Study Evaluating Safety Of Patients Switching To ReFacto AF In Usual Care Settings

Study Overview
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Brief Summary
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The study will be investigating safety in patients who switch to ReFacto AF from ReFacto and other Factor VIII products.

Detailed Description
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The trial was terminated prematurely on 28 March 2013, due to the inability to recruit the planned number of subjects. The decision to terminate the trial was not based on any safety or efficacy concerns and agreement to close the study in March 2013 was agreed with EMA prior to closure activity.

Official Title
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A Postauthorization Safety Surveillance Study Of Patients Switching To ReFacto AF From ReFacto Or Other Factor VIII Products In Usual Care Settings

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: moroctocog alfa (AF-CC) (ReFacto AF)
* Procedure: Laboratory tests


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male patients greater than or equal to 12 years of age with severe hemophilia A (FVIII:C less than 1%). Treatment history of greater than 150 EDs to prior recombinant or plasma-derived FVIII replacement products. Transitioning to ReFacto AF from ReFacto or other recombinant or plasma-derived FVIII replacement products. Serum albumin greater than or equal to the lower limit of normal (LLN). Platelet count greater than or equal to 100,000/µL. Prothrombin time (PT) less than or equal to1.25 × ULN, or international normalized ratio (INR) less than or equal to 1.5. HIV positive subjects must have a CD4 count greater than 200/µL and HIV viral load less than 200 particles/µL. Exclusion Criteria: Presence of any bleeding disorder in addition to hemophilia A. A positive FVIII inhibitor, according to the local laboratory, at screening; or any Bethesda Inhibitor Titer greater than 0.6, regardless of the normal range for the testing laboratory. Treated with immunomodulatory therapy (including Immune Tolerance Induction [ITI]) during the screening period. Prior exposure to moroctocog alfa (AF-CC). Known hypersensitivity to hamster protein.

Ages Eligible for Study
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Minimum Age: 12 Years

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: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ReFacto AF<br> | Drug: moroctocog alfa (AF-CC) (ReFacto AF)<br>* Providing moroctocog alfa (AF-CC) as test article for use during this study.<br>Procedure: Laboratory tests<br>* Laboratory samples are collected during study visits, in order to collect safety and efficacy data related to the administration of test article.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Factor VIII Inhibitor Development | Number of participants with clinically significant FVIII inhibitor development after switching from ReFacto to moroctocog alfa (AF-CC). Clinically significant inhibitors are defined as a central laboratory confirmed positive inhibitor (≥ 0.6 Bethesda unit (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval) and within 28 days before the initial or within 28 days following the second positive FVIII inhibitor sample collection one of the following: the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, or ≥2 adverse event reports of decreased drug effect (or other adverse event indicating a decrease in the efficacy of the test article). The blood sample collection for these results must also be between the date of first dose of study medication and 28 days after the last dose of study medication. | 100 exposure days to study medication (approx. 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rates (ABRs) | An ABR for each participant will be calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by his total therapy duration (in days), then multiplied by 365.25. | 100 exposure days to study medication (approx. 2 years) | 
| Response Assessment of First On-demand Treatment of New Bleeds | A 4-point scale of assessment of 'on-demand' treatment (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) is defined as: Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode; or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following the infusion, with no additional infusion administered. Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens. | 100 exposure days to study medication (approx. 2 years) | 
| Number of ReFacto AF Infusions to Treat Each New Bleed | The Infusion Log Diary case report form (CRF) was used to determine the number of test article infusions administered to treat a bleed. This was calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time). | 100 exposure days to study medication (approx. 2 years) | 
| Number of Bleeding Episodes Occurring ≤48 Hours After a Prophylaxis Infusion | First, the bleed start time from the Infusion Log Diary CRF was used to determine the number of breakthrough bleeds that occurred ≤48 hours after an infusion marked as Prophylaxis (which had no associated bleed). If there was more than 1 bleed location (ie, ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. If a response was given, or if a bleed time was given, but On Demand was not listed as treatment type, it was still counted as an on-demand bleed for analyses/summaries. Bleeding episodes were not categorized as spontaneous (atraumatic) or traumatic. | 100 exposure days to study medication (approx. 2 years) | 
| Number of Participants With Breakthrough Bleeds | The number of participants with any breakthrough bleed was reported. | 100 exposure days to study medication (approx. 2 years) | 
| Total Factor Consumption (TFC) Following a Non-prophylaxis Regimen at Baseline for All Participants | The total amount (in International Units [IU]) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each participant. | 100 exposure days to study medication (approx. 2 years) | 
| TFC Following a Prophylaxis Regimen at Baseline for All Participants | The total amount (in IU) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each participant. | 100 exposure days to study medication (approx. 2 years) | 
| Average Infusion Dose | The average infusion dose for each participant was calculated as his total factor consumption (in IU) divided by the number of infusions administered. Summary statistics were reported for both of these variables separately for those participants classified at baseline as following an on-demand regimen, and for those on a primary or secondary prophylaxis regimen. | 100 exposure days to study medication (approx. 2 years) | 
| Incidence of Less-than-expected-therapeutic Effect (LETE) in the On-demand Setting | The calculation of incidence of on-demand LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the On Demand LETE CRF), and the denominator was the number of bleeding episodes treated in an on-demand setting. This denominator could include new bleeding episodes in prophylaxis participants breakthrough bleeds), and if subsequent on-demand doses for such a bleed met the on-demand LETE criteria, then an on-demand LETE was reported. | 100 exposure days to study medication (approx. 2 years) | 
| Incidence of Less-than-expected-therapeutic Effect (LETE) in the Prophylaxis Setting | The calculation of incidence of prophylaxis LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the Prophylactic LETE CRF), and the denominator was the number of routine prophylaxis infusions. Each infusion was classified in the infusion log (Prophylaxis/ On Demand/ Preventive), and participants were instructed to select On Demand if the infusion was to treat a bleed, even if the participant typically followed a prophylaxis regimen. Only the infusions classified as Prophylaxis were counted in this denominator. | 100 exposure days to study medication (approx. 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia A