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Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients (ITI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02479087
Recruitment Status : Unknown
Verified June 2015 by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico.
Recruitment status was:  Recruiting
First Posted : June 23, 2015
Last Update Posted : June 23, 2015
Sintesi Research Srl
Information provided by (Responsible Party):
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Brief Summary:
The purpose of this study is to assess the role of a FVIII/VWF complex concentrate (Emoclot) in successfully inducing immune tolerance (I.T.I.) in patients with Haemophilia A with inhibitors, including patients at high risk of failure.

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: Plasma-derived FVIII/VWF concentrate Phase 4

Detailed Description:
The development of factor VIII inhibitors occurs in approximately 30 to 40% of patients with severe Haemophilia A. The main negative clinical and cost consequence is the ineffectiveness of replacement therapy in patients with high-titer antibodies, who have a shorter life and greater morbidity than those who do not develop inhibitors. It is known from immunology that a regular and frequent exposure to the antigen of FVIII can induce tolerance of the immune system of the patient with inhibitors. This effect, called "immune tolerance induction" (ITI) is usually achieved after a prolonged exposure of the patient to FVIII, and is a common way of managing the condition of patients with inhibitors as well as the treatment of bleeding episodes with large amounts of hemostatic agents. In vitro and retrospective clinical studies suggest that FVIII/VWF complex concentrates may have less immunogenicity with respect to those plasma-derived concentrates purified with monoclonal antibodies (MABs), and recombinant DNA factor VIII concentrates (rFVIII), in both which the von Willebrand factor (VWF) is absent. Immune tolerance induction (ITI) showed to be effective in about 70% of Haemophiliacs with inhibitors. Poor prognosis factors have been identified by different registries: age ≥ 6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titer >10 BU at the start of ITI and previously failed ITI. The results of clinical studies suggest that complex concentrates of VWF/FVIII can be effective in ITI, even in patients at high risk of failure. To explain these findings, a role for VWF (i.e. prolonged antigen exposure) has been hypothesized.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : January 2015
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Plasma-derived FVIII/VWF concentrate

The drug will be delivered through intravenous slow infusion/injection. The starting dosage can vary between the minimum dosage of 50 IU/Kg 3 times a week up to a maximum of 200 IU/kg per day.

This starting dosage will be decided by the Principal Investigator according to patient's condition and other variables.

The initial dosage can be then adjusted on the base of response.

Drug: Plasma-derived FVIII/VWF concentrate

The investigational treatment is with lyophilized plasma-derived Factor VIII. The product belongs to the factor VIII concentrates class, containing also VW Factor in an average ratio VW/VIII of > 1: 4.5.

The product is as a powder and a solvent solution for continuous infusion of Factor VIII. The specific activity of Factor VIII is of approximately 80 IU/mg protein.

The number of units of FVIII administered is expressed in International Units (IU), which are consistent with current WHO standards for products containing Factor VIII. The activity of Factor VIII in plasma is expressed either as a percentage (compared to normal human plasma) or in International Units (compared to the international standard for FVIII in plasma).

Other Name: Emoclot

Primary Outcome Measures :
  1. Efficacy: evaluation of the success of IT induction [ Time Frame: Up to33 months ]
    Success:Inhibitor disappearance/reduction to <0.6 BU/ml with FVIII activity recovery of at least ≥ 66% within 33 months of treatment ; Partial Success: inhibitor reduction to <5 BU/ml with clinical response to FVIII treatment, not followed by an inhibitor increase to values >5 BU/ml for a treatment period of 6 months on demand, or for 12 months of prophylactic treatment; No Response (Failure):Failure in relation to the above criteria defining complete response and partial response within 33 months, OR a reduction of the concentration of the inhibitor, less than 20%, compared to the peak of inhibitor in the IT, in every period of 6 months after the first 3 months of treatment. This implies that 9 months represents the minimum period of treatment and 33 months the maximum possible duration of ITI without success, OR patient withdrawal from the study for any reason.

Secondary Outcome Measures :
  1. Safety (adverse events) [ Time Frame: Up to 33 months ]
    Description and incidence of adverse events during the course of prophylactic treatment, with severity, correlation with the investigational product and final outcome.

  2. Analysis of treatment compliance [ Time Frame: Up to 33 months ]
    Description of the patient's adherence to the optimal prolonged treatment.

  3. Efficacy evaluation - Time to achieve ITI [ Time Frame: Up to 33 months ]
    Time to achieve the complete or partial response (as defined in the primary outcome measure).

  4. Evaluation of the cost of therapy [ Time Frame: Up to 33 months ]
    Recording of overall amount of direct costs of therapy.

