BAX 826 Dose-Escalation Safety Study

Study Overview
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Brief Summary
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To assess tolerability and safety of BAX 826 after a single infusion in previously treated patients (PTPs) with severe hemophilia A To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE To evaluate immunogenicity of polysialic acid linked to Factor VIII (FVIII)

Official Title
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A Phase 1, Prospective, Open Label, Two Period, Fixed Sequence, Dose-Escalation Study of the PK and Safety of BAX 826 (PSA-rFVIII) in Previously Treated Patients With Severe (FVIII <1%) Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: BAX 826
* Biological: Octocog alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated male participants aged 18 to 65 years (inclusive) at the time of screening Diagnosis of severe hemophilia A (Factor VIII level <1%) Previously treated with FVIII concentrates for ≥150 documented Exposure Days (EDs) Karnofsky performance score of ≥60 Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease Hepatitis C virus negative (HCV-); or HCV+ with chronic stable hepatitis as assessed by the investigator Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC) Have provided written authorization for use and disclosure of protected health information Agree to abide by the study schedule and to return for the required assessments Willing and able to comply with the requirements of the protocol Exclusion Criteria: Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU) Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA) Scheduled elective surgery during study participation Severe chronic hepatic dysfunction Severe renal impairment 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 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 Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy 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 Is a family member or employee of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Low dose<br>The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | Biological: BAX 826<br> <br> * Other names: BAX826;Biological: Octocog alfa<br> <br> * Other names: ADVATE;|
| Experimental: Cohort 2 - Medium dose<br>The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | Biological: BAX 826<br> <br> * Other names: BAX826;Biological: Octocog alfa<br> <br> * Other names: ADVATE;|
| Experimental: Cohort 3 - High dose<br>The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | Biological: BAX 826<br> <br> * Other names: BAX826;Biological: Octocog alfa<br> <br> * Other names: ADVATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 6 weeks ± 4 days post infusion with BAX826. | 
| 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 | 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 | 
| 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. | 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 | 
| Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) | Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM | 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 | 
| Immunogenicity: Binding Antibodies to Factor VIII (FVIII) | Binding antibodies to FVIII IgG and IgM | 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 | 
| Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies | Binding antibodies to PSA (IgG and IgM) | 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 | 
| Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies | Binding antibodies to CHO | 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 | 
| Immunogenicity: Human Anti-murine Antibodies (HAMA) | Binding antibodies HAMA (IgG) | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 
| 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. | 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. | 
| Pharmacokinetics: Mean Residence Time (MRT) | Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion | 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. | 
| Pharmacokinetics: Total Body Clearance (CL) | Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/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. | 
| Pharmacokinetics: Incremental Recovery (IR) | Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg) | 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. | 
| 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 | 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. | 
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) | Maximum observed FVIII activity, obtained directly from FVIII activity versus time data | 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. | 
| Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) | Time of maximum FVIII activity is obtained directly from FVIII activity versus time data | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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). | 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. |