Clinical trial NCT01051544: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Severe Hemophilia A
Keywords: ITI
HAEMOPHILIA A
INHIBITORS
VWF/FVIII Concentrates
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: Charta Foundation
name: Grifols Biologicals, LLC
name: CSL Behring
name: Biotest Pharmaceuticals Corporation
name: Grifols Therapeutics LLC
First posted: 2010-01-18
Enrollment: 0
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 33 months
Secondary outcomes:
measure: Absence of relapse, up to 12 months after achievement of Immune Tolerance
timeFrame: 12 months
measure: Time to achieve partial or complete success as defined in the protocol.
timeFrame: 33 months
measure: Safety Compliance to treatment
timeFrame: 33 months
measure: Cost of Care
timeFrame: 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Clinical Professor of Pediatrics, City of Hope National Medical Center, Dept. of Pediatrics, 1500 E. Duarte Rd. Duarte, CA 91010
name: Nadia P Ewing, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Berntorp E, Ekman M, Gunnarsson M, Nilsson IM. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations. Haemophilia. 1996 Apr;2(2):95-9. doi: 10.1111/j.1365-2516.1996.tb00022.x.
citation: Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica2001; 86 (S4):16-20
citation: Gringeri A, Musso R, Mazzucconi MG, Piseddu G, Schiavoni M, Pignoloni P, Mannucci PM; RITS-FITNHES Study Group. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia. 2007 Jul;13(4):373-9. doi: 10.1111/j.1365-2516.2007.01484.x.