Early Prophylaxis Immunologic Challenge (EPIC) Study

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01376700

Acronym

EPIC

Enrollment

Registered

2011-06-20

Start date

2011-08-26

Completion date

2012-11-16

Last updated

2021-05-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hemophilia A

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.

Interventions

BIOLOGICALRecombinant 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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

No minimum to 1 Years

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

Design outcomes

Primary

Measure	Time frame	Description
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	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

Measure	Time frame	Description
Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE	50 exposure days to ADVATE	Possibly or probably related adverse events
Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment	50 exposure days to ADVATE	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	50 exposure days to ADVATE	\- 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)	50 exposure days to ADVATE	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 of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE	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).
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 and Type of Surgeries	50 exposure days to ADVATE	\- Elective surgery is not allowed during period of first 20 exposure days (EDs) - Peripherally inserted central catheter (PICC)

Countries

Austria, Bulgaria, Canada, Czechia, Germany, Lithuania, Netherlands, Poland, Russia, Serbia, Spain, United States

Participant flow

Recruitment details

Enrollment was conducted in Europe and North America at 19 clinical sites.

Pre-assignment details

22 participants were enrolled. One was a screen failure; one did not have screening laboratory assessments performed prior to study termination; and one met screening criteria, but was not exposed to investigational product prior to study termination. Therefore 19 participants were treated

Participants by arm

Arm	Count
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.	19
Total	19

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Low or high titer inhibitor	8
Overall Study	Sponsor terminated study early	8

Baseline characteristics

Characteristic	ADVATE - Prophylactic Regimen
Age, Continuous	43.3 weeks STANDARD_DEVIATION 10.2
Region of Enrollment Austria	1 Participants
Region of Enrollment Bulgaria	1 Participants
Region of Enrollment Canada	1 Participants
Region of Enrollment Czech Republic	2 Participants
Region of Enrollment Germany	2 Participants
Region of Enrollment Netherlands	1 Participants
Region of Enrollment Poland	4 Participants
Region of Enrollment Russian Federation	3 Participants
Region of Enrollment Serbia	1 Participants
Region of Enrollment Spain	1 Participants
Region of Enrollment United States	2 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	19 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	19 / 19
serious Total, serious adverse events	11 / 19

Outcome results

Primary

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).