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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Baxter Healthcare Corporation
Sponsor:
Collaborator:
Baxter Innovations GmbH
Information provided by (Responsible Party):
Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:
NCT01913405
First received: June 27, 2013
Last updated: January 12, 2014
Last verified: January 2014
  Purpose

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


Condition Intervention Phase
Hemophilia A
Biological: PEGylated Recombinant factor VIII (rFVIII)
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 3, Multi-Center, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures

Resource links provided by NLM:


Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:
  • Global Hemostatic Efficacy Assessment score (GHEA)- composed of 3 individual ratings [ Time Frame: up to 4 weeks post discharge ] [ Designated as safety issue: No ]

    GHEA=Sum of 1-3 ratings, below Excellent: 7-9 (no category <2) Good: 5-7 (no category <1) Fair: 3-4 (no category <1)

    1. Intraoperative hemostasis Excellent=3: Blood Loss (BL) ≤expected for procedure type in non-hemophilic population(NHP)(≤100%) Good=2: BL ≤50% more than expected for procedure type in NHP(101-150%) Fair=1: BL >50% of expected for procedure type in NHP(>150%) None=0: Uncontrolled-requiring rescue therapy
    2. Hemostasis postoperative day 1 Excellent=3: As good or better than expected for type of procedure in NHP Good=2: Probably as good as expected for procedure type in NHP Fair=1: <optimal for procedure type None=0: Uncontrolled-requiring rescue therapy
    3. Postoperative hemostasis after Day 1 with BAX855 at End of Study visit Excellent=3: As good or better than expected for procedure type in NHP Good=2: Probably as good as expected for procedure type in NHP Fair=1: <optimal for procedure type None=0: Uncontrolled after Day 1-requiring rescue therapy


Secondary Outcome Measures:
  • Development of inhibitory antibodies to Factor VIII (FVIII) [ Time Frame: Within 45 days prior to surgery (Screening visit); and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    Immunogenicity assessment using FVIII inhibitor by Nijmegen method. A 72-hour washout period is required prior to immunogenicity tests.

  • Development of binding antibodies to Factor VIII (FVIII), Baxter's PEGylated recombinant FVIII, and polyethylene glycol (PEG) [ Time Frame: Within 45 days prior to surgery (Screening visit); and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    A 72-hour washout period is required prior to immunogenicity tests.

  • Development of anti-chinese hamster ovary (CHO) antibodies [ Time Frame: Within 45 days prior to surgery (Screening visit); and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    A 72-hour washout period is required prior to immunogenicity tests.

  • Occurrence of thrombotic events [ Time Frame: Throughout the study period- please see Outcome Description for more details ] [ Designated as safety issue: Yes ]
    Thrombotic events may occur at any time point throughout the study period and will be reported. Additionally, Thrombotic markers (thrombin-antithrombin III complexes(TAT), D-dimers, fibrinogen, and prothrombin fragment 1.2) will be checked via clinical laboratory assessments at the: screening visit (Within 45 days prior to surgery), Pre-operative visit, Postoperative Day 1, and End of Study Visit (4 weeks after discharge)

  • Other investigational product (IP)-related AEs [ Time Frame: Throughout the study period, within 45 days prior to surgery to 4 weeks after discharge (End of Study Visit) ] [ Designated as safety issue: Yes ]
  • Clinically significant changes in vital signs - Body temperature [ Time Frame: Within 45 days prior to surgery; within 30 - 60 minutes after administration of BAX 855 for pharmacokinetics (PK); preoperatively within 2 hours of surgery; on Day 1, 3, 7 post-surgery; and during End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    Body temperature (°C or °F)

  • Clinically significant changes in vital signs - Respiratory rate [ Time Frame: Within 45 days prior to surgery; within 30 - 60 minutes after administration of BAX 855 for pharmacokinetics (PK); preoperatively within 2 hours of surgery; on Day 1, 3, 7 post-surgery; and during End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    Respiratory rate (breaths/min)

  • Clinically significant changes in vital signs - Systolic and Diastolic Blood Pressure (BP) [ Time Frame: Within 45 days prior to surgery; within 30 - 60 minutes after administration of BAX 855 for pharmacokinetics (PK); preoperatively within 2 hours of surgery; on Day 1, 3, 7 post-surgery; and during End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    Systolic and diastolic blood pressure (mmHg)

  • Clinically significant changes in vital signs - Pulse Rate [ Time Frame: Within 45 days prior to surgery; within 30 - 60 minutes after administration of BAX 855 for pharmacokinetics (PK); preoperatively within 2 hours of surgery; on Day 1, 3, 7 post-surgery; and during End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    Pulse rate (beats/min)

  • Clinically significant changes in routine laboratory parameters- Hematology [ Time Frame: Within 45 days prior to surgery (Screening visit); Postoperative Day 1-3 until discharge- whichever is earlier; and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    The hematology panel consists of complete blood count [hemoglobin, hematocrit, erythrocytes (ie, red blood cell count), and leukocytes (ie, white blood cell count)] with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts.

  • Clinically significant changes in routine laboratory parameters - Clinical chemistry [ Time Frame: Within 45 days prior to surgery (Screening visit); Postoperative Day 1 until discharge- whichever is earlier; and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    The clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, protein, albumin, alanine aminotransferase, bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.

