Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and safety of BAX 855 in severe hemophilia A previously treated (PTP) males, 12 to 65 years of age who are undergoing elective surgical or other invasive procedures.

Official Title
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A Phase 3, Multi-Center, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: PEGylated Recombinant factor VIII (rFVIII)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant requires an elective major or minor surgical, dental or other invasive procedure (e.g. biopsy, endoscopy). Participant and/or legal representative has/have provided signed informed consent. Participant has severe hemophilia A (Factor VIII (FVIII) level <1%) as confirmed by the central lab at screening or a documented FVIII activity level <1%. Participant was previously treated with FVIII concentrates with ≥150 documented exposure days (EDs). Participant is currently receiving prophylaxis or on-demand therapy with FVIII concentrate. 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, as confirmed by central laboratory at screening. Participant is Hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator. Participant is willing and able to comply with the requirements of the study protocol. Exclusion Criteria: Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Unit (BU) using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay). History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC). Participant has a platelet count <100 x 10^9/L, as confirmed by central laboratory at screening. Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening. Participant has severe chronic hepatic dysfunction (eg ≥5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by the central laboratory at screening, or a documented International Normalized Ratio (INR) > 1.5). Participant has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG. Participant is currently using or has recently (< 30 days) used pegylated drugs (other than BAX 855) prior to study participation or is scheduled to use such drugs during trial participation. Participant is currently participating in another clinical drug (other than BAX 855) or device study or use of another investigational product or device within 30 days prior to study entry. Participant has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A. Participant is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (eg, systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy. 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 safety or compliance.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 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: BAX855<br>Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and character of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-150% FVIII trough level, and minor surgery will target an initial 30-100% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and character of the surgery performed. | Biological: PEGylated Recombinant factor VIII (rFVIII)<br>* Lyophilized powder and solvent for solution for injection<br>* Other names: ADYNOVATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings | GHEA=Sum of 1-3 ratings: Excellent: 7-9 (no category <2), Good: 5-7 (no category <1), Fair: 3-4 (no category <1) 1. Intraoperative and 2. Postoperative (postoperative day 1) hemostatic efficacy assessments: Excellent=3: Blood Loss (BL) ≤ than expected for procedure type in non-hemophilic population (NHP) (≤100%), Good=2: BL ≤50% more than expect. for procedure type in NHP (101-150%), Fair=1: BL >50% more than expect. for procedure type in NHP (>150%), None=0: Significant bleeding-requiring rescue therapy (RT) 3. Perioperative hemostatic efficacy assessment (day 14 or discharge, whatever is first): Excellent=3: BL and required blood transfusions (BT) less than or similar (≤100%) to that expected for procedure type in NHP, Good=2: BL ≤50% more (101-150%) and BT less than or similar to that expected for procedure type in NHP, Fair=1: BL >50% more (>150%) and BT greater than expected in NHP, None=0: Significant bleeding-requiring RT, BT substantially greater than expected in NHP | Hemostatic efficacy assessments were performed intraoperatively, postoperatively on day 1 (approximately 24 hours after surgery) and perioperatively at day 14 or discharge (whichever was first). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative Blood Loss | Actual intraoperative blood loss was assessed at the end of surgery and was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected intraoperative blood loss was predicted preoperatively by the investigator/surgeon. | From initiation of surgery until end of surgery. | 
| Postoperative Blood Loss | Actual post-operative blood loss assessed at postoperative day 1 was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected postoperative blood loss was predicted pre-operatively by the investigator/surgeon. | From completion of surgery until 24 hours after surgery. | 
| Overall Perioperative Blood Loss | Actual overall perioperative blood loss (assessed at the end of surgery, at postoperative day 1 and until discharge or day 14 - whichever is first) was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected perioperative blood loss was predicted pre-operatively by the investigator/surgeon. | From start of surgery until discharge or day 14, whichever occurred first. | 
| Transfusion Requirements | Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study. | From initiation of the surgery to 24 hours after completion of the surgery. | 
| Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention | Any clinically relevant bleeding episodes (as assessed by the investigator) as well as the need for any further surgical interventions were recorded. If the subject had not resumed his previous treatment after discharge, the occurrence and treatment of bleeding episodes were recorded in the subject's diary. | Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks) | 
| Consumption of BAX855 | Daily and total weight-adjusted consumption of BAX855 per subject. | From initial loading dose until discharge for daily weight-adjusted dose and from first infusion (PK/IR) until end of study for total weight-adjusted dose. | 
| Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞) | Following at least a 72 hour washout period a single dose of BAX855 was administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to infinity (AUC 0-inf) and the area under the first movement curve from time 0 to infinity (AUMC 0-inf) was calculated as the sum of AUC and AUMC from time 0 to the time of the last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h) | Following at least a 72 hour (h) washout period a single dose of BAX855 will be administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to 96 hours postinfusion (AUC 0-96h) was computed using the linear trapezoidal rule. For the calculation of AUC 0-96h the levels at 96 hours were linearly interpolated/extrapolated from the 2 nearest sampling time points. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Terminal Half-life (T1/2) | Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Terminal or disposition half-life (HL) was calculated as log e(2)/λz where the terminal or disposition rate constant (λz) was estimated as the slope of a log-linear least squares regression model. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Mean Residence Time (MRT) | Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Clearance (CL) | Following a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Systemic clearance (CL) was calculated as the dose in IU/kg divided by the total AUC. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. h = hours | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss) | Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Apparent steady state volume of distribution (Vss) was calculated as dose multiplied with AUMC(0-inf) divided by AUC(0-inf) to square. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Pharmacokinetics (PK) - Incremental Recovery(IR) | Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Incremental recovery (IR) was calculated as C post infusion minus C pre-infusion divided by the dose. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. | PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours. | 
| Development of Inhibitory Antibodies to Factor VIII (FVIII) | Immunogenicity assessment using FVIII inhibitor by Nijmegen method. A 72-hour washout period is required prior to immunogenicity tests. | Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days). | 
| Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) | A 72-hour washout period is required prior to immunogenicity tests. | Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days). | 
| Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies | A 72-hour washout period is required prior to immunogenicity tests. | Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days). | 
| Occurrence of Thrombotic Events |  | Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days). | 
| Incidence of Severe Allergic Reactions (e.g. Anaphylaxis) |  | Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days). | 
| Other Investigational Product (IP) - Related Adverse Events |  | Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days). | 
| Clinically Significant Changes in Vital Signs - Body Temperature | Changes in body temperature were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values. | Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion. | 
| Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) | Changes in systolic and diastolic blood pressure (mmHg) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values. | Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion. | 
| Clinically Significant Changes in Vital Signs - Respiratory Rate | Changes in Respiratory rate were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values. | Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion. | 
| Clinically Significant Changes in Vital Signs - Pulse Rate | Changes in the pulse rate (beats/minute) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values. | Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion. | 
| Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry | Changes in clinical chemistry and hematology parameters from a normal or abnormal not clinically significant (ncs) result at screening to an abnormal and clinically significant (cs) result at the end of study assessment (EOS) are listed. Changes did occur in the following laboratory parameters: Alanine Aminotransferase (ALT) (U/L), Hemoglobin (g/L), Hematocrit, Erythrocytes(TI/L), Eosinophils/Leucocytes. | Throughout the entire study period from screening to completion/termination (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days). |