Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic. Effectiveness of FVIII Concentrates in Haemophiliac A With Inhibitors (PredicTGA)

June 14, 2013 updated by: Grifols Italia S.p.A

Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic Effectiveness of Factor VIII (FVIII) Concentrates in Patients Affected by Inherited Haemophilia A With FVIII Inhibitors High and Low Anamnestic Response.

This is an observational, prospective, longitudinal, multicenter, cohort study designed with the scope to verify whether or not TGA may predict effectiveness of different FVIII concentrates class (devoid or rich of VWF) in patient affected by severe or moderately severe inherited haemophilia A and inhibitors.

Study Overview

Status

Unknown

Detailed Description

Rationale:

Hemophilia A is a serious and common hereditary bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). Patients with this disease are treated with recombinant factor VIII or factor VIII concentrates derived from plasma.

Administration of exogenous FVIII in 15-35% of cases, cause the formation of antibodies to FVIII (inhibitors) that neutralize the activity of factor VIII, making the treatment ineffective.The development of inhibitors of factor VIII (FVIII) is the most serious and challenging complication of the treatment of hemophilia A and represents the highest economic burden for a chronic disease. Therefore, research is making great efforts to optimize the best therapeutic approach for the disease.

It has been observed that FVIII inhibitors display a wide range of immunoreactivity when tested against different classes of FVIII concentrates (with/without von Willebrand factor -VWF). It has been demonstrated that the different inhibitors reactivity may correlate with different ability of inhibitors to impair thrombin generation, as tested by Thrombin Generation Assay (TGA). In these patients TGA assay might be a tool to predict which FVIII concentrate has the greater haemostatic effectiveness.

It is also uncertain if the different classes of FVIII used in ITI protocols may have a different effectiveness in reducing the occurrence of BT bleedings and if this may correlate to lower reactivity, epitope specificity, VWF content and may be predicted by TGA. It would be very helpful to be able to give an evidence based diagnostic and prognostic instrument, the TGA, to aid physician to optimize the therapy for all inhibitors patients.

Study Type

Observational

Enrollment (Anticipated)

25

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Palermo, Italy
        • Recruiting
        • Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina
        • Contact:
        • Principal Investigator:
          • Fabio Gagliano, Dr.
    • Calabria
      • Cosenza, Calabria, Italy, 87100
        • Recruiting
        • Ospedale Civile dell' Annunziata
        • Contact:
        • Principal Investigator:
          • Filomena Daniele, MD
    • Campania
      • Napoli, Campania, Italy, 80131
        • Active, not recruiting
        • Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica
    • Emilia Romagna
      • Bologna, Emilia Romagna, Italy, 40138
        • Recruiting
        • UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi
        • Contact:
        • Principal Investigator:
          • Gualtiero Palareti, MD
        • Sub-Investigator:
          • Lelia Valdrè, MD
        • Sub-Investigator:
          • Giuseppina Rodorigo, MD
    • Friuli Venezia Giulia
      • Udine, Friuli Venezia Giulia, Italy, 33100
        • Recruiting
        • Azienda Ospedaliera "Santa Maria della Misericordia"
        • Contact:
        • Principal Investigator:
          • Giovanni Barillari, MD
        • Sub-Investigator:
          • Samantha Pasca, BS PhD
    • Lazio
      • Rome, Lazio, Italy, 00161
        • Active, not recruiting
        • Ematologia Dipartimento di Biotecnologie Cellulari Università La Sapienza - Policlinico Umberto I
      • Rome, Lazio, Italy, 00165
      • Rome, Lazio, Italy, 00168
        • Active, not recruiting
        • Università Cattolica - Policlinico A. Gemelli
    • Piemonte
      • Turin, Piemonte, Italy, 10126
        • Recruiting
        • Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna
        • Contact:
        • Principal Investigator:
          • Maria Messina, MD
        • Sub-Investigator:
          • Berardino Pollio, MD
      • Turin, Piemonte, Italy, 10126
        • Recruiting
        • Ospedale Le Molinette "S. G. Battista"
        • Contact:
        • Principal Investigator:
          • Alessandra Borchiellini, MD
    • Puglia
      • BAri, Puglia, Italy, 70124
        • Active, not recruiting
        • Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
    • Tuscany
      • Florence, Tuscany, Italy, 50134
        • Recruiting
        • Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi
        • Contact:
        • Principal Investigator:
          • Massimo Morfini, MD
        • Sub-Investigator:
          • Silvia Linari, MD
    • Veneto
      • Padua, Veneto, Italy, 35128
        • Recruiting
        • Az. Ospedaliera di Padova, Clinica Medica IIa
        • Contact:
        • Principal Investigator:
          • Ezio Zanon, MD
      • Verona, Veneto, Italy, 37126
        • Active, not recruiting
        • Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma
      • Vicenza, Veneto, Italy, 36100
        • Recruiting
        • Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo
        • Contact:
          • Giancarlo Castaman, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Sampling Method