  5. Efficacy evaluation - IT persistence [ Time Frame: Up to 33 months+ 12 months FU ]
    Absence of relapse, assessed at 12 months from IT achievement

  6. Efficacy evaluation - FVIII genetic defect role in IT achievement [ Time Frame: Up to 33 months ]
    Role of FVIII mutations in influencing IT achievement

  7. Efficacy evaluation - Role of an immediate IT to delayed IT in IT induction. [ Time Frame: Up to 33 months ]
    Time elapsing between the onset of the inhibitor and the beginning of treatment and its importance for induction of IT in achieving primary endpoints.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 12 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subjects (his/her parent/legal representative), must have given a written informed consent.
  2. Male children: age <12 years.
  3. Severe or moderate Haemophilia A (FVIII <2%).
  4. High responders (clinical history of inhibitor peak > 5BU) or low-responders (clinical history of inhibitor peak < 5 BU) with potential bleedings, assessed by responsible physicians as not to be treated with high FVIII doses.
  5. Any level of inhibitor at study enrollment.
  6. Willingness and ability to participate in the study.
  7. No other experimental treatments (involving or not FVIII concentrates).

Exclusion Criteria:

  1. Any clinically relevant abnormality, in hematological, biochemical and urinary routine examinations, or any condition or treatment which in the investigator's opinion, makes the patient not eligible for the study.
  2. Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates.
  3. Concomitant systemic treatment with immunosuppressive drugs.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02479087

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Contact: Pier Mannuccio Mannucci, MD +39 0255038377
Contact: Elena Santagostino, MD +39 0255035273

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Ain Shams Pediatric hospital, Ain Shams University Not yet recruiting
Cairo, Egypt
Contact: Mohssen El-Alfy, MD    +20 1000864343   
Contact: Shereen Abdel Ghany, MD    +20 1200533484   
Principal Investigator: Mohssen El-Alfy, MD         
Sub-Investigator: Shereen Abdel Ghany, MD         
Sub-Investigator: Neveen Gamal, MD         
Almoneera Pediatric Cairo University Hospital (Abu El- Reesh) Not yet recruiting
Cairo, Egypt
Contact: Amal El-Beshlawy, MD    +20 1223124674   
Contact: Sonia Aldof, MD    +20 1223431046   
Principal Investigator: Amal El-Beshlawy, MD         
Sub-Investigator: Sonia Aldof, MD         
Sub-Investigator: Shaymaa Mohamed, MD         
St. John's Medical College Hospital Recruiting
Bangalore, India, 560034
Contact: Cecil Ross, MD    +91 9448493705   
Contact: Sita Lakshmi, MD    +91 8022065178   
Principal Investigator: Cecil Ross, MD         
Sub-Investigator: Sita Lakshmi, MD         
Sub-Investigator: Fulton D'souza, MD         
All India Institute of Medical Sciences Recruiting
New Delhi, India, 110029
Contact: Tulika Seth, MD    +91 9868397236   
Contact: Renu Saxena, MD    +91 1126594670   
Principal Investigator: Tulika Seth, MD         
Sub-Investigator: Renu Saxena, MD         
Sub-Investigator: Vandana Sharma, MD         
Sponsors and Collaborators
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sintesi Research Srl
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Study Chair: Pier Mannuccio Mannucci, MD IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico
Study Director: Flora Peyvandi, MD Università di Milano, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico
Study Director: Elena Santagostino, MD Centro Emofilia e Trombosi Angela Bianchi Bonomi, IRCCS Fondazione Ospedale Maggiore Policlinico

Gilles JG, Saint-Remy JMR. Recombinant and plasma-derived factor VIII are immunologically distinct in in vitro assays. Thromb Haemost 1995; 73:1213.
Rokicka-Milewska R, Klukowska A, Dreger B, Beer H-J. Incidence of factor VIII inhibitor development in previously untreated Haemophilia A patients after exposure to a double viral inactivated factor VIII concentrate. Ann Hematol 1999; 78 (suppl 1)
Gensana M, Altisent C. Aznar JA, Casana P, Hernandez F, Jorquera JI, Magallon M, Massot M, Puig L. Factor VIII inhibitors directed to the A2 domain and the light chain may also show less reactivity to FVIII complexed with VWF. World Federation of Haemophilia, The Hague, May 1998, (Abstract book).
Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica 2001; 86 (S4):16-20
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).
Haya S, Casaña P, Moret A, Cid RA, Cabrera N, Abad L, Aznar AJ. Immunotolerance Induction Treatments in Hemophilia. J.of Coagulation Disorders 2009; 1(1): 37-42.

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Responsible Party: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Identifier: NCT02479087    
Other Study ID Numbers: FCG-CNS-001
First Posted: June 23, 2015    Key Record Dates
Last Update Posted: June 23, 2015
Last Verified: June 2015
Keywords provided by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico:
von Willebrand Factor
Factor VIII
Immune Tolerance
Hemophilia A
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII