Efficacy and Safety of Fanhdi®, a High-purity Von Willebrand Containing FVIII Concentrate, in Pediatric Patients With Von Willebrand Disease

Study Overview
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Brief Summary
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Multicenter, prospective, non-controlled study in a pediatric cohort (<6 years-old) with severe (type 2 or 3) hereditary Von Willebrand Disease (VWD).

Detailed Description
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This is a multicenter, prospective, open-label, and single-arm study. The study population is planned to include 8 pediatric subjects (<6 years of age) with severe (type 2 or 3) hereditary VWD without inhibitors and with no active bleeding at the time of inclusion. Eligible subjects will receive a single dose of Fanhdi for a PK evaluation and will be followed for 12 months for which the efficacy and safety of Fanhdi will be assessed. In addition, the type 3 VWD subjects, after 6 months of follow-up of the first infusion, will receive the second dose as in the 1st PK evaluation and undergo a 2nd PK evaluation. The study will consist of 2 phases: PK profile evaluation in which all eligible subjects will receive a single dose of 80 IU/kg von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) of Fanhdi. In addition, after 6 months of follow-up of the first infusion, type 3 VWD subjects will receive the second dose of Fanhdi and undergo a 2nd PK evaluation with a reduced sampling schedule. A 12-month Follow-up period during which the safety and efficacy of Fanhdi will be assessed in the prevention and management of bleeding episodes and/or management of perioperative hemostasis during surgery and/or invasive procedures.

Official Title
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Evaluation of the Pharmacokinetic Profile, Clinical Efficacy and Safety of the Von Willebrand Factor Contained in FANHDI® (Double-inactivated Human Anti-hemophilic Factor) in Pediatric Subjects With Severe Von Willebrand Disease

Conditions
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Von Willebrand Disease

Intervention / Treatment
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* Drug: plasma-derived FVIII/VWF concentrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects diagnosed with severe (type 2 or 3) hereditary VWD (VWF:RCo<15-20 IU/dL), or VWF:Act<15-20 IU/dL. Subjects under 6 years of age. Signed informed consent form (ICF) provided by an authorized representative on behalf of the subject in accordance with local law and institutional policy. Exclusion Criteria: Subjects diagnosed with acquired VWD. Subjects with active bleeding at the time of the first infusion or within 10 days prior to the infusion. Subjects who have been treated with DDAVP or another FVIII containing VWF concentrate during the 5 days prior to the infusion of the Fanhdi. This treatment-free period may be reduced to 3 days for subjects with type 3 VWD. Subject who are positive for anti-VWF or anti-FVIII antibodies (≥0.5 Bethesda Units) or has been positive in the history of their disease. Subjects with a known allergies/intolerance to any substance contained in Fanhdi. Subjects with a known history of anaphylactic reaction(s) to blood or blood components. Subjects presenting severe platelet activity dysfunction due to the use of drugs (aspirin, other nonsteroidal anti-inflammatory drugs [NSAIDs], etc.) or a congenital or acquired platelet function disorder or other concomitant processes that may interfere with coagulation. Subjects have a known previous infection with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV), or have clinical signs and symptoms consistent with current HAV, HBV, HCV or HIV infection. Subjects presenting anemia (hemoglobin <11 g/dL). Subjects diagnosed with metabolic diseases that are not clinically controlled, such as diabetes mellitus, which could potentially interfere with the interpretations of the study. Participated in another clinical trial within 30 days prior to the screening visit or has received any investigational product (IP) within 3 months prior to the screening visit. If it is anticipated that the subject will be treated with other products containing FVIII or VWF different from Fanhdi throughout the subject's participation. Subjects who, in the opinion of the investigator, may have compliance problems with the protocol.

