Hemophilia A
Conditions
Brief summary
1. To assess tolerability and safety of BAX 826 after a single infusion in previously treated patients (PTPs) with severe hemophilia A 2. To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE 3. To evaluate immunogenicity of polysialic acid linked to Factor VIII (FVIII)
Interventions
BIOLOGICALBAX 826
BIOLOGICALOctocog alfa
Sponsors
Baxalta now part of Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Previously treated male participants aged 18 to 65 years (inclusive) at the time of screening 2. Diagnosis of severe hemophilia A (Factor VIII level \<1%) 3. Previously treated with FVIII concentrates for ≥150 documented Exposure Days (EDs) 4. Karnofsky performance score of ≥60 5. Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease 6. Hepatitis C virus negative (HCV-); or HCV+ with chronic stable hepatitis as assessed by the investigator 7. Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC) 8. Have provided written authorization for use and disclosure of protected health information 9. Agree to abide by the study schedule and to return for the required assessments 10. Willing and able to comply with the requirements of the protocol
Exclusion criteria
1. Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU) 2. Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening 3. Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA) 4. Scheduled elective surgery during study participation 5. Severe chronic hepatic dysfunction 6. Severe renal impairment 7. Currently receiving, or has recently received (less than 3 months prior to study participation), or is scheduled to receive during the course of the study, other PSA-ylated drugs 8. Have received another investigational drug within 30 days prior to study entry and/or is scheduled to receive additional investigational drug during the course of the study in the context of another investigational drug study 9. Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A 10. Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy 11. Has a clinically significant medical, psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect the safety or compliance of the participant during the study 12. Is a family member or employee of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Up to 6 weeks ± 4 days post infusion with BAX826. | Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826. |
| Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days | Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides |
| Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay. |
| Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM |
| Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Binding antibodies to FVIII IgG and IgM |
| Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Binding antibodies to PSA (IgG and IgM) |
| Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Binding antibodies to CHO |
| Immunogenicity: Human Anti-murine Antibodies (HAMA) | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days | Binding antibodies HAMA (IgG) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method. |
| Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | AUC from time zero to exactly 72 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 72 hours is missing, the activity at 72 hours will be interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). |
| Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Area under the FVIII activity-time curve from zero extrapolated to infinity, calculated by linear-up/log-down trapezoidal method and extrapolated to infinity, calculated as AUC last + C last / lambda z, where Clast is the estimated concentration at the last quantifiable time point |
| Comparison of Key Pharmacokinetic Parameters by Cohort | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from 0 to 72 hours (AUC0-72h), Maximum plasma concentration (Cmax), Terminal half-life (t1/2), Mean residence time (MRT) and Total body clearance (CL)) for ADVATE and BAX 826 have been compared. |
| Summary of Assessment of Dose Proportionality for BAX 826 | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours. | Dose Proportionality for BAX 826 was calculated for the parameters Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from time 0 to the last quantifiable time point (AUC0-last) and Maximum plasma concentration (Cmax). |
| Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours. | AUC from time zero to exactly 168 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 168 hours is missing, the activity at 168 hours was interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). This parameter will be calculated for BAX 826 only. |
| Pharmacokinetics: Terminal Half-life (t1/2) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Terminal elimination phase half-life, calculated by (ln2)/lambda z, where lambda z is the terminal rate constant, determined by linear regression of the terminal points of the log-linear FVIII activity-time curve. |
| Pharmacokinetics: Mean Residence Time (MRT) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion |
| Pharmacokinetics: Total Body Clearance (CL) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞ |
| Pharmacokinetics: Incremental Recovery (IR) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg) |
| Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Volume of distribution at steady state is calculated by MRT\*CL MRT=Mean residence time CL=Clearance rate |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Maximum observed FVIII activity, obtained directly from FVIII activity versus time data |
| Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. | Time of maximum FVIII activity is obtained directly from FVIII activity versus time data |
Countries
Bulgaria, Germany, Hungary, Italy, Netherlands, Poland, Russia, Spain, United Kingdom
Participant flow
Recruitment details
The study was conducted at 20 study sites in the EU and Russia. 44 participants signed informed consent. Of these, 4 participants were not treated (2 screen failures and 2 participants withdrew from study prior to receiving any dosing).
