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

City of Hope Medical Center

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Conditions

Severe Hemophilia A

Interventions

FVIII ConcentratesDRUG

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.

FVIII/VWF concentratesDRUG

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.

Eligibility

Sex: MALE

Medical Language ↔ Plain English

Inclusion Criteria: 1. severe hemophilia A (FVIII\<1%); 2. male, any age; 3. high responders (peak inhibitor levels \> 5 BU); 4. any inhibitor level at study enrolment; 5. ability and willingness to participate in the study; 6. 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 7. absence of high risk of cardiovascular, cerebrovascular or other thromboembolic events as deemed by the treating clinician. Exclusion Criteria: 1. concomitant systemic treatment with immunosuppressive drugs; 2. concomitant experimental treatment; 3. previous ITI attempt; 4. previous history of myocardial infarction and/or cerebral stroke.

Outcomes

Primary Outcomes

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.

Time frame: 33 months

Secondary Outcomes

Absence of relapse, up to 12 months after achievement of Immune Tolerance

Time frame: 12 months

Time to achieve partial or complete success as defined in the protocol.

Time frame: 33 months

Safety Compliance to treatment

Time frame: 33 months

Cost of Care

Time frame: 12 months

Data from ClinicalTrials.gov

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