Ages Eligible for Study
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Minimum Age: 2 Months
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: plasma-derived FVIII/VWF concentrate<br>Pharmacokinetic single dose study with Fanhdi (high-purity Von Willebrand containing FVIII concentrate) | Drug: plasma-derived FVIII/VWF concentrate<br>* 1 single dose of 80 IU/kg VWF:RCo of Fanhdi will be administered<br>* Other names: Fanhdi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC^0-inf of coagulation factor VIII activity (FVIII:C) | Cumulative area under the concentration time curve extrapolated to infinity of FVIII:C | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-inf of von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) | Cumulative area under the concentration time curve extrapolated to infinity of VWF:RCo | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-inf of von Willebrand factor antigen (VWF:Ag) | Cumulative area under the concentration time curve extrapolated to infinity of VWF:Ag | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-inf of von Willebrand factor: Collagen binding activity (VWF:CB) | Cumulative area under the concentration time curve extrapolated to infinity of VWF:CB | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-T of FVIII:C | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration of FVIII:C | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-T of VWF:RCo | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration of VWF:RCo | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-T of VWF:Ag | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration of VWF:Ag | Prior to the first infusion up to 72 hours postinfusion | 
| AUC^0-T of VWF:CB | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration of VWF:CB | Prior to the first infusion up to 72 hours postinfusion | 
| in vivo recovery of FVIII:C |  | Prior to the first infusion up to 72 hours postinfusion | 
| in vivo recovery of VWF:RCo |  | Prior to the first infusion up to 72 hours postinfusion | 
| in vivo recovery of VWF:Ag |  | Prior to the first infusion up to 72 hours postinfusion | 
| in vivo recovery of VWF:CB |  | Prior to the first infusion up to 72 hours postinfusion | 
| Half-life of FVIII:C | Terminal elimination half-life | Prior to the first infusion up to 72 hours postinfusion | 
| Half-life of VWF:RCo | Terminal elimination half-life | Prior to the first infusion up to 72 hours postinfusion | 
| Half-life of VWF:Ag | Terminal elimination half-life | Prior to the first infusion up to 72 hours postinfusion | 
| C^max of FVIII:C | Maximum observed plasma and/or serum concentration of FVIII:C | Prior to the first infusion up to 72 hours postinfusion | 
| C^max of VWF:RCo | Maximum observed plasma and/or serum concentration of VWF:RCo | Prior to the first infusion up to 72 hours postinfusion | 
| C^max of VWF:Ag | Maximum observed plasma and/or serum concentration of VWF:Ag | Prior to the first infusion up to 72 hours postinfusion | 
| C^max of VWF:CB | Maximum observed plasma and/or serum concentration of VWF:CB | Prior to the first infusion up to 72 hours postinfusion | 
| T^max of FVIII:C | Time of maximum observed plasma and/or serum concentration of FVIII:C | Prior to the first infusion up to 72 hours postinfusion | 
| T^max of VWF:RCo | Time of maximum observed plasma and/or serum concentration of VWF:RCo | Prior to the first infusion up to 72 hours postinfusion | 
| T^max of VWF:Ag | Time of maximum observed plasma and/or serum concentration of VWF:Ag | Prior to the first infusion up to 72 hours postinfusion | 
| T^max of VWF:CB | Time of maximum observed plasma and/or serum concentration of VWF:CB | Prior to the first infusion up to 72 hours postinfusion | 
| Mean residence time of FVIII:C | Average amount of time that a single molecule of drug stays in the body. | Prior to the first infusion up to 72 hours postinfusion | 
| Mean residence time of VWF:RCo | Average amount of time that a single molecule of drug stays in the body of VWF:RCo | Prior to the first infusion up to 72 hours postinfusion | 
| Mean residence time of VWF:Ag | Average amount of time that a single molecule of drug stays in the body of VWF:Ag | Prior to the first infusion up to 72 hours postinfusion | 
| Mean residence time of VWF:CB | Average amount of time that a single molecule of drug stays in the body of VWF:CB | Prior to the first infusion up to 72 hours postinfusion | 
| Clearance of FVIII:C | Total plasma and/or serum clearance | Prior to the first infusion, 30 minutes postinfusion, 10 hours postinfusion, and at 24, 48, and 72 hours postinfusion | 
| Clearance of VWF:RCo | Total plasma and/or serum clearance | Prior to the first infusion, 30 minutes postinfusion, 10 hours postinfusion, and at 24, 48, and 72 hours postinfusion | 
| Clearance of VWF:Ag | Total plasma and/or serum clearance | Prior to the first infusion, 30 minutes postinfusion, 10 hours postinfusion, and at 24, 48, and 72 hours postinfusion | 
| Clearance of VWF:CB | Total plasma and/or serum clearance | Prior to the first infusion, 30 minutes postinfusion, 10 hours postinfusion, and at 24, 48, and 72 hours postinfusion | 
| Elimination rate constant of FVIII:C |  | Prior to the first infusion up to 72 hours postinfusion | 
| Elimination rate constant of VWF:RCo |  | Prior to the first infusion up to 72 hours postinfusion | 
| Elimination rate constant of VWF:Ag |  | Prior to the first infusion up to 72 hours postinfusion | 
| Elimination rate constant of VWF:CB |  | Prior to the first infusion up to 72 hours postinfusion | 
| Volume of distribution of FVIII:C |  | Prior to the first infusion up to 72 hours postinfusion | 
| Volume of distribution of VWF:RCo |  | Prior to the first infusion up to 72 hours postinfusion | 
| Volume of distribution of VWF:Ag |  | Prior to the first infusion up to 72 hours postinfusion | 
| Volume of distribution of VWF:CB |  | Prior to the first infusion up to 72 hours postinfusion | 
| VWF multimeric pattern | For type 3 VWD subjects | Prior to the first infusion up to 12 hours postinfusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, plasma-derived FVIII concentrate