To assess efficacy and safety, including immunogenicity of BAX 855 administered as prophylaxis and as on-demand therapy in adult and adolescent (12-65 years) previously treated patients (PTPs) with severe hemophilia A To determine the pharmacokinetic (PK) parameters of BAX 855.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
159
Pharmacokinetic (PK) evaluation of ADVATE
Pharmacokinetic (PK) evaluation of BAX 855
Prophylaxis treatment
Annualized Bleeding Rate (ABR)
Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.
Time frame: 9 months
Rate of Success of BAX 855 for Treatment of Bleeding Episodes
Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. 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. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.
Time frame: At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.
Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes
Time frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].
Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes
Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)\*(12/365.2425)
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On-demand treatment
University of Colorado
Aurora, Colorado, United States
University of Florida, College of Medicine
Gainesville, Florida, United States
Children's Healthcare of Atlanta
Atlanta, Georgia, United States
Bleeding and Clotting Disorders Institute
Peoria, Illinois, United States
University of Kentucky Medical Center
Lexington, Kentucky, United States
University of Louisville Hospital
Louisville, Kentucky, United States
Tulane University Medical School
New Orleans, Louisiana, United States
Children's Mercy Hospitals & Clinics
Kansas City, Missouri, United States
Weill Cornell Medical College-New York Presbyterian Hospital
New York, New York, United States
University of North Carolina Chapel Hill
Chapel Hill, North Carolina, United States
...and 62 more locations
Time frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].
Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion
Time frame: Prophylactic Infusion: ≥50 exposure days or 6 months (±2 weeks), whichever occurs last. PK Infusion: PK #1 Pre-infusion within 30 minutes; Post-infusion 10 min, and 0.5, 1, 3, 6, 24, 32, 48, 56 hours (h). PK #2 also at Post-infusion 96h
Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis
Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.
Time frame: Treatment of Bleeding Episode (BE): Minor/Moderate BE every 12 to 24 hours until bleeding is resolved; Major BE every 8 to 12 hours until bleeding is resolved. Per BE for Maintenance of Hemostasis: within 48 hours after bleeding episode resolution.
Percentage of Participants With Adverse Events
Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].
Immunogenicity - Number of Participants With Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, PEG-VIII, PEG and Anti-CHO Antibodies at Study Completion/Termination
Number of participants who received BAX855, with immunogenicity data from study completion/termination visit. FVIII = factor VIII; PEG-VIII = polyethylene glycol-factor VIII; Anti-CHO = Anti-Chinese hamster ovary
Time frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].
Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study
The HAEMO-SYM has two subscales: pain and bleeds. HAEMO-SYM subscale scores are calculated by taking the mean of the items in each subscale and transforming them to a 0 (none or absent) to 100 (very severe) scale. Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.
Time frame: Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study
Change from Baseline to End of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL.
Time frame: Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm]
Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay)
Terminal half-life calculated as log\_e2/λz where λz is the terminal elimination rate constant. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay)
The mean residence time (MRT) w as calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay)
Clearance in dL/(kg.h) will be calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay)
Incremental recovery (IR) in (IU/dL)/ (IU/kg) calculated as: IR = (Cmax- (C pre-infusion)) / (Dose/kg), where C =concentration. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay)
Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay)
The apparent volume of distribution at steady state (Vss) will be calculated as: Vss = Clearance \* Mean Residence Time. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay)
Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay)
Tmax in hours will be defined as the time to reach Cmax. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
Change in Vital Signs From Screening - Temperature
Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
Change in Vital Signs From Screening - Pulse Rate
Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
Change in Vital Signs From Screening - Respiratory Rate
Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
Changes in Vital Signs From Screening - Blood Pressure
Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)
Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase
Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN)
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Hematology Laboratory Assessments From Screening - Hematocrit
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Hematology Laboratory Assessments From Screening - Hemoglobin
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Hematology Laboratory Assessments From Screening - Erythrocytes
Time frame: Screening, week 2, week 4, month 3, study completion/termination
Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL)
Time frame: Screening, week 2, week 4, month 3, study completion/termination