24 hours after study drug administration | 
| Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. | From start of study treatment up to bleed resolution (approximately 5 years) | 
| Number of Participants With Weight-adjusted Consumption of BAX 855 | Weight-adjusted consumption of BAX 855 will be determined based upon the record in participants diaries of the actual amount of BAX 855 infused, indication (treatment of bleeding episode, prophylaxis,surgery) and the participants weight, as measured in the clinic. | Throughout Part A of the study, approximately 5 years | 
| Number of Infusions During Weight-adjusted Consumption of BAX 855 | The number of BAX 855 infusions needed for each bleeding episode is determined by the participant, caregiver, clinician treating the participant, and is based upon the participant's response to treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes. | Throughout Part A of the study, approximately 5 years | 
| Number of Participants With Hemostatic Efficacy in Case of Surgery | The hemostatic efficacy will be assessed during and after any surgical or invasive procedures, and overall as a perioperative assessment. | Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first) | 
| Blood Loss Per Participant in Case of Surgery | The intraoperative blood loss will be measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Post-operatively, blood loss will be determined by the drainage volume collected, which will mainly consist of drainage fluid via vacuum or gravity drain, as applicable. | Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first) | 
| Incremental Recovery (IR) of BAX 855 | BAX 855 will be administered in participants for the determination of FVIII IR at the study site at baseline and every study visit other than study visits. | Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours | 
| Half-life (T1/2) of BAX 855 | The Half-life to determine FVIII half-life is an optional assessment that will be performed at baseline, Visit 1, or Visit 2. | Pre-infusion, Post-infusion: 15-30 minutes and 24-48 hours | 
| Immune Tolerance Induction (ITI) - Rate of Partial Success and Failure of ITI | Partial success defined as which meet two of following criteria, 1) inhibitor titer <0.6 BU (confirmed by a central laboratory with a second blood specimen obtained within 2 months), 2) FVIII in vivo recovery >=66% of baseline value (confirmed within a two month period), and 3) FVIII half-life >=6 hours. Failure defined as the failure to meet the criteria for partial success. | Up to 33 months | 
| Immune Tolerance Induction (ITI) - Annualized Bleeding Rate (ABR) | ABR is assessed based upon each individual bleeding episode. A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding occurring at multiple locations related to the same injury (example, knee and ankle bleed following a fall) will be counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) will be reported. | Up to 33 months | 
| Immune Tolerance Induction (ITI) - Weight-adjusted Consumption of BAX 855 for Each ITI Regimen Employed | Weight-adjusted consumption of BAX 855 will be determined based upon the record in participant's diaries of the actual amount of BAX 855 infused, indication (treatment of bleeding episode, prophylaxis) and the participant's weight, as measured in the clinic. | Up to 33 months | 
| Immune Tolerance Induction (ITI) - Catheter-related Complications | The frequency per subject and per subject-year of catheter-related complications will be calculated. | Up to 33 months | 
| Immune Tolerance Induction (ITI) - Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies | Binding IgG and IgM antibodies to Factor VIII (FVIII), Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG). | Up to 33 months |