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 (RESIST NAIVE)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Charta Fondazione Grant Provided by
Grifols Biologicals Inc.
CSL Behring
Biotest Pharmaceuticals Corporation
City of Hope Grant Provided by
Grifols Therapeutics Inc. (Talecris Biotherapeutics)
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01051544
First received: January 15, 2010
Last updated: March 17, 2014
Last verified: March 2014
  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:


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: 33 months ] [ Designated as safety issue: Yes ]
  • Safety Compliance to treatment [ Time Frame: 33 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 2020
Estimated Primary Completion Date: June 2020 (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
  • 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:
  • Koate-DVI
  • 8Y
  • Optivate
  • Alphanate
  • Fahndi
  • Haemate P
  • Humate P
  • Haemoctine SDH
  • Octanate
  • Wilate
  • Emoclot DI
  • Factane

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:

  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Sponsors and Collaborators
City of Hope Medical Center
Charta Fondazione Grant Provided by
Grifols Biologicals Inc.
CSL Behring
Biotest Pharmaceuticals Corporation
City of Hope Grant Provided by
Grifols Therapeutics Inc. (Talecris Biotherapeutics)
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
  More Information

Additional Information:
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

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: March 17, 2014
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 September 16, 2014