Early Prophylaxis Immunologic Challenge (EPIC) Study (EPIC)

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

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.

Study Overview

• Status: Terminated
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
• Bulgaria
  • Sofia, Bulgaria
• Canada
  • Ontario
    • Kingston, Ontario, Canada
• Czechia
  • Brno, Czechia
• 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
• United States
  • Indiana
    • Indianapolis, Indiana, United States
  • New Jersey
    • New Brunswick, New Jersey, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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 Names: ADVATE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	50 exposure days to ADVATE

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	50 exposure days to ADVATE
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).	50 exposure days to ADVATE
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)	50 exposure days to ADVATE
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	50 exposure days to ADVATE
Number and Type of Surgeries	- Elective surgery is not allowed during period of first 20 exposure days (EDs) - Peripherally inserted central catheter (PICC)	50 exposure days to ADVATE
Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation		50 exposure days to ADVATE
Total Factor VIII (FVIII) Consumption by Participant		50 exposure days to ADVATE
FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)		50 exposure days to ADVATE
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	50 exposure days to ADVATE

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Collaborators: Baxter Innovations GmbH

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2011
• Primary Completion (Actual): November 16, 2012
• Study Completion (Actual): November 16, 2012

Study Registration Dates

• First Submitted: June 17, 2011
• First Submitted That Met QC Criteria: June 17, 2011
• First Posted (Estimate): June 20, 2011

Study Record Updates

• Last Update Posted (Actual): May 24, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: 061002; 2011-000410-18 (EudraCT Number)