BAX 855 PK-guided Dosing

Study Overview
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Brief Summary
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To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%) To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Official Title
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Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A

Conditions
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Hemophilia A

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


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study: Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory. Participant is willing and able to comply with the requirements of the protocol. Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study: Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs) Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months. Participant has a Karnofsky performance score of ≥ 60 at screening Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory at screening Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study Participant is willing and able to comply with the requirements of the protocol. EXCLUSION CRITERIA: Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study: Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A. The participant's weight is < 35 kg or > 100 kg. Participant's platelet count is < 100,000/mL. Participant has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal). Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal. Participant is scheduled to receive 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 during the study. Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance. Participant is planning to take part in any other clinical study during the course of the study. Participant is 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. Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study: 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 confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) 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). The participant's weight is < 35 kg or > 100 kg. Participant's platelet count is < 100,000/mL. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80. Participant has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR > 1.5]. 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 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. Participant 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. Participant is 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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacokinetic (PK) evaluation of BAX 855<br>Participants will first undergo an initial pharmacokinetic (PK) assessment. Following the PK assessment participants will be randomized to one of 2 dosing regimens. | Biological: PEGylated Recombinant Factor VIII<br>* Pharmacokinetic (PK) evaluation<br>* Other names: BAX 855;|
| Experimental: FVIII trough target 1-3%<br>Standard treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 1-3% | Biological: PEGylated Recombinant Factor VIII<br>* Standard treatment<br>* Other names: BAX855;|
| Experimental: FVIII trough target 8-12%<br>Intensified treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 8-12% | Biological: PEGylated Recombinant Factor VIII<br>* Intensified treatment<br>* Other names: BAX 855;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months | Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. | Day 183 to Day 364 (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Annualized Bleeding Rate for Second Six Months | Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. | Day 183 to Day 364 (6 months) | 
| Annualized Spontaneous Bleeding Rate for Second Six Months | Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma. | Day 183 to Day 364 (6 months) | 
| Annualized Traumatic Bleeding Rate for Second Six Months | Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma. | Day 183 to Day 364 (6 months) | 
| Annualized Joint Bleeding Rate (AJBR) for Second Six Months | Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function. | Day 183 to Day 364 (6 months) | 
| Total Weight-adjusted Consumption of BAX 855 | Total weight-adjusted consumption of BAX 855 were reported. | From start of study treatment up to 12 months (completion or termination) | 
| Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | 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. | 8 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 (up to 12 months) | 
| Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution | Infusions of BAX 855 that were required until bleed resolution were reported. | From start of study treatment up to 12 months (completion or termination) | 
| Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score | HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant. | Baseline, Month 12 | 
| Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | 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. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first). | Day 0 through discharge or 14 days post-surgery | 
| Blood Loss Per Participant in Case of Surgery | The intraoperative blood loss was 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. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as not available. Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first). | Day 0 through discharge or 14 days post-surgery | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes. | From start of study treatment up to 12 months (completion or termination) | 
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events | Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature. | From start of study treatment up to 12 months (completion or termination) | 
| Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events | Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology. | From start of study treatment up to 12 months (completion or termination) | 
| Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here. | From start of study treatment up to 12 months (completion or termination) | 
| Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey | Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores. | Baseline, Month 12 (completion or termination) | 
| Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) | Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 | IR at Cmax of BAX 855 were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Plasma Half-life (T1/2) of BAX 855 | T1/2 of BAX 855 in plasma were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Mean Residence Time (MRT) of BAX 855 | MRT of BAX 855 were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Maximum Plasma Concentration (Cmax) of BAX 855 | Cmax of BAX 855 were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Time to Maximum Concentration of BAX 855 in Plasma (Tmax) | Tmax of BAX 855 were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Total Body Clearance (CL) of BAX 855 | Total body clearance of BAX 855 from blood by the kidney were reported. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Volume of Distribution at Steady State (Vss) | Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate. | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | 
| Incremental Recovery (IR) Over Time | Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg). | Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination) |