Pre-assignment details
44 participants signed informed consent. Of these, 4 participants were not treated (2 screen failures and 2 participants withdrew from study prior to receiving any dosing).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Low Dose Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | 11 |
| Cohort 2 - Medium Dose After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | 16 |
| Cohort 3 - High Dose After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | 13 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1 - ADVATE | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 34.0 Years | 33.0 Years | 36.0 Years | 34.0 Years |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 10 Participants | 16 Participants | 13 Participants | 39 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 16 Participants | 13 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 16 | 0 / 13 | 0 / 10 | 0 / 15 | 0 / 13 |
| other Total, other adverse events | 3 / 11 | 0 / 16 | 4 / 13 | 6 / 10 | 6 / 15 | 5 / 13 |
| serious Total, serious adverse events | 0 / 11 | 0 / 16 | 0 / 13 | 0 / 10 | 0 / 15 | 0 / 13 |
Outcome results
Primary
Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments)
Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides
Time frame: Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Low Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after Advate | 0 Participants |
| Cohort 1 - Low Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically significant vital signs | 0 Participants |
| Cohort 1 - Low Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after BAX826 | 0 Participants |
| Cohort 2 - Medium Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after Advate | 0 Participants |
| Cohort 2 - Medium Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically significant vital signs | 0 Participants |
| Cohort 2 - Medium Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after BAX826 | 0 Participants |
| Cohort 3 - High Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically significant vital signs | 0 Participants |
| Cohort 3 - High Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after BAX826 | 3 Participants |
| Cohort 3 - High Dose | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) | Clinically sign. laboratory results after Advate | 1 Participants |
Primary
Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies
Binding antibodies to CHO
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Population: The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies | 0 Participants |
Primary
Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies
Binding antibodies to PSA (IgG and IgM)
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Population: The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 3 Participants |
| Cohort 3 - High Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: At least 1 positive result (includ.predose) | 3 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | IgG: At least 1 positive result (includ.predose) | 0 Participants |
Primary
Immunogenicity: Binding Antibodies to Factor VIII (FVIII)
Binding antibodies to FVIII IgG and IgM
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Population: The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 1 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
Primary
Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826)
Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Population: The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 1 - Low Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 1 - Low Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 0 Participants |
| Cohort 2 - Medium Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: Predose negative / Postdose positive | 1 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: At least 1 positive result (includ.predose) | 1 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgM: Predose negative / Postdose positive | 0 Participants |
| Cohort 3 - High Dose BAX 826 | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | IgG: At least 1 positive result (includ.predose) | 1 Participants |
Primary
Immunogenicity: Human Anti-murine Antibodies (HAMA)
Binding antibodies HAMA (IgG)
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Human Anti-murine Antibodies (HAMA) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Human Anti-murine Antibodies (HAMA) | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Human Anti-murine Antibodies (HAMA) | 0 Participants |
Primary
Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII)
Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.
Time frame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Population: The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - Low Dose | Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 2 - Medium Dose | Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) | 0 Participants |
| Cohort 3 - High Dose | Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) | 0 Participants |
Primary
Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826
Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826.
Time frame: Up to 6 weeks ± 4 days post infusion with BAX826.
