BAX 802 in CHA With Inhibitors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of BAX 802 in males with congenital hemophilia A (CHA) with inhibitors who are undergoing major or minor elective surgical, dental, or other invasive procedures.

Official Title
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A Phase 3, Multicenter, Open-label Study of the Efficacy and Safety of B-Domain Deleted Recombinant Porcine Factor VIII (BAX 802) in Subjects With Congenital Hemophilia A With Factor VIII Inhibitors Undergoing Surgical or Other Invasive Procedures

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Antihemophilic Factor (Recombinant), Porcine Sequence (BAX 802)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participant requires a major or minor elective surgical, dental or other invasive procedure Participant is male and ≥ 12 to ≤ 75 years old at the time of screening Participant has provided signed informed consent (and assent for adolescent participants, as applicable) in accordance with local regulatory requirements Participant has severe (factor VIII (FVIII) level < 1%) or moderately severe (FVIII level ≤ 2%) congenital hemophilia A (CHA) with inhibitors to human factor VIII (hFVIII) of ≥ 0.6 Bethesda units (BU), as tested at screening at the central laboratory Participant is not currently receiving or has recently received (< 30 days) immune tolerance induction (ITI) therapy Participant has a Karnofsky performance score of ≥ 60 at screening Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3 at screening Participant is hepatitis C virus negative (HCV-) by antibody or polymerase chain reaction (PCR) testing; or HCV+ with chronic stable hepatitis disease. Positive serologies will be confirmed by PCR testing. Participant is willing and able to comply with the requirements of the protocol. Exclusion Criteria The participant requires emergency surgery Severe chronic liver dysfunction or disease (e.g., ≥ 5 × upper limit of normal [ULN] alanine aminotransferase [ALT], as confirmed by central laboratory at screening or a documented prothrombin time/international normalized ratio [PT/INR] > 1.5) Clinically symptomatic renal disease (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening Anti-porcine factor VIII (pFVIII) inhibitor > 10 BU prior to surgery Platelet count < 100,000/μL at screening Participant has another active coagulation disorder, other than hemophilia A, as per the medical history Planned use of α-interferon with or without ribavirin for HCV infected patients or planned use of a protease inhibitor for HIV infected patients. Patients currently taking any of these medications for ≥ 30 days are eligible Known hypersensitivity to recombinant porcine factor VIII (rpFVIII), or hamster or murine proteins Participant has an ongoing or recent (within 3 months of screening) thrombo-embolic disease, fibrinolysis or disseminated intravascular coagulation (DIC) Participant has been exposed to an IP within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product (IP) or investigational device during the course of this study Participant is unable to tolerate quantity of blood to be drawn for protocol procedures Participant is a family member or employee of the Investigator.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

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: BAX 802 in Surgery<br>Participants who are undergoing major or minor elective surgical, dental, or other invasive procedures. | Biological: Antihemophilic Factor (Recombinant), Porcine Sequence (BAX 802)<br>* In case of major surgery, FVIII target level is ≥80% for major surgeries/ procedures and ≥50% for minor surgeries/ procedures.<br>* Other names: rpFVIII;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Surgeries With a Good or Excellent Response as Measured by the Global Hemostatic Efficacy Assessment (GHEA) Score | GHEA score consisted of 3 individual rating scales: (1) Intra-operative Efficacy Assessment Scale, (2) Post-operative Efficacy Assessment Scale, and (3) Overall Peri-operative Efficacy Assessment Scale. Scales 1 and 2 was performed by the operating surgeon on Day 1, and Scale 3 was performed by the investigator on Day 14. Each rating scale was based on 4 points scale ranging from: 3 (Excellent), 2 (Good), 1 (Fair), and 0 (None). Total score ranged from 0 to 9, where scores evaluated as: excellent (7 to 9), good (5 to 7), fair (3 to 4), and none (0 to 2). The scores of 3 individual ratings scales were added together to form a GHEA score. For a GHEA score of 7 to be rated excellent with no individual assessment scores less than (<) 2 and at least 1 assessment score equal to (=) 3; otherwise a score of 7 was rated good. Percentage of Surgeries With a Good or Excellent response as measured by the GHEA score were reported. | Day 1 up to discharge or Day 14 (whichever was earlier) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actual Blood Loss, Estimated Volume of Expected Average Blood Loss and Expected Maximum Blood Loss During Intra-operative, Post-operative and Peri-operative Period | Prior to the surgery, the surgeon/investigator