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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Grifols Italia S.p.A
Sponsor:
Collaborator:
Thrombinoscope
Information provided by (Responsible Party):
Grifols Italia S.p.A
ClinicalTrials.gov Identifier:
NCT01505946
First received: January 5, 2012
Last updated: June 14, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention
Severe Hemophilia A With Inhibitor
Other: TGA (Thrombin generation Assay)

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Grifols Italia S.p.A:

Primary Outcome Measures:
  • Thrombin generation result [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Thrombin generation results of the TGA applied on plasma patients whith inhibitor matched with different class of FVIII concentrate


Secondary Outcome Measures:
  • Epitope mapping results [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    epitope mapping test on the plasma patient during the therapy for a follow-up period of 12 month

  • Incidence of all breakthrough (BT) bleedings [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    events/month

  • Total FVIII dose required to treat the patients [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    (IU/year)

  • the inhibitor titre course [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Use of bypassing agents [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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)

  • ITI outcome only for patient under this kind of treatment [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    % 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)


Biospecimen Retention:   Samples Without DNA

plasma samples


Estimated Enrollment: 25
Study Start Date: March 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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)
Other: TGA (Thrombin generation Assay)
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
Other: TGA (Thrombin generation Assay)
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

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.

  Eligibility

Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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
Criteria

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
  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: NCT01505946

Contacts
Contact: Elena Santagostino, Scientific Coordinator +39 02 55035273 hemophilia_ctr@policlinico.mi.it
Contact: Elisa Mancuso +39 02 55035273 hemophilia_ctr@policlinico.mi.it

Locations
Italy
Ospedale Civile dell' Annunziata Recruiting
Cosenza, Calabria, Italy, 87100
Contact: Filomena Daniele, MD       fildaniele@libero.it   
Principal Investigator: Filomena Daniele, MD         
Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica Active, not recruiting
Napoli, Campania, Italy, 80131
UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi Recruiting
Bologna, Emilia Romagna, Italy, 40138
Contact: Lelia Valdrè, MD       lvaldre@aosp.bo.it   
Principal Investigator: Gualtiero Palareti, MD         
Sub-Investigator: Lelia Valdrè, MD         
Sub-Investigator: Giuseppina Rodorigo, MD         
Azienda Ospedaliera "Santa Maria della Misericordia" Recruiting
Udine, Friuli Venezia Giulia, Italy, 33100
Contact: Giovanni Barillari, MD       barillari.giovanni@aoud.sanita.fvg.it   
Principal Investigator: Giovanni Barillari, MD         
Sub-Investigator: Samantha Pasca, BS PhD         
Università Cattolica - Policlinico A. Gemelli Active, not recruiting
Rome, Lazio, Italy, 00168
Ematologia Dipartimento di Biotecnologie Cellulari Università La Sapienza - Policlinico Umberto I Active, not recruiting
Rome, Lazio, Italy, 00161
Ospedale Pediatrico Bambino Gesù di Roma Recruiting
Rome, Lazio, Italy, 00165
Contact: Matteo Luciani, MD       matteo.luciani@opbg.net   
Principal Investigator: Matteo Luciani, MD         
Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna Recruiting
Turin, Piemonte, Italy, 10126
Contact: Maria Messina, MD       maria.messina@oirmsantanna.piemonte.it   
Principal Investigator: Maria Messina, MD         
Sub-Investigator: Berardino Pollio, MD         
Ospedale Le Molinette "S. G. Battista" Recruiting
Turin, Piemonte, Italy, 10126
Contact: Alessandra Borchiellini, MD       aborchiellini@molinette.piemonte.it   
Principal Investigator: Alessandra Borchiellini, MD         
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari Active, not recruiting
BAri, Puglia, Italy, 70124
Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi Recruiting
Florence, Tuscany, Italy, 50134
Contact: Massimo Morfini, MD       massimo.morfini@unfi.it   
Principal Investigator: Massimo Morfini, MD         
Sub-Investigator: Silvia Linari, MD         
Az. Ospedaliera di Padova, Clinica Medica IIa Recruiting
Padua, Veneto, Italy, 35128
Contact: Ezio Zanon, MD       ezio.zanon@unipd.it   
Principal Investigator: Ezio Zanon, MD         
Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma Active, not recruiting
Verona, Veneto, Italy, 37126
Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo Recruiting
Vicenza, Veneto, Italy, 36100
Contact: Giancarlo Castaman, MD         
Principal Investigator: Giancarlo Castaman, MD         
Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina Recruiting
Palermo, Italy
Contact: Fabio Gagliano, Physician       ematopediatriaob@teletu.it   
Principal Investigator: Fabio Gagliano, Dr.         
Sponsors and Collaborators
Grifols Italia S.p.A
Thrombinoscope
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
  More Information

Publications:

Responsible Party: Grifols Italia S.p.A
ClinicalTrials.gov Identifier: NCT01505946     History of Changes
Other Study ID Numbers: PredicTGA, 373
Study First Received: January 5, 2012
Last Updated: June 14, 2013
Health Authority: Italy: The Italian Medicines Agency
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health

Keywords provided by Grifols Italia S.p.A:
Thrombin
Hemophilia
Inhibitors
Immunotolerance
Haemostatic
FVIII
Epitopes
Moderately severe Hemophilia A with inhibitor

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Thrombin
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014