Clinical trial NCT01051076: Rescue Immunotolerance Study in Induction of Immune Tolerance (ITI)-Experienced Patients (RES.I.S.T. Experienced)
Official title: Immune Tolerance Induction Study in Patients With Severe Type A Haemophilia With Inhibitor After Failure of a Previous Induction of Immune Tolerance With FVII Concentrates Without Von Willebrand Factor Rescue
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Severe Hemophilia A
Keywords: ITI
Haemophilia A
Inhibitors
Failed ITI
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: 3
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate whether a concentrate containing both FVIII and von Willebrand Factor (VWF) given at a high dose will induce immune tolerance in subjects who have already experienced and failed ITI with VWF-free FVIII concentrates. The treatment on this study is expected to last up to 33 months.

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 what is called "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 VWF, and concentrates of FVIII without VWF. Both types of concentrates are commonly used to induce immune tolerance in patients with Hemophilia A. Retrospective studies on subjects who were treated with VWF containing Factor VIII concentrates after failing ITI with pure factor VIII concentrates, have shown that tolerance can be achieved in a large percentage of patients. This study will access prospectively whether treatment with a FVIII concentrate containing VWF given at a high dose (200 units per kilogram) daily for up to 33 months is able to induce immune tolerance after previous attempts with concentrates containing only FVIII have failed.

Eligibility criteria: Inclusion Criteria:

1. severe hemophilia A (FVIII\<1%) with high responding inhibitors (peak levels \>5 BU)
2. male, any age;
3. any inhibitor level at study enrollment;
4. ability and willingness to participate to the study;
5. previous ITI course of at least 9 months with a VWF-free FVIII concentrate at any dosage, such as recombinant FVIII and/or monoclonally purified FVIII.

Exclusion Criteria:

1. concomitant systemic treatment with immunosuppressive drugs;
2. concomitant experimental treatment;
3. previous history of myocardial infarction and/or cerebral stroke

Primary outcomes:
measure: Achievement of an inhibitor titer of <0.6 BU/failure to achieve an inhibitor titer of <0.6 BU within 33 months, or failure to decrease inhibitor titer by at least 20% compared to titer in prior 6 months, beginning at 3 months after starting ITI
timeFrame: 3 years
Secondary outcomes:
measure: Time to achieve success- either partial or complete.
timeFrame: 33 months
measure: Safety - assessment of adverse events through treatment and compliance with prolonged regimen.
timeFrame: 33 months
measure: Cost of care.
timeFrame: Up to 45 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
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: Kreuz W, Steiner J, Auerswald G, Beeg T, Becker S. Successful immunetolerance therapy of FVIII-inhibitor in chldren after changing from high to intermediate purity FVIII concentrate. Ann Hematol 1996; 72 (suppl 1).
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.