Population: Participants in Cohort 1, 2 and 3 in Period 2 (receiving BAX 826) are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any non-serious AE | 20 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any serious AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe systemic AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related non-serious AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE with outcome = Death | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related systemic AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe non-serious AE | 8 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related local/non-systemic AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any systemic AE | 1 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related serious AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE leading to study treatment withdrawal | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE | 20 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe serious AE | 0 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe local/non-systemic AE | 8 Adverse Events |
| Cohort 1 - Low Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any local/non-systemic AE | 19 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any local/non-systemic AE | 12 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE | 12 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE with outcome = Death | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any serious AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related serious AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe serious AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any non-serious AE | 12 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related non-serious AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe non-serious AE | 3 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any systemic AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related systemic AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe systemic AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related local/non-systemic AE | 0 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe local/non-systemic AE | 3 Adverse Events |
| Cohort 2 - Medium Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE leading to study treatment withdrawal | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any non-serious AE | 15 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe local/non-systemic AE | 3 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe systemic AE | 1 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe serious AE | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related serious AE | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any local/non-systemic AE | 11 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any serious AE | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE | 15 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related local/non-systemic AE | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any moderate or severe non-serious AE | 4 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE with outcome = Death | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any systemic AE | 4 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related non-serious AE | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any AE leading to study treatment withdrawal | 0 Adverse Events |
| Cohort 3 - High Dose | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 | Any treatment related systemic AE | 0 Adverse Events |
Secondary
Comparison of Key Pharmacokinetic Parameters by Cohort
The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from 0 to 72 hours (AUC0-72h), Maximum plasma concentration (Cmax), Terminal half-life (t1/2), Mean residence time (MRT) and Total body clearance (CL)) for ADVATE and BAX 826 have been compared.
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: One Stage Clotting Assay | 116.20 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: Chromogenic Assay | 141.10 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: One Stage Clotting Assay | 109.28 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: Chromogenic Assay | 135.27 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: One Stage Clotting Assay | 61.15 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: Chromogenic Assay | 82.85 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: One Stage Clotting Assay | 142.10 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: Chromogenic Assay | 136.97 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: One Stage Clotting Assay | 157.83 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: Chromogenic Assay | 148.12 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: One Stage Clotting Assay | 85.97 Ratio of Geometric Means (%) |
| Cohort 1 - Low Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: Chromogenic Assay | 70.73 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: Chromogenic Assay | 65.44 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: One Stage Clotting Assay | 122.53 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: One Stage Clotting Assay | 147.44 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: One Stage Clotting Assay | 165.99 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: Chromogenic Assay | 155.57 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: Chromogenic Assay | 89.17 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: One Stage Clotting Assay | 83.21 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: One Stage Clotting Assay | 115.60 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: Chromogenic Assay | 130.84 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: One Stage Clotting Assay | 63.28 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: Chromogenic Assay | 150.69 Ratio of Geometric Means (%) |
| Cohort 2 - Medium Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: Chromogenic Assay | 151.69 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: Chromogenic Assay | 133.20 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: One Stage Clotting Assay | 54.40 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: Chromogenic Assay | 156.29 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | Cmax: Chromogenic Assay | 73.68 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: One Stage Clotting Assay | 159.52 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | t 1/2: Chromogenic Assay | 138.28 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: One Stage Clotting Assay | 100.98 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: One Stage Clotting Assay | 100.79 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-∞: Chromogenic Assay | 138.99 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | MRT: One Stage Clotting Assay | 171.33 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | AUC 0-72: One Stage Clotting Assay | 96.07 Ratio of Geometric Means (%) |
| Cohort 3 - High Dose | Comparison of Key Pharmacokinetic Parameters by Cohort | CL: Chromogenic Assay | 73.26 Ratio of Geometric Means (%) |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826
AUC from time zero to exactly 168 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 168 hours is missing, the activity at 168 hours was interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). This parameter will be calculated for BAX 826 only.
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - One Stage Clotting Assay | 1124 IU*h/dL | Geometric Coefficient of Variation 72.9 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - Chromogenic Assay | 1231 IU*h/dL | Geometric Coefficient of Variation 67.2 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - One Stage Clotting Assay | 2358 IU*h/dL | Geometric Coefficient of Variation 24.2 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - Chromogenic Assay | 2739 IU*h/dL | Geometric Coefficient of Variation 36.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - One Stage Clotting Assay | 2572 IU*h/dL | Geometric Coefficient of Variation 54.7 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 | Period 2 (BAX 826) - Chromogenic Assay | 3783 IU*h/dL | Geometric Coefficient of Variation 55.6 |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h)
AUC from time zero to exactly 72 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 72 hours is missing, the activity at 72 hours will be interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z).
