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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

Tracking Information
First Submitted Date  ICMJE June 16, 2015
First Posted Date  ICMJE June 23, 2015
Last Update Posted Date June 23, 2015
Study Start Date  ICMJE January 2015
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 22, 2015)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 22, 2015)
  • 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.
  • Analysis of treatment compliance [ Time Frame: Up to 33 months ]
    Description of the patient's adherence to the optimal prolonged treatment.
  • 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).
  • Evaluation of the cost of therapy [ Time Frame: Up to 33 months ]
    Recording of overall amount of direct costs of therapy.
  • Efficacy evaluation - IT persistence [ Time Frame: Up to 33 months+ 12 months FU ]
    Absence of relapse, assessed at 12 months from IT achievement
  • Efficacy evaluation - FVIII genetic defect role in IT achievement [ Time Frame: Up to 33 months ]
    Role of FVIII mutations in influencing IT achievement
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia A
Intervention  ICMJE 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
Study Arms  ICMJE 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.

Intervention: Drug: Plasma-derived FVIII/VWF concentrate
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 22, 2015)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE up to 12 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Egypt,   India
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02479087
Other Study ID Numbers  ICMJE FCG-CNS-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Study Sponsor  ICMJE Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Collaborators  ICMJE Sintesi Research Srl
Investigators  ICMJE
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
PRS Account Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Verification Date June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP