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 - Full Text View

Sponsor:	City of Hope Medical Center
Collaborators:	Grifols Biologicals Inc. CSL Behring Talecris Biotherapeutics Biotest Pharmaceuticals Corporation
Information provided by (Responsible Party):	City of Hope Medical Center
ClinicalTrials.gov Identifier:	NCT01051544

Purpose

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.

Condition	Intervention
Severe Hemophilia A	Drug: FVIII Concentrates Drug: FVIII/VWF concentrates

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
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

Resource links provided by NLM:

Genetics Home Reference related topics: hemophilia Help Me Understand Genetics

MedlinePlus related topics: Hemophilia

Drug Information available for: Allopurinol sodium Octocog alfa Moroctocog Alfa Allopurinol Factor VIII

U.S. FDA Resources

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:

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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Absence of relapse, up to 12 months after achievement of Immune Tolerance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Time to achieve partial or complete success as defined in the protocol. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Safety Compliance to treatment [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Cost of Care [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	148
Study Start Date:	June 2009
Estimated Study Completion Date:	June 2015
Estimated Primary Completion Date:	June 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: von Willebrand factor-free FVIII concentrates Patients treated with FVIII concentrates	Drug: FVIII Concentrates 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. Other Names: Including but not limited to: Advate Beriate P Hemofil M Helixate Kogenate Kogenate SF Monarch M Monoclate Recombinate Refacto Replenate Koate-DVI Emoclot DI Factane 8Y Optivate Alphanate Fahndi Haemate P Humate P Haemoctine SDH Octanate Wilate Xyntha
Active Comparator: FVIII/VWF concentrates Patients treated with FVIII/VWF concentrates	Drug: FVIII/VWF concentrates 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. Other Names: Including but not limited to: Advate Beriate P Hemofil M Helixate Kogenate Kogenate SF Monarch M Monoclate Recombinate Refacto Replenate Koate-DVI Emoclot DI Factane 8Y Optivate Alphanate Fahndi Haemate P Humate P Haemoctine SDH Octanate Wilate Xyntha

Arms

Assigned Interventions

Active Comparator: von Willebrand factor-free FVIII concentrates

Patients treated with FVIII concentrates

Drug: FVIII Concentrates

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.

Other Names:

Including but not limited to:
Advate
Beriate P
Hemofil M
Helixate
Kogenate
Kogenate SF
Monarch M
Monoclate
Recombinate
Refacto
Replenate
Koate-DVI
Emoclot DI
Factane
8Y
Optivate
Alphanate
Fahndi
Haemate P
Humate P
Haemoctine SDH
Octanate
Wilate
Xyntha

Active Comparator: FVIII/VWF concentrates

Patients treated with FVIII/VWF concentrates

Drug: FVIII/VWF concentrates

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.

Other Names:

Including but not limited to:
Advate
Beriate P
Hemofil M
Helixate
Kogenate
Kogenate SF
Monarch M
Monoclate
Recombinate
Refacto
Replenate
Koate-DVI
Emoclot DI
Factane
8Y
Optivate
Alphanate
Fahndi
Haemate P
Humate P
Haemoctine SDH
Octanate
Wilate
Xyntha

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

Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01051544

Contacts

Contact: Nadia P Ewing, MD	626 301-8858	newing@coh.org
Contact: Alessandro Gringeri, MD	+ 39 02 55035305	alessandro.gringeri@unimi.it

Locations

United States, California
City of Hope Medical Center	Recruiting
Duarte, California, United States, 91010
Contact: Nadia P. Ewing, MD 626-301-8858 newing@coh.org
Contact: Cheryl De Guzman, CCRP 626 256-4673 ext 64350 cdeguzman@coh.org
Principal Investigator: Nadia P. Ewing, MD
Italy
University of Milan	Recruiting
Milan, Italy
Contact: Alessandro Gringeri, MD +39 02 55035305 alessandro.gringeri@unimi.it
Contact: Silvia Riva +39 02 55035290 Silvia.Riva@unicatt.it
Principal Investigator: Alessandro Gringeri, MD

Sponsors and Collaborators

City of Hope Medical Center

Grifols Biologicals Inc.

CSL Behring

Talecris Biotherapeutics

Biotest Pharmaceuticals Corporation

Investigators

Principal Investigator:	Nadia P Ewing, MD	Clinical Professor of Pediatrics, City of Hope National Medical Center, Dept. of Pediatrics, 1500 E. Duarte Rd. Duarte, CA 91010
Principal Investigator:	Alessandro Gringeri, MD	Associate Professor of Internal Medicine, University of Milan, Dept. of Internal Medicine-Haemophilia and Thrombosis, Via Pace,9 20122 Milan, Italy

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

Publications:

Bentorp E, Ekman M, Gunnarson M. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations Haemophilia 1996; 2: 95-99.

Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica2001; 86 (S4):16-20

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.

Responsible Party:	City of Hope Medical Center
ClinicalTrials.gov Identifier:	NCT01051544 History of Changes
Other Study ID Numbers:	06201, 2008-007016-15
Study First Received:	January 15, 2010
Last Updated:	September 19, 2011
Health Authority:	United States: Institutional Review Board; Italy: Ethics Committee; Italy: National Bioethics Committee; Italy: The Italian Medicines Agency

Keywords provided by City of Hope Medical Center:

ITI
HAEMOPHILIA A
INHIBITORS
VWF/FVIII Concentrates

Additional relevant MeSH terms:

Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders

Genetic Diseases, Inborn
Factor VIII
Coagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 09, 2012