predicted and compared the estimated volume (in milliliter [mL]) of the expected average blood loss and expected maximum blood loss for the planned surgical intervention in a comparable healthy individual with similar demographic characteristics; for intraoperative, postoperative, and overall perioperative time periods. Intra-operative defined as period from start of surgery to completion of surgical procedure. Post-operative defined as period from completion of surgical procedure till 24 hours post-surgery. Peri-operative defined as period from start of surgical procedure till discharge or 14 days post surgery (whichever was earlier). Actual blood loss, estimated volume of expected average blood loss and expected maximum blood loss during each operative period was reported. | Intra-operative: up to completion of surgery (Day 1), Post-operative: at 24 hours post-surgery, and Peri-operative: at discharge or Day 14 (whichever was earlier) | 
| Ratio of Actual Blood Loss and Estimated Volume of Expected Average Blood Loss During Intra-operative, Post-operative and Peri-operative Period | Prior to the surgery, the surgeon/investigator predicted and compared the estimated volume (mL) of the expected average blood loss and expected maximum blood loss for the planned surgical intervention in a comparable healthy individual with similar demographic characteristics; for intraoperative, postoperative, and overall perioperative time periods. Intra-operative defined as period from start of surgery to completion of surgical procedure. Post-operative defined as period from completion of surgical procedure till 24 hours post-surgery. Peri-operative defined as period from start of surgical procedure till discharge or 14 days post surgery (whichever was earlier). Ratio of actual blood loss and estimated volume of expected average blood loss during each operative period was reported. | Intra-operative: up to completion of surgery (Day 1), Post-operative: at 24 hours post-surgery, and Peri-operative: at discharge or Day 14 (whichever was earlier) | 
| Ratio of Actual Blood Loss and Expected Maximum Blood Loss During Intra-operative, Post-operative and Peri-operative Period | Prior to the surgery, the surgeon/investigator predicted and compared the estimated volume (mL) of the expected average blood loss and expected maximum blood loss for the planned surgical intervention in a comparable healthy individual with similar demographic characteristics; for intraoperative, postoperative, and overall perioperative time periods. Intra-operative defined as period from start of surgery to completion of surgical procedure. Post-operative defined as period from completion of surgical procedure till 24 hours post-surgery. Peri-operative defined as period from start of surgical procedure till discharge or 14 days post surgery (whichever was earlier). Ratio of actual blood loss and expected maximum blood loss during each operative period was reported. | Intra-operative: up to completion of surgery (Day 1), Post-operative: at 24 hours post-surgery, and Peri-operative: at discharge or Day 14 (whichever was earlier) | 
| Percentage of Major Surgeries With Good or Excellent Hemostatic Score | Percentage of major surgeries with good or excellent hemostatic score was analyzed by GHEA score. It consisted of 3 individual ratings: (1) Intra-operative Efficacy Assessment Scale, (2) Post-operative Efficacy Assessment Scale, (3) Postoperative Efficacy Assessment Scale. Ratings 1 and 2 was performed by the operating surgeon on Day 1, and Rating 3 was performed by the investigator on Day 14. Each rating scale was based on 4 point scale ranging from: 3 (Excellent), 2 (Good), 1 (Fair), and 0 (None). The scores of each of the 3 individual ratings scales, was added together to form a GHEA score. Total score ranged from 0 to 9 where scores evaluated as excellent (7 to 9), good (5 to 7), fair (3 to 4), and none (0 to 2). Hemostatic efficacy success was defined as excellent or good outcome for >=70% of hemostatic efficacy assessments. Percentage of major surgeries with good or excellent hemostatic score were reported. | Day 1 up to discharge or Day 14 (whichever was earlier) | 
| Average Daily Weight-adjusted Dose of BAX 802 Per Participant During Pre-operative, Intra-operative and Post-operative Period | Body-weight adjusted dose equals to amount infused/body-weight (kilogram [kg]), where amount infused as amount of drug infused (International Units [IU]) and body-weight as the last available body-weight (kg) prior to the infusion. Pre-operative defined as period prior to surgery. Intra-operative defined as period from start of surgery to completion of surgical procedure. Post-operative defined as period from completion of surgical procedure till discharge or 14 days post surgery (whichever was earlier). Average daily weight-adjusted dose of BAX 802 per participant during each operative period was reported. | Pre-operative: before surgery, Intra-operative: up to completion of surgery (Day 1), Post-operative: from completion of surgical procedure till discharge or 14 days post surgery (whichever was earlier) | 
