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BAX 826 Dose-Escalation Safety Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02716194
Recruitment Status : Completed
First Posted : March 23, 2016
Results First Posted : September 20, 2018
Last Update Posted : September 20, 2018
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

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)

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: BAX 826 Biological: Octocog alfa Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 3, 2016
Actual Primary Completion Date : January 17, 2017
Actual Study Completion Date : January 17, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Cohort 1 - Low dose
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
Other Name: BAX826

Biological: Octocog alfa
Other Names:
  • ADVATE (Antihemophilic Factor [Recombinant])
  • ADVATE

Experimental: Cohort 2 - Medium dose
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
Other Name: BAX826

Biological: Octocog alfa
Other Names:
  • ADVATE (Antihemophilic Factor [Recombinant])
  • ADVATE

Experimental: Cohort 3 - High dose
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
Other Name: BAX826

Biological: Octocog alfa
Other Names:
  • ADVATE (Antihemophilic Factor [Recombinant])
  • ADVATE




Primary Outcome Measures :
  1. Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 [ Time Frame: 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.

  2. Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) [ 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 ]
    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

  3. Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) [ 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 ]
    Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.

  4. Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) [ 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 ]
    Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM

  5. Immunogenicity: Binding Antibodies to Factor VIII (FVIII) [ 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 ]
    Binding antibodies to FVIII IgG and IgM

  6. Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies [ 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 ]
    Binding antibodies to PSA (IgG and IgM)

  7. Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies [ 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 ]
    Binding antibodies to CHO

  8. Immunogenicity: Human Anti-murine Antibodies (HAMA) [ 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 ]
    Binding antibodies HAMA (IgG)


Secondary Outcome Measures :
  1. Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (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. ]
    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

  2. Pharmacokinetics: Terminal Half-life (t1/2) [ 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. ]
    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.

  3. Pharmacokinetics: Mean Residence Time (MRT) [ 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. ]
    Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion

  4. Pharmacokinetics: Total Body Clearance (CL) [ 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. ]
    Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞

  5. Pharmacokinetics: Incremental Recovery (IR) [ 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. ]
    Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg)

  6. Pharmacokinetics: Volume of Distribution at Steady State (Vss) [ 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. ]
    Volume of distribution at steady state is calculated by MRT*CL MRT=Mean residence time CL=Clearance rate

  7. Pharmacokinetics: 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, 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

  8. Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) [ 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. ]
    Time of maximum FVIII activity is obtained directly from FVIII activity versus time data

  9. Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) [ 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. ]
    Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method.

  10. Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) [ 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. ]
    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).

  11. Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 [ 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. ]
    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.

  12. Comparison of Key Pharmacokinetic Parameters by Cohort [ 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. ]
    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.

  13. Summary of Assessment of Dose Proportionality for BAX 826 [ 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. ]
    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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02716194


Locations
Show Show 28 study locations
Sponsors and Collaborators
Baxalta now part of Shire
Investigators
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Study Director: Shouryadeep Srivastava, MBBS, PhD Baxalta now part of Shire
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT02716194    
Other Study ID Numbers: 291501
2015-004079-60 ( EudraCT Number )
First Posted: March 23, 2016    Key Record Dates
Results First Posted: September 20, 2018
Last Update Posted: September 20, 2018
Last Verified: January 2018
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants