Early Prophylaxis Immunologic Challenge (EPIC) Study

This study has been terminated.
(It became unlikely to achieve the study objective of 50% reduction over published inhibitor rates. The Data Monitoring Committee supported this decision.)
Sponsor:
Collaborator:
Baxter Innovations GmbH
Information provided by (Responsible Party):
Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:
NCT01376700
First received: June 17, 2011
Last updated: October 7, 2014
Last verified: October 2014
  Purpose

The purpose of the study was to assess if a once-weekly prophylactic regimen of 25 IU/kg ADVATE started at or before 1 year of age and before the onset of a severe bleeding phenotype (ie, joint bleeding), together with the minimization of immunological danger signals, can reduce the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A.


Condition Intervention Phase
Hemophilia A
Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Phase 3b Clinical Study to Assess Whether Regular Administration of ADVATE in the Absence of Immunological Danger Signals Reduces the Incidence Rate of Inhibitors in Previously Untreated Patients With Hemophilia A

Resource links provided by NLM:


Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:
  • Number of Participants With Severe and Moderately Severe Hemophilia A (FVIII ≤ 2%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]

    Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing.

    Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

    • i. High FVIII inhibitor titer (> 5 BU/mL) or
    • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).


Secondary Outcome Measures:
  • Number of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]

    Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing.

    Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

    • i. High FVIII inhibitor titer (> 5 BU/mL) or
    • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).

  • Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]

    Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 BU/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

    • i. High FVIII inhibitor titer (> 5 BU/mL) or
    • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).

  • Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]
    • High FVIII inhibitor titer (> 5 Bethesda Unit (BU)/mL)
    • Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL)

  • Number, Type, and Severity of All Bleeds Experienced When Different Prophylactic Dosing Frequencies Are Used (Once or Twice Per Week and Unknown Frequency) [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]

    Nominal Dosing Frequency:

    • 1 time per week
    • 2 times per week
    • Unknown dosing frequency (UK)

    Bleeding Type (BT):

    • Skin
    • Muscle and Soft Tissue
    • Mucosal
    • Joint
    • Other
    • Multiple
    • Total

    Bleeding severity:

    • Minor
    • Moderate
    • Severe
    • Total

  • Number and Type of Surgeries [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: No ]
    • Elective surgery is not allowed during period of first 20 exposure days (EDs)
    • Peripherally inserted central catheter (PICC)

  • Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: No ]
  • Total Factor VIII (FVIII) Consumption by Participant [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: No ]
  • FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs) [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: No ]
  • Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE [ Time Frame: 50 exposure days to ADVATE ] [ Designated as safety issue: Yes ]
    Possibly or probably related adverse events


Enrollment: 22
Study Start Date: August 2011
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ADVATE - Prophylactic Regimen
Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.
Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.
Other Name: ADVATE

  Eligibility

Ages Eligible for Study:   up to 1 Year
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants with severe and moderately severe hemophilia A (FVIII ≤ 2%)
  • Participants < 1 year of age
  • Participants must have ≤ 3 exposure days (EDs) to any FVIII concentrate or FVIII-containing product used for treatment of minor bleeds (bleeds requiring no more than 2 infusions per event), or for preventative or precautionary infusions following possible injury
  • Participants with prior circumcision are allowed to enroll only if bleeding issues related to circumcision were the cause for the original diagnosis of hemophilia A and no more than 2 EDs of FVIII treatment were required
  • Adequate venous access (without need for central venous access device (CVAD)-placement) as determined by the physician
  • Written informed consent from legally authorized representative(s)

Exclusion Criteria:

  • Life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment
  • Evidence of inhibitor ≥ 0.6 Bethesda Unit (BU) in Nijmegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitor test results)
  • Inherited or acquired hemostatic defect other than hemophilia A
  • Any clinically significant, chronic disease other than hemophilia A
  • Known hypersensitivity to ADVATE or any of its constituents
  • Any planned elective surgery that cannot be postponed until after the first 20 EDs
  • Participation in the Hemophilia Inhibitor Previously Untreated Patient Study
  • Application of red blood cell, platelet, or leukocyte concentrates, or plasma
  • Administration of any medication affecting coagulation or platelet function
  • Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
  • Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this study
  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: NCT01376700

Locations
United States, Indiana
Indianapolis, Indiana, United States
United States, New Jersey
New Brunswick, New Jersey, United States
Austria
Vienna, Austria
Bulgaria
Sofia, Bulgaria
Canada, Ontario
Kingston, Ontario, Canada
Czech Republic
Brno, Czech Republic
Germany
Bonn, Germany
Bremen, Germany
Giessen, Germany
Munich, Germany
Lithuania
Vilnius, Lithuania
Netherlands
Nijmegen, Netherlands
Poland
Lublin, Poland
Olsztyn, Poland
Russian Federation
Chelyabinsk, Russian Federation
Krasnodar, Russian Federation
St. Petersburg, Russian Federation
Serbia
Belgrade, Serbia
Spain
A Coruña, Spain
Sponsors and Collaborators
Baxter Healthcare Corporation
Baxter Innovations GmbH
Investigators
Study Director: Armin Reininger, MD Baxter Healthcare Corporation
  More Information

No publications provided

Responsible Party: Baxter Healthcare Corporation
ClinicalTrials.gov Identifier: NCT01376700     History of Changes
Other Study ID Numbers: 061002, 2011-000410-18
Study First Received: June 17, 2011
Results First Received: September 17, 2014
Last Updated: October 7, 2014
Health Authority: Austria: Agency for Health and Food Safety
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
Czech Republic: State Institute for Drug Control
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
Serbia: Agency for Drugs and Medicinal Devices
Spain: Spanish Agency of Medicines
United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 23, 2014