The EPIC study: a lesson to learn.
BACKGROUND
Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not.


OBJECTIVE
The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg(-1) rAHF-PFM before 1 year of age and immunological danger signals are minimized.


METHODS
These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3-4 days before or after FVIII.


RESULTS
Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board.


CONCLUSIONS
Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity ≥0.6 BU mL(-1) may not always reflect the presence of FVIII-neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response.
Prof. Hess Children's Hospital, Klinikum Bremen-Mitte, Bremen, Germany.
G
G
Auerswald
Klinikum der Universitaet Muenchen, Dr von Haunersches Children's Hospital, Munich, Germany.
K
K
Kurnik
Mount Sinai School of Medicine, New York, NY, USA.
L M
LM
Aledort
Baxter Innovations GmbH, Vienna, Austria.
H
H
Chehadeh
Baxter Innovations GmbH, Vienna, Austria.
A
A
Loew-Baselli
Baxter Innovations GmbH, Vienna, Austria.
K
K
Steinitz
Baxter Innovations GmbH, Vienna, Austria.
A J
AJ
Reininger
D000906:Antibodies / Q000378:metabolism; D005169:Factor VIII / Q000037:antagonists & inhibitors; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D007223:Infant
D000906:Antibodies; D005169:Factor VIII
EPIC; advate; danger theory; haemophilia; inhibitors; octocog alfa; prophylaxis; rAHF-PFM