Study of First TIME Immunotolerance Induction in Severe Hemophilia A Patients With Inhibitor at High Risk of Failure: Comparison With FVIII Concentrates With or Without Von Willebrand Factor - RES.I.S.T. Naive

Study Overview
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Brief Summary
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This is a prospective, controlled, randomized, open label study, aimed at comparing FVIII/VWF concentrates with FVIII concentrates at 200 IU/kg daily in their ability to induce immune tolerance in Haemophilia A patients with high responding inhibitors and poor prognosis for success.

Detailed Description
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The presence of Factor VIII (FVIII) inhibitor prevents FVIII infusions from working properly and makes treatment of bleeding episodes very difficult. Having an inhibitor is a serious and life-threatening complication in patients with Hemophilia. The usual treatment of patients with FVIII inhibitors involves immune tolerance induction (ITI). Immune Tolerance means that the body can accept infused FVIII and that FVIII is again effective in controlling bleeds. ITI involves giving high doses of FVIII regularly until the inhibitor disappears. This treatment is not always effective. The inhibitor persists in about 1 in 5 patients who undergo ITI. There are 2 types of FVIII concentrates: FVIII concentrates derived from human plasma, which contain the von Willebrand factor, and concentrates of FVIII without VWF (recombinant or plasma derived). Both types of concentrates are commonly used to induce immune tolerance in patients with Hemophilia A. Retrospective studies in subjects with hemophilia and inhibitors at risk for failing ITI, have indicated a higher rate of success if patients were treated with von Willebrand containing factor VIII concentrates. It is not known whether the addition of Von Willebrand factor offers an advantage to achieving immune tolerance.

Official Title
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Randomised Study of First TIME Immunotolerance Induction in Patients With Severe Type A Haemophilia With Inhibitor at High Risk of Failure: Comparison of Induction of Immune Tolerance With FVIII Concentrates With or Without Von Willebrand Factor Acronym: RES.I.S.T.- Naive

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: FVIII Concentrates
* Drug: FVIII/VWF concentrates


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: severe hemophilia A (FVIII<1%); male, any age; high responders (peak inhibitor levels > 5 BU); any inhibitor level at study enrolment; ability and willingness to participate in the study; at least one of the following risk factors for ITI failure: peak inhibitor titer > 200 BU titer at ITI start > 10 BU age > 7 years time between inhibitor occurrence and ITI > 2 years absence of high risk of cardiovascular, cerebrovascular or other thromboembolic events as deemed by the treating clinician. Exclusion Criteria: concomitant systemic treatment with immunosuppressive drugs; concomitant experimental treatment; previous ITI attempt; previous history of myocardial infarction and/or cerebral stroke.
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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: von Willebrand factor-free FVIII concentrates<br>Patients treated with FVIII concentrates | Drug: FVIII Concentrates<br>* Patients will be centrally randomized to receive a von Willebrand factor-free FVIII concentrate (recombinant or plasma-derived, monoclonally-purified). The choice of product brand will be based on physician / patients preferences.<br>* Other names: Xyntha;|
| Active Comparator: FVIII/VWF concentrates<br>Patients treated with FVIII/VWF concentrates | Drug: FVIII/VWF concentrates<br>* Patients will be centrally randomized to receive a FVIII/VWF concentrate of 200 IU/Kg by one or two bolus injections daily.The choice of product brand will be based on physician / patients preferences.<br>* Other names: Factane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary end point is the success in inducing immune tolerance, defined as: the abolition of the inhibitor to < 0.6 BU within 33 months of ITI with a factor VIII recovery ≥ 66% and half-life ≥ 6 hrs, and measured after a 72-hour washout period. |  | 33 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absence of relapse, up to 12 months after achievement of Immune Tolerance |  | 12 months | 
| Time to achieve partial or complete success as defined in the protocol. |  | 33 months | 
| Safety Compliance to treatment |  | 33 months | 
| Cost of Care |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ITI, HAEMOPHILIA A, INHIBITORS, VWF/FVIII Concentrates