Survey of Inhibitors in Plasma-Product Exposed Toddlers

Study Overview
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Brief Summary
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The primary objective of the study is to assess the immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in previously untreated patients (PUPs) or minimally blood component-treated (MBCTPs) in the first 50 EDs or in the first 3 years from enrollment, whichever occurs first. .

Detailed Description
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Patients meeting the enrollment criteria will be consecutively enrolled at each participating centre, randomized to be treated exclusively with a single FVIII product either plasma-derived or recombinant, and followed up until inhibitor development or until 50 exposure days (EDs) or 3 years from enrolment have elapsed, whichever comes first. Study products, belonging to the class of rFVIII concentrates and to the class of plasma-derived VWF/FVIII concentrates, will be provided for free to the patients for all the duration of the study

Official Title
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Inhibitor Development in Previously Untreated Patients (PUPs) or Minimally Blood Component-Treated Patients (MBCTPs) When Exposed to Plasma-derived Von Willebrand Factor-Containing Factor VIII (VWF/FVIII) Concentrates and to Recombinant Factor VIII (rFVIII) Concentrates: An Independent, International, Multicentre, Prospective, Controlled, Randomised, Open Label, Clinical Trial

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: PLASMA DERIVED Factor VIII
* Drug: Recombinant FVIII


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects Any ethnicity Age <6 years Severe haemophilia A (FVIII:C <1%), as confirmed at enrolment by the central laboratory. o Those patients diagnosed locally as severe but subsequently found to have FVIII levels >= 1% on testing at the central laboratory will be separately recorded in the screening list. Previously untreated (0 EDs to any FVIII concentrates or blood products) or minimally treated (<5 EDs) with blood components, namely whole blood, fresh frozen plasma, packed red blood cells, platelets or cryoprecipitate. o Patients not meeting these criteria will be separately recorded in the screening list. Negative inhibitor measurement at both local and central laboratory at screening Ability to comply with study requirements Signed informed consent of legal tutors o Patients who will not accept to enter into the study or to be randomized will be separately recorded. Exclusion Criteria: Previous history of FVIII inhibitor Other congenital or acquired bleeding defects Plasma FVIII level >= 1%, as assayed at the central laboratory o Those patients originally diagnosed locally as severe but subsequently found to have FVIII levels ranging from 1% to 2% on testing at the central laboratory will be separately recorded in the screening list. Concomitant congenital or acquired immunodeficiency Concomitant treatment with systemic immunosuppressive drugs Concomitant treatment with any investigational drug

Ages Eligible for Study
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Minimum Age: 1 Minute
Maximum Age: 6 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PLASMA DERIVED Factor VIII<br>Plasma-derived vWF/FVIII | Drug: PLASMA DERIVED Factor VIII<br>* Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding<br>* Other names: ALPHANATE;|
| Active Comparator: rFVIII<br>Recombinant FVIII | Drug: Recombinant FVIII<br>* Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding<br>* Other names: ADVATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs | Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Anamnestic Response of Inhibitor Patients |  | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 
| To Evaluate the Frequency of Transient Inhibitors | Number of participants for each group who developed transient inhibitors (this means, those inhibitors which disappeared spontaneously within 6 months without immunotolerance treatment). | In the 6 months after inhibitor development | 
| To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs) | Number of EDs: Number of Exposure Days (EDs) after which the inhibitors develop | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 
| To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset) | Inhibitor Titre at Onset | During 6 months of observation, from the inhibitor occurrence | 
| To Evaluate Clinical Factors Potentially Associated to Inhibitor Development |  | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 
| To Evaluate Laboratory Factors Potentially Associated to Inhibitor Development |  | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 
| To Evaluate the Incidence of All Other Adverse Events Related and Not Related to the Products Used |  | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia A, Factor VIII inhibitors, vWF/FVIII, rFVIII