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - One Stage Clotting Assay | 885.9 IU*h/dL | Geometric Coefficient of Variation 41.8 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - One Stage Clotting Assay | 1041 IU*h/dL | Geometric Coefficient of Variation 68.4 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - Chromogenic Assay | 803.3 IU*h/dL | Geometric Coefficient of Variation 37.3 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - Chromogenic Assay | 1157 IU*h/dL | Geometric Coefficient of Variation 63.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - Chromogenic Assay | 2609 IU*h/dL | Geometric Coefficient of Variation 35.9 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - One Stage Clotting Assay | 1736 IU*h/dL | Geometric Coefficient of Variation 29.2 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - Chromogenic Assay | 1717 IU*h/dL | Geometric Coefficient of Variation 30 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - One Stage Clotting Assay | 2168 IU*h/dL | Geometric Coefficient of Variation 23.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - Chromogenic Assay | 3556 IU*h/dL | Geometric Coefficient of Variation 51.5 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 2 (BAX 826) - One Stage Clotting Assay | 2421 IU*h/dL | Geometric Coefficient of Variation 49.7 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - Chromogenic Assay | 2638 IU*h/dL | Geometric Coefficient of Variation 34 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) | Period 1 (ADVATE) - One Stage Clotting Assay | 2463 IU*h/dL | Geometric Coefficient of Variation 37.5 |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞)
Area under the FVIII activity-time curve from zero extrapolated to infinity, calculated by linear-up/log-down trapezoidal method and extrapolated to infinity, calculated as AUC last + C last / lambda z, where Clast is the estimated concentration at the last quantifiable time point
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - One Stage Clotting Assay | 901.3 IU*h/dL | Geometric Coefficient of Variation 43.3 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - One Stage Clotting Assay | 1127 IU*h/dL | Geometric Coefficient of Variation 73.1 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - Chromogenic Assay | 818.9 IU*h/dL | Geometric Coefficient of Variation 38.6 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - Chromogenic Assay | 1234 IU*h/dL | Geometric Coefficient of Variation 67.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - Chromogenic Assay | 2742 IU*h/dL | Geometric Coefficient of Variation 36.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - One Stage Clotting Assay | 1771 IU*h/dL | Geometric Coefficient of Variation 30.9 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - Chromogenic Assay | 1747 IU*h/dL | Geometric Coefficient of Variation 31 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - One Stage Clotting Assay | 2363 IU*h/dL | Geometric Coefficient of Variation 24.3 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - Chromogenic Assay | 3791 IU*h/dL | Geometric Coefficient of Variation 55.9 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 2 (BAX 826) - One Stage Clotting Assay | 2578 IU*h/dL | Geometric Coefficient of Variation 55 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - Chromogenic Assay | 2693 IU*h/dL | Geometric Coefficient of Variation 34.9 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) | Period 1 (ADVATE) - One Stage Clotting Assay | 2496 IU*h/dL | Geometric Coefficient of Variation 39.3 |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last)
Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method.
