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Early Prophylaxis Immunologic Challenge (EPIC) Study (EPIC)

Primary Purpose

Hemophilia A

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
Sponsored by
Baxalta now part of Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Hemophilia A

Eligibility Criteria

undefined - 1 Year (Child)MaleDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ADVATE - Prophylactic Regimen

Arm Description

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.

Outcomes

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
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
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
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
- 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)
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
- 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
Total Factor VIII (FVIII) Consumption by Participant
FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)
Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE
Possibly or probably related adverse events

Full Information

First Posted
June 17, 2011
Last Updated
April 28, 2021
Sponsor
Baxalta now part of Shire
Collaborators
Baxter Innovations GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT01376700
Brief Title
Early Prophylaxis Immunologic Challenge (EPIC) Study
Acronym
EPIC
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Terminated
Why Stopped
It became unlikely to achieve the study objective of 50% reduction over published inhibitor rates. The Data Monitoring Committee supported this decision.
Study Start Date
August 26, 2011 (Actual)
Primary Completion Date
November 16, 2012 (Actual)
Study Completion Date
November 16, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Baxalta now part of Shire
Collaborators
Baxter Innovations GmbH

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ADVATE - Prophylactic Regimen
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
Other Intervention Name(s)
ADVATE
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Description
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).
Time Frame
50 exposure days to ADVATE
Secondary Outcome Measure Information:
Title
Number of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE
Description
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).
Time Frame
50 exposure days to ADVATE
Title
Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment
Description
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).
Time Frame
50 exposure days to ADVATE
Title
Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors
Description
- High FVIII inhibitor titer (> 5 Bethesda Unit (BU)/mL) - Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL)
Time Frame
50 exposure days to ADVATE
Title
Number, Type, and Severity of All Bleeds Experienced When Different Prophylactic Dosing Frequencies Are Used (Once or Twice Per Week and Unknown Frequency)
Description
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
Time Frame
50 exposure days to ADVATE
Title
Number and Type of Surgeries
Description
- Elective surgery is not allowed during period of first 20 exposure days (EDs) - Peripherally inserted central catheter (PICC)
Time Frame
50 exposure days to ADVATE
Title
Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation
Time Frame
50 exposure days to ADVATE
Title
Total Factor VIII (FVIII) Consumption by Participant
Time Frame
50 exposure days to ADVATE
Title
FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)
Time Frame
50 exposure days to ADVATE
Title
Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE
Description
Possibly or probably related adverse events
Time Frame
50 exposure days to ADVATE

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
City
Indianapolis
State/Province
Indiana
Country
United States
City
New Brunswick
State/Province
New Jersey
Country
United States
City
Vienna
Country
Austria
City
Sofia
Country
Bulgaria
City
Kingston
State/Province
Ontario
Country
Canada
City
Brno
Country
Czechia
City
Bonn
Country
Germany
City
Bremen
Country
Germany
City
Giessen
Country
Germany
City
Munich
Country
Germany
City
Vilnius
Country
Lithuania
City
Nijmegen
Country
Netherlands
City
Lublin
Country
Poland
City
Olsztyn
Country
Poland
City
Chelyabinsk
Country
Russian Federation
City
Krasnodar
Country
Russian Federation
City
St. Petersburg
Country
Russian Federation
City
Belgrade
Country
Serbia
City
A Coruña
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
25912619
Citation
Auerswald G, Kurnik K, Aledort LM, Chehadeh H, Loew-Baselli A, Steinitz K, Reininger AJ; EPIC clinical study group. The EPIC study: a lesson to learn. Haemophilia. 2015 Sep;21(5):622-8. doi: 10.1111/hae.12666. Epub 2015 Apr 23.
Results Reference
result

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Early Prophylaxis Immunologic Challenge (EPIC) Study

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