Non-Probability Sample

Study Population

Patients with moderate or severe hemophilia A with inhibitors divided into two groups:

  1. Patients with inhibitors to FVIII and low anamnestic response: Low responders cohort
  2. Patients with inhibitors to FVIII and high anamnestic response: High responders cohort

Description

Inclusion Criteria:

  • Diagnosis of inherited, severe (FVIII:C < 1%) or moderately severe haemophilia A (FVIII ≤ 2%)
  • Any age
  • Ability to comply with study methods and willingness to participate to the study
  • Written informed consent.

FOR THE LOW RESPONDERS COHORT

- Documented low anamnestic response after FVIII exposure (FVIII inhibitors titre >0.6 and < 5 BU/ml tested by Bethesda assay, Nijmegen modification). It will be included in this study those patients who have never been submitted to ITI and also those patients who have completed ITI with partial success (defined as inhibitors titre >0.6 and < 5 BU/ml and no increase in the INH titer > 5 BU over treatment with FVIII)

INCLUSION CRITERIA FOR THE HIGH RESPONDERS COHORT

  • Documented high response after FVIII exposure (FVIII inhibitors titre > 5 BU/ml tested by Bethesda assay, Nijmegen modification). It will be included in this study those patients who are potential candidates to a first or rescue ITI.
  • Any historical peak ≥ 5 BU

Exclusion Criteria:

  • Diagnosis of acquired haemophilia
  • Diagnosis of inherited mild haemophilia A (FVIII > 2%)
  • Life expectancy lower than 1 year
  • Psychiatric illness and any other conditions may impair ability to comply with study methods

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
LOW RESPONDERS
Documented low anamnestic response after FVIII exposure (FVIII inhibitors titre >0.6 and < 5 BU/ml tested by Bethesda assay, Nijmegen modification). Patients who have never been submitted to ITI and also those patients who have completed ITI with partial success (defined as inhibitors titre >0.6 and < 5 BU/ml and no increase in the INH titer > 5 BU over treatment with FVIII)
TGA will be performed on plasma in order to evaluate differences in the ability to stimulate the thrombin generation among the different class of FVIII concentrates and possibly identify the "most effective". The TGA will be quarterly repeated in order to verify if it is also adequate to check the therapy effectiveness during the study period
HIGH RESPONDERS
Patients who documented high response after FVIII exposure (FVIII inhibitors titre > 5 BU/ml tested by Bethesda assay, Nijmegen modification) and who are potential candidates to a first or rescue ITI
TGA will be performed on plasma in order to evaluate differences in the ability to stimulate the thrombin generation among the different class of FVIII concentrates and possibly identify the "most effective". The TGA will be quarterly repeated in order to verify if it is also adequate to check the therapy effectiveness during the study period

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Thrombin generation result
Time Frame: 12 months
Thrombin generation results of the TGA applied on plasma patients whith inhibitor matched with different class of FVIII concentrate
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Epitope mapping results
Time Frame: 12 months
epitope mapping test on the plasma patient during the therapy for a follow-up period of 12 month
12 months
Incidence of all breakthrough (BT) bleedings
Time Frame: 12 months
events/month
12 months
Total FVIII dose required to treat the patients
Time Frame: 12 months
(IU/year)
12 months
the inhibitor titre course
Time Frame: 12 months
12 months
Use of bypassing agents
Time Frame: 12 months
incidence of BT bleedings who require bypassing agents (events/months) average dose of bypassing agents (or days of treatment) needed to treat BT bleedings total dose of bypassing agent (and days of treatment) required overall (IU/year) and (days of treatment/year)
12 months
ITI outcome only for patient under this kind of treatment
Time Frame: 3 years
% of Success (total, partial success or failure will be defined as in ITI study protocol) Time to tolerance (months), defined as the time to ITI success (total/partial)
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Elena Santagostino, MD, PhD, Angelo Bianchi Bonomi" Haemophilia Thrombosis Centre I.R.C.S.S. Maggiore Hospital and University of Milan Via Pace 9, 20122 Milan - Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2012

Primary Completion (Anticipated)

December 1, 2015

Study Completion (Anticipated)

June 1, 2016

Study Registration Dates

First Submitted

January 5, 2012

First Submitted That Met QC Criteria

January 6, 2012

First Posted (Estimate)

January 9, 2012

Study Record Updates

Last Update Posted (Estimate)

June 17, 2013

Last Update Submitted That Met QC Criteria

June 14, 2013

Last Verified

June 1, 2013

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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