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - One Stage Clotting Assay | 1078 IU*h/dL | Geometric Coefficient of Variation 73.7 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - Chromogenic Assay | 1181 IU*h/dL | Geometric Coefficient of Variation 70.8 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - Chromogenic Assay | 785.4 IU*h/dL | Geometric Coefficient of Variation 39.2 |
| Cohort 1 - Low Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - One Stage Clotting Assay | 861.8 IU*h/dL | Geometric Coefficient of Variation 42.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - Chromogenic Assay | 1703 IU*h/dL | Geometric Coefficient of Variation 30.3 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - Chromogenic Assay | 2717 IU*h/dL | Geometric Coefficient of Variation 37.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - One Stage Clotting Assay | 2296 IU*h/dL | Geometric Coefficient of Variation 25.8 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - One Stage Clotting Assay | 1712 IU*h/dL | Geometric Coefficient of Variation 30.9 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - Chromogenic Assay | 3726 IU*h/dL | Geometric Coefficient of Variation 57.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - One Stage Clotting Assay | 2445 IU*h/dL | Geometric Coefficient of Variation 38.3 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 1 (ADVATE) - Chromogenic Assay | 2625 IU*h/dL | Geometric Coefficient of Variation 34.6 |
| Cohort 3 - High Dose | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) | Period 2 (BAX 826) - One Stage Clotting Assay | 2528 IU*h/dL | Geometric Coefficient of Variation 55.9 |
Secondary
Pharmacokinetics: Incremental Recovery (IR)
Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg)
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - One Stage Clotting Assay | 2.506 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 18.1 |
| Cohort 1 - Low Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX 826) - One Stage Clotting Assay | 1.544 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 27.5 |
| Cohort 1 - Low Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - Chromogenic Assay | 2.850 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 14.6 |
| Cohort 1 - Low Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX826) - Chromogenic Assay | 2.391 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 26.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX826) - Chromogenic Assay | 2.781 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 35.2 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - One Stage Clotting Assay | 2.594 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 17 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - Chromogenic Assay | 3.194 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 13 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX 826) - One Stage Clotting Assay | 1.560 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 22 |
| Cohort 3 - High Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX826) - Chromogenic Assay | 2.512 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 26.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 2 (BAX 826) - One Stage Clotting Assay | 1.641 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 41.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - Chromogenic Assay | 3.467 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 20.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Incremental Recovery (IR) | Period 1 (ADVATE) - One Stage Clotting Assay | 3.059 (IU/dL)/(IU/kg) | Geometric Coefficient of Variation 25.3 |
Secondary
Pharmacokinetics: Maximum Plasma Concentration (Cmax)
Maximum observed FVIII activity, obtained directly from FVIII activity versus time data
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 63.32 IU/dL | Geometric Coefficient of Variation 16.4 |
| Cohort 1 - Low Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 38.53 IU/dL | Geometric Coefficient of Variation 26.7 |
| Cohort 1 - Low Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - Chromogenic Assay | 72.00 IU/dL | Geometric Coefficient of Variation 12.8 |
| Cohort 1 - Low Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX826) - Chromogenic Assay | 59.65 IU/dL | Geometric Coefficient of Variation 23.8 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX826) - Chromogenic Assay | 142.00 IU/dL | Geometric Coefficient of Variation 35.1 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 130.06 IU/dL | Geometric Coefficient of Variation 16.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - Chromogenic Assay | 160.16 IU/dL | Geometric Coefficient of Variation 12.1 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 79.65 IU/dL | Geometric Coefficient of Variation 21.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX826) - Chromogenic Assay | 191.01 IU/dL | Geometric Coefficient of Variation 25.7 |
| Cohort 3 - High Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 124.78 IU/dL | Geometric Coefficient of Variation 40.8 |