  • Intraoperative and postoperative blood loss [ Time Frame: Initiation of the surgery to 24 hours after completion or drain removal, if applicable ] [ Designated as safety issue: No ]
    Actual intraoperative and postoperative blood loss until drain removal, if applicable, compared to average and maximum blood loss predicted preoperatively for the planned surgery in a hemostatically normal individual of the same sex, age, and stature as the study participant

  • Transfusion Requirements [ Time Frame: From initiation of the surgery to 24 hours after completion of the surgery ] [ Designated as safety issue: No ]
    The type and volume of blood product utilized

  • Bleeding Episodes [ Time Frame: Intra- and post-operative period, until the time of discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks) ] [ Designated as safety issue: Yes ]
    Any clinically relevant bleeding episodes (as assessed by the investigator), as well as the need for any further surgical interventions

  • Consumption of BAX855 [ Time Frame: From initiation of the surgery until the time of discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks) ] [ Designated as safety issue: No ]
    Daily and total weight-adjusted dose of BAX855 per subject.

  • Development of antibodies to murine immunoglobulin G (IgG) [ Time Frame: Within 45 days prior to surgery (Screening visit); and End of Study Visit (4 weeks after discharge) ] [ Designated as safety issue: Yes ]
    A 72-hour washout period is required prior to immunogenicity tests.

  • Pharmacokinetics (PK) - Incremental recovery(IR) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    IR= (Concentration(maximum post-infusion)[International Unit(IU)/dL] - Concentration(pre-infusion)[IU/dL]) / Dose[IU/kg]

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Terminal half-life (T1/2) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    Computed from the regression slope in the terminal phase of the model (the slope is biphasic). Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    (AUC0-∞) is calculated as the sum of AUC from time 0 to the time of last quantifiable concentration using the linear trapezoidal rule plus a tail area correction.

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Mean residence time (MRT) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    The MRT in hours is calculated as total area under the moment curve divided by the total area under the curve

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Clearance (CL) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    CL in dL/(kg*h) is calculated as the dose in IU/kg divided by the total AUC

    h = hours

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Apparent volume of distribution at steady state (Vss) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    Vss in dL/kg is calculated as MRT [h] * CL [dL/(kg*h)]

    h = hours

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.


  • Pharmacokinetics (PK) - Area under the plasma concentration/time curve from time 0 to 96 hours post-infusion (AUC0-96h) [ Time Frame: Within 30 minutes pre-infusion and post-infusion at, 10 min and 0.5, 1, 3, 6, 9, 24, 32, 48, 56, 72, and 96 hours ] [ Designated as safety issue: No ]

    Following at least a 72 hour (h) washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period.

    Computed using the linear trapezoidal rule. For the calculation of AUC0-96h the levels at 96 hours will be linearly interpolated from the 2 nearest sampling time points or extrapolated from the last quantifiable concentration.

    PK evaluations must be repeated if:

    • Bleeding episode occurs prior to a 72-hour time point.
    • ≥2 PK blood sample results are not evaluable.
    • >60 calendar days between the 96 hour post-infusion time point and the planned surgery elapse.

    However, if participants enter study from other BAX855 studies, exceptions may be approved by the medical director.



Estimated Enrollment: 30
Study Start Date: December 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BAX855

Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and character of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-150% FVIII trough level, and minor surgery will target an initial 30-100% FVIII trough level.

Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and character of the surgery performed.

Biological: PEGylated Recombinant factor VIII (rFVIII)
Other Name: BAX 855

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant requires an elective major or minor surgical, dental or other invasive procedure (e.g. biopsy, endoscopy).
  • Participant and/or legal representative has/have provided signed informed consent.
  • Participant has severe hemophilia A (Factor VIII (FVIII) level <1%) as confirmed by the central lab at screening or a documented FVIII activity level <1%.
  • Participant was previously treated with FVIII concentrates with ≥150 documented exposure days (EDs).
  • Participant is currently receiving prophylaxis or on-demand therapy with FVIII concentrate.
  • Participant has a Karnofsky performance score of ≥60 at screening.
  • Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥200 cells/mm^3, as confirmed by central laboratory at screening.
  • Participant is Hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator.
  • Participant is willing and able to comply with the requirements of the study protocol.

Exclusion Criteria:

  • Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Unit (BU) using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay).
  • History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
  • Participant has a platelet count <100 x 10^9/L, as confirmed by central laboratory at screening.
  • Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
  • Participant has severe chronic hepatic dysfunction (eg ≥5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by the central laboratory at screening, or a documented International Normalized Ratio (INR) > 1.5).
  • Participant has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG.
  • Participant is currently using or has recently (< 30 days) used pegylated drugs (other than BAX 855) prior to study participation or is scheduled to use such drugs during trial participation.
  • Participant is currently participating in another clinical drug (other than BAX 855) or device study or use of another investigational product or device within 30 days prior to study entry.
  • Participant has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.
  • Participant is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (eg, systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy.
  • Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01913405

Contacts
Contact: Eli Taube 43 1201002471240 eli_taube@baxter.com

Locations
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
United States, Washington
Puget Sound Blood Center Not yet recruiting
Seattle, Washington, United States, 98104
Bulgaria
SHAT of Oncohaematology Diseases Not yet recruiting
Sofia, Bulgaria, 1527
United Kingdom
Royal Free Hospital Not yet recruiting
London, Greater London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Baxter Healthcare Corporation
Baxter Innovations GmbH
Investigators
Study Director: Brigitt Abbuehl, MD Baxter Innovations GmbH
  More Information

No publications provided

Responsible Party: Baxter Healthcare Corporation
ClinicalTrials.gov Identifier: NCT01913405     History of Changes
Other Study ID Numbers: 261204
Study First Received: June 27, 2013
Last Updated: January 12, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Bulgaria: Bulgarian Drug Agency
Germany: Paul-Ehrlich-Institut
Lithuania: State Medicine Control Agency - Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: FSI Scientific Center of Expertise of Medical Application
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Ukraine: State Pharmacological Center - Ministry of Health
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 27, 2014