Efficacy and Safety Study of a Recombinant Protein-Free Manufactured Factor VIII (rAHF-PFM) in Previously Untreated Hemophilia A Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM) is effective and safe in the treatment of hemophilia A patients who have not been treated with factor VIII (FVIII) before.

Official Title
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Recombinant Antihemophilic Factor Manufactured and Formulated Without Added Human or Animal Proteins (rAHF-PFM): Evaluation of Immunogenicity, Efficacy, and Safety in Previously Untreated Patients With Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level <= 2% of normal, as documented at screening The subject is < 6 years of age The subject's legally authorized representative has provided written informed consent Exclusion Criteria: The subject has a history of exposure to factor VIII other than rAHF PFM or more than 3 infusions of commercially available rAHF PFM (i.e., ADVATE) within 28 days prior to screening, as determined by the subject's medical history. Any infusion of factor VIII replacement products prior to the 28-day period excludes the subject from participation The subject has received more than 3 infusions of rAHF PFM (commercially available and/or study product) between screening and prior to the initial recovery infusion The subject has a detectable inhibitor to factor VIII, as measured in the screening sample by the Nijmegen assay in the central laboratory The subject has a history of inhibitor to factor VIII at any time prior to screening The subject has a known hypersensitivity to rAHF PFM The subject has any 1 of the following laboratory abnormalities at the time of screening: Platelet count < 100,000/mm^3 Hemoglobin concentration < 10 g/dL (100 g/L) Serum creatinine > 1.5 times the upper limit of normal (ULN) for age Total bilirubin > 2 times the ULN for age The subject has an inherited or acquired hemostatic defect other than hemophilia A (e.g., qualitative platelet defect or von Willebrand's disease) The subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV), as determined by the subject's medical history At the time of enrollment, the subject has a clinically significant chronic disease other than hemophilia A The subject is currently participating in another investigational drug study, or has participated in any clinical study involving an investigational drug within 120 days of the screening visit The subject (or the subject's legally authorized representative) is identified by the investigator as being unable or unwilling to cooperate with study procedures The subject has received any blood product, including packed red blood cells (RBC), platelets, plasma, or cryoprecipitate

Ages Eligible for Study
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Maximum Age: 6 Years

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm - All Participants<br>All subjects enrolled in the study who meet the eligibility criteria. | Biological: Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM)<br>* Treatment regimens were determined by the investigator, and may have been any combination of standard prophylaxis (25 to 50 IU/kg body weight, 3 to 4 times per week), investigator-determined prophylaxis, and/or on-demand treatment (dose selected by investigator). The treatment of bleeding episodes and perioperative management was at the discretion of the investigator and consistent with the institution's standard of care. For incremental recovery assessments, a single infusion at 50 +/- 5 IU/kg was to be given. Immune tolerance induction (ITI) therapy for subjects who developed factor VIII inhibitors was at the discretion of the investigator, based on the institution's guidelines or described in peer-reviewed literature, and was to be approved by the sponsor's medical director. rAHF-PFM was to be administered intravenously via bolus infusion, except for perioperative management when it may have been given either by continuous or bolus infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Factor VIII Inhibitor Development | Percentage of treated participants who developed factor VIII inhibitors | Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding Episodes Treated With 1 to ≥4 Infusions | The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | 
| Assessment of Hemostasis for Treatment of Bleeding Episodes | Number of rAHF-PFM-treated bleeding episodes with treater assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within  8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within  8 hrs after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within  8 hrs after infusion. Requires >1 infusion for complete resolution; or None: No improvement or condition worsens. | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | 
| Annualized Rate of Bleeding Episodes | Number of bleeding episodes per subject annualized over 1 year for all etiologies | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | 
| Weekly rAHF-PFM Utilization | Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management. rAHF-PFM dose determined by the investigator (ie: standard regimen [25-50 IU/kg body weight, 3-4 times per week]; modified prophylactic regimen [dose and frequency selected by investigator] or on-demand treatment [dose selected by investigator]). Dosing to treat BEs was at investigator's discretion and in accordance with institution's standard of care. rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion. | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | 
| In Vivo Incremental Recovery | Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. | 30 minutes pre-infusion to 30 minutes post-infusion | 
| Assessment of Intra-operative Hemostasis | Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale: Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals Good: > average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals Fair: > maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen | Assessed at the time of discharge from recovery room | 
| Assessment of Postoperative Hemostasis | Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale: Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure Fair: hemostasis was clearly < optimal for matched procedure, without need to change regimen None: bleeding from inadequate response with proper dosing, necessitating a change in regimen | Assessed at the time of discharge from hospital or clinic | 
| Assessment of Blood Loss During Surgical Procedures | Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records) | Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded | 
| Adverse Events Deemed Related to Treatment | Percentage of participants who reported AEs deemed related to treatment with rAHF-PFM | Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first) | 
| Development of Antibodies to Heterologous Proteins | Percentage of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF) | Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Factor VIII Deficiency