| Cohort 3 - High Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - Chromogenic Assay | 258.68 IU/dL | Geometric Coefficient of Variation 21.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 228.24 IU/dL | Geometric Coefficient of Variation 23.5 |
Secondary
Pharmacokinetics: Mean Residence Time (MRT)
Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - One Stage Clotting Assay | 15.55 hours | Geometric Coefficient of Variation 39.9 |
| Cohort 1 - Low Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX 826) - One Stage Clotting Assay | 26.96 hours | Geometric Coefficient of Variation 43.4 |
| Cohort 1 - Low Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - Chromogenic Assay | 15.23 hours | Geometric Coefficient of Variation 36.1 |
| Cohort 1 - Low Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX826) - Chromogenic Assay | 24.26 hours | Geometric Coefficient of Variation 34.1 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX826) - Chromogenic Assay | 22.83 hours | Geometric Coefficient of Variation 20.3 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - One Stage Clotting Assay | 16.30 hours | Geometric Coefficient of Variation 30.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - Chromogenic Assay | 14.56 hours | Geometric Coefficient of Variation 29.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX 826) - One Stage Clotting Assay | 28.90 hours | Geometric Coefficient of Variation 17.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX826) - Chromogenic Assay | 24.10 hours | Geometric Coefficient of Variation 28.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 2 (BAX 826) - One Stage Clotting Assay | 24.33 hours | Geometric Coefficient of Variation 27.8 |
| Cohort 3 - High Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - Chromogenic Assay | 15.36 hours | Geometric Coefficient of Variation 29.1 |
| Cohort 3 - High Dose | Pharmacokinetics: Mean Residence Time (MRT) | Period 1 (ADVATE) - One Stage Clotting Assay | 14.00 hours | Geometric Coefficient of Variation 29.7 |
Secondary
Pharmacokinetics: Terminal Half-life (t1/2)
Terminal elimination phase half-life, calculated by (ln2)/lambda z, where lambda z is the terminal rate constant, determined by linear regression of the terminal points of the log-linear FVIII activity-time curve.
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - One Stage Clotting Assay | 10.57 hours | Geometric Coefficient of Variation 39.1 |
| Cohort 1 - Low Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX 826) - One Stage Clotting Assay | 16.18 hours | Geometric Coefficient of Variation 41.3 |
| Cohort 1 - Low Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - Chromogenic Assay | 11.23 hours | Geometric Coefficient of Variation 35.4 |
| Cohort 1 - Low Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX826) - Chromogenic Assay | 16.04 hours | Geometric Coefficient of Variation 35.6 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX826) - Chromogenic Assay | 15.21 hours | Geometric Coefficient of Variation 20.2 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - One Stage Clotting Assay | 11.30 hours | Geometric Coefficient of Variation 29.6 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - Chromogenic Assay | 11.21 hours | Geometric Coefficient of Variation 35.7 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX 826) - One Stage Clotting Assay | 16.90 hours | Geometric Coefficient of Variation 21 |
| Cohort 3 - High Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX826) - Chromogenic Assay | 16.72 hours | Geometric Coefficient of Variation 28.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 2 (BAX 826) - One Stage Clotting Assay | 16.22 hours | Geometric Coefficient of Variation 28.1 |
| Cohort 3 - High Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - Chromogenic Assay | 12.11 hours | Geometric Coefficient of Variation 28.5 |
| Cohort 3 - High Dose | Pharmacokinetics: Terminal Half-life (t1/2) | Period 1 (ADVATE) - One Stage Clotting Assay | 9.948 hours | Geometric Coefficient of Variation 34.8 |
Secondary
Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax)
Time of maximum FVIII activity is obtained directly from FVIII activity versus time data
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.3000 hours |
| Cohort 1 - Low Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.3000 hours |
| Cohort 1 - Low Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - Chromogenic Assay | 0.3000 hours |
| Cohort 1 - Low Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - Chromogenic Assay | 0.3835 hours |
| Cohort 2 - Medium Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - Chromogenic Assay | 0.3165 hours |
| Cohort 2 - Medium Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.3330 hours |
| Cohort 2 - Medium Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - Chromogenic Assay | 0.3330 hours |
| Cohort 2 - Medium Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.5165 hours |
| Cohort 3 - High Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - Chromogenic Assay | 0.3000 hours |
| Cohort 3 - High Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.5500 hours |
