Early Prophylaxis Immunologic Challenge (EPIC) Study

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 1 Year

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADVATE - Prophylactic Regimen<br>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)<br>* 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.<br>* Other names: ADVATE;|

What is the study measuring?
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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 |