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

Severe Hemophilia A Clinical Trial

— RESIST 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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01051544
• Other study ID #: 06201
• Secondary ID: 2008-007016-15
• Status: Withdrawn
• Phase: N/A
• Start date: September 25, 2009
• Est. completion date: June 25, 2020

Study information

• Verified date: December 2020
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 25, 2020
• Est. primary completion date: June 25, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemophilia A
• Severe Hemophilia A

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (6)

Lead Sponsor	Collaborator
City of Hope Medical Center	Biotest Pharmaceuticals Corporation, Charta Foundation, CSL Behring, Grifols Biologicals, LLC, Grifols Therapeutics LLC

References & Publications (3)

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. — View 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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		33 months
Secondary	Absence of relapse, up to 12 months after achievement of Immune Tolerance		12 months
Secondary	Time to achieve partial or complete success as defined in the protocol.		33 months
Secondary	Safety Compliance to treatment		33 months
Secondary	Cost of Care		12 months

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