| Cohort 3 - High Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - Chromogenic Assay | 0.3085 hours |
| Cohort 3 - High Dose | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.3170 hours |
Secondary
Pharmacokinetics: Total Body Clearance (CL)
Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.02803 dL/kg*h | Geometric Coefficient of Variation 47 |
| Cohort 1 - Low Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.02213 dL/kg*h | Geometric Coefficient of Variation 74.8 |
| Cohort 1 - Low Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - Chromogenic Assay | 0.03085 dL/kg*h | Geometric Coefficient of Variation 42.2 |
| Cohort 1 - Low Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - Chromogenic Assay | 0.02022 dL/kg*h | Geometric Coefficient of Variation 69.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - Chromogenic Assay | 0.01862 dL/kg*h | Geometric Coefficient of Variation 37.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.02831 dL/kg*h | Geometric Coefficient of Variation 31.4 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - Chromogenic Assay | 0.02871 dL/kg*h | Geometric Coefficient of Variation 31.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.02161 dL/kg*h | Geometric Coefficient of Variation 25.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - Chromogenic Assay | 0.02006 dL/kg*h | Geometric Coefficient of Variation 57 |
| Cohort 3 - High Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.02950 dL/kg*h | Geometric Coefficient of Variation 55.8 |
| Cohort 3 - High Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - Chromogenic Assay | 0.02771 dL/kg*h | Geometric Coefficient of Variation 33.7 |
| Cohort 3 - High Dose | Pharmacokinetics: Total Body Clearance (CL) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.02989 dL/kg*h | Geometric Coefficient of Variation 39.3 |
Secondary
Pharmacokinetics: Volume of Distribution at Steady State (Vss)
Volume of distribution at steady state is calculated by MRT\*CL MRT=Mean residence time CL=Clearance rate
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
Population: In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Low Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.4359 dL/kg | Geometric Coefficient of Variation 17.4 |
| Cohort 1 - Low Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.5967 dL/kg | Geometric Coefficient of Variation 29.7 |
| Cohort 1 - Low Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - Chromogenic Assay | 0.4700 dL/kg | Geometric Coefficient of Variation 14.6 |
| Cohort 1 - Low Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - Chromogenic Assay | 0.4906 dL/kg | Geometric Coefficient of Variation 34.6 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - Chromogenic Assay | 0.4253 dL/kg | Geometric Coefficient of Variation 35.5 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.4615 dL/kg | Geometric Coefficient of Variation 17.7 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - Chromogenic Assay | 0.4181 dL/kg | Geometric Coefficient of Variation 20.6 |
| Cohort 2 - Medium Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.6246 dL/kg | Geometric Coefficient of Variation 24.2 |
| Cohort 3 - High Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - Chromogenic Assay | 0.4835 dL/kg | Geometric Coefficient of Variation 32.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 2 (BAX 826) - One Stage Clotting Assay | 0.7176 dL/kg | Geometric Coefficient of Variation 28.4 |
| Cohort 3 - High Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - Chromogenic Assay | 0.4256 dL/kg | Geometric Coefficient of Variation 26.7 |
| Cohort 3 - High Dose | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | Period 1 (ADVATE) - One Stage Clotting Assay | 0.4183 dL/kg | Geometric Coefficient of Variation 17.9 |
Secondary
Summary of Assessment of Dose Proportionality for BAX 826
Dose Proportionality for BAX 826 was calculated for the parameters Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from time 0 to the last quantifiable time point (AUC0-last) and Maximum plasma concentration (Cmax).
Time frame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.
Population: The PK analysis set consists of all subjects that have received at least 1 administration of ADVATE or BAX 826 and are evaluable for PK for one or both treatments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | AUC 0-∞: One Stage Clotting Assay | 1.668 Doubling dose increase |
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | AUC 0-∞: Chromogenic Assay | 1.979 Doubling dose increase |
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | AUC 0-last: One Stage Clotting Assay | 1.696 Doubling dose increase |
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | AUC 0-last: Chromogenic Assay | 2.014 Doubling dose increase |
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | Cmax: One Stage Clotting Assay | 2.058 Doubling dose increase |
| Cohort 1 - Low Dose | Summary of Assessment of Dose Proportionality for BAX 826 | Cmax: Chromogenic Assay | 2.055 Doubling dose increase |