| Total Weight-adjusted Dose of BAX 802 Per Participant During Pre-operative, Intra-operative and Post-operative Period | Body-weight adjusted dose equals to amount infused/body-weight (kg), where amount infused as amount of drug infused (IU) and body-weight as the last available body-weight (kg) prior to the infusion. Pre-operative defined as period prior to surgery. Intra-operative defined as period from start of surgery to completion of surgical procedure. Post-operative defined as period from completion of surgical procedure till discharge or 14 days post surgery (whichever was earlier). Total weight-adjusted dose of BAX 802 per participant during each operative period was reported. | Pre-operative: before surgery, Intra-operative: up to completion of surgery (Day 1), Post-operative: from completion of surgical procedure till discharge or 14 days post surgery (whichever was earlier) | 
| Volume of Blood Products Transfused | The volume (in mL) of blood products transfused from initiation of the intervention to discharge or Day 14 (whichever came earlier) was reported. | From initiation of the surgery up to discharge or Day 14 (whichever came earlier) | 
| Number of Participants With De Novo Inhibitors | De novo inhibitor was defined as a post-baseline inhibitor titer to FVIII (hFVIII or porcine factor VIII [pFVIII])of >=0.6 Bethesda units per milliliter (BU/mL) given a baseline of <0.6 BU/mL. Number of participants with de novo inhibitors were reported. | Baseline up end of study (EOS) (up to 44 months) | 
| Number of Participants With Anamnestic Reactions | An anamnestic reaction was defined as an increase from a measurable baseline (>0.6 BU/mL) in the inhibitor titer to FVIII (human or porcine) of >=10 BU/mL. Number of participants with anamnestic reactions were reported. | Baseline up to EOS (up to 44 months) | 
| Mean Change From Baseline up to EOS in Inhibitory and Binding Antibodies to pFVIII | The assessment of inhibitory antibodies (immunoglobulin G [IgG] and immunoglobulin M [IgM]) to pFVIII was determined using Bethesda assay, and assessment of binding antibodies (IgG and IgM) to pFVIII was determined using validated enzyme-linked immunosorbent assays (ELISAs). Mean change from baseline in inhibitory and binding antibodies to pFVIII was reported. | Baseline up to EOS (up to 44 months) | 
| Mean Change From Baseline up to EOS in Inhibitory and Binding Antibodies to hFVIII | The assessment of inhibitory antibodies (IgG and IgM) to hFVIII was determined using Bethesda assay, and assessment of binding antibodies (IgG and IgM) to hFVIII was determined using ELISA. Mean change from baseline in inhibitory and binding antibodies to hFVIII was reported. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Clinically Significant Change From Baseline in Binding Antibodies to Baby Hamster Kidney (BHK) Proteins | The assessment of binding antibodies to BHK proteins was determined using ELISA. Clinical significance was judged by the investigator. Number of participants with clinically significant change from baseline in binding antibodies to BHK proteins were reported. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Thromboembolic Events | Thromboembolism defined as formation in a blood vessel of a clot (thrombus) that breaks loose and carried by the blood stream to plug another vessel. Number of participants with thromboembolic events was reported. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Severe Allergic Reactions | Number of participants with severe allergic reaction (example: anaphylaxis) after administration of study drug were reported. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Investigational Product (IP) Related Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Serious AE was any untoward medical occurrence (whether considered to be related to study assigned treatment or not) that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital abnormality/birth defect, or was an important medical event. TEAEs was defined as any adverse events (classified by preferred term) that had a start date on or after the first dose of study treatment or that had a start date before the date of first dose of study treatment, but increased in severity after the first dose of study treatment. TEAEs included both serious and non-serious TEAEs. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Sign | Vital sign parameters included: temperature, pulse rate, respiration rate, systolic and diastolic blood pressure. Any changes in vital signs which were deemed clinically significant was judged by the investigator. Number of participants with clinically significant change from baseline in vital signs were reported. | Baseline up to EOS (up to 44 months) | 
| Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values | Clinical laboratory assessment included hematology and clinical chemistry. Any changes in clinical laboratory results which were deemed clinically significant was judged by the investigator. Number of participants with clinical significant change from baseline in clinical laboratory values were reported. | Baseline up to EOS (up to 44 months) |