Thrombin Generation Numerical Models Validation in Haemophilic Case

• ClinicalTrials.gov Identifier: NCT02300519
• Recruitment Status: Completed
• First Posted: November 25, 2014
• Last Update Posted: August 13, 2015
• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Pfizer; Ecole Normale Supérieure des Mines de Saint-Etienne
• Information provided by (Responsible Party): Centre Hospitalier Universitaire de Saint Etienne

Study Description

Brief Summary:

Personalized therapy in haemophilia has not been reached yet. Treatment is substitutive and its doses are only based on the levels of deficient factor VIII (for haemophilia A) or IX (for haemophilia B). The bleeding severity is not only related to the factor deficiency but also to levels of other coagulation factors (e.g. factor X, II, AT or TFPI). It's necessary to take them into account in order to individualize treatments; and Thrombin Generation Assay (TGA) with the CAT method (Calibrated Automated Thrombography) is a good way because it measures the result of the coagulation cascade. TGA on Platelet Rich Plasma (PRP) is even closer to physiological conditions than on Platelet Poor Plasma (PPP) because platelet influence is represented. It has already been shown (at least in PPP) that the bleeding tendency in haemophilic patients is usually well correlated to TG. Some TG parameters are used to characterize the individual coagulation phenotype, the most important being the Endogenous Thrombin Potential (ETP) and the Lag Time (LT). A hemorrhagic profile usually provides a longer lag time and / or a lower ETP. However, only few studies tried to determine the influence of each coagulation factor and inhibitor on TG. They were done on Platelet Poor Plasma (PPP) or on lyophilized plasma. So the relation between coagulation factors and the different TG parameters remains to be determined, especially in the haemophilic case. It is possible, experimentally, to find the optimal dose of the factor to be added by measuring TG in samples with different factor VIII or IX concentrations, but this method would be time consuming and expensive, especially because it should be done for each haemophilic patient. A better way consists in using TG numerical models. For a set of initial factor levels they simulate the TG and its associated parameters. It is now essential to validate the existing models, especially in haemophilic cases, in order to see whether they are reliable and can be used in clinical practice afterwards.The objective of this study is to validate thrombin generation numerical models which could predict the factor VIII or IX activity correction to reach a thrombin generation sufficient to avoid bleeding. A comparison between the TG observed in haemophilic patients and the TG predicted by the models is needed to validate the models. In order to define a 'safe' TG i.e. sufficient to avoid bleeding, normal ranges of TG parameters have to be measured.

Condition or disease	Intervention/treatment
Haemophilia B; Haemophilia A	Other: blood sampling

Study Design

• Study Type: Observational
• Actual Enrollment: 40 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Thrombin Generation Numerical Models Validation in Haemophilic Case
• Study Start Date: March 2015
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: July 2015

Groups and Cohorts

Group/Cohort	Intervention/treatment
Volunteers; Blood sampling : 1 blood punction of 36.5 ml for each volunteer	Other: blood sampling; Samplings will be taken on 4 citrated S-monovette tubes, 3 citrated tubes and 1 EDTA tube, namely 36.5 ml for each volunteer

Outcome Measures

Primary Outcome Measures :

1. Endogenous Thrombin Potential (ETP) predicted by numerical models [ Time Frame: up to 12 monthes ]
   ETP (i.e. the aera under the thrombin generation curve, nM.min) measured in haemophilic patients is compared to ETP predicted by numerical models.
2. Lag Time of the thrombin generation curve predicted by numerical models [ Time Frame: up to 12 monthes ]
   Lag time (min) measured in haemophilic patients is compared to the lag time predicted by numerical models
3. Peak value of the thrombin generation curve predicted by numerical models [ Time Frame: up to 12 monthes ]
   Peak value (nmol thrombin) measured in haemophilic patients is compared to the peak value predicted by numerical models
4. Time to peak (TTP) of the thrombin generation curve predicted by numerical models [ Time Frame: up to 12 monthes ]
   TTP (min) measured in haemophilic patients is compared to TTP predicted by numerical models
5. Velocity Index (V) of the thrombin generation curve predicted by numerical models [ Time Frame: up to 12 monthes ]
   Velocity Index measured in haemophilic patients is compared to TTP predicted by numerical models

Secondary Outcome Measures :

1. Endogenous Thrombin Potential (ETP) for volunteers [ Time Frame: day 1 ]
   ETP (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Tests (TGTs)
2. Lag Time of the thrombin generation curve for volunteers [ Time Frame: day 1 ]
   Lag time (min) of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)
3. Peak value of the thrombin generation curve for volunteers [ Time Frame: day 1 ]
   Peak value of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)
4. Time to peak (TTP) of the thrombin generation curve for volunteers [ Time Frame: day 1 ]
   TTP of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)
5. Velocity Index (V) of the thrombin generation curve for volunteers [ Time Frame: day 1 ]
   Velocity Index (V) of the thrombin generation curves measured by Thromboplastin Generation Tests (TGTs)

Biospecimen Retention:   Samples Without DNA

blood

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

volunteers witch work in CHU Saint-Etienne

Criteria

Inclusion Criteria:

• Signed consent form
• Age between 18 and 45 years old
• Male
• no smoker

Exclusion Criteria:

• other clinical research protocol participation during the 3 months before inclusion
• Personal or familial history of hemorrhagic disease (parents, brothers and sisters
• Personal history of thrombosis (arterial or venous)
• Familial history of thrombosis before 45 years old (parents, brothers and sisters)
• Drug treatments of aspirin or anti-inflammatory type during the week before sampling
• Surgery the month before sampling
• Chronic pathology responsible for inflammatory syndrome
• Infectious episode in course

Contacts and Locations

Locations

France

Chu Saint-Etienne

Saint-Etienne, France, 42055

Sponsors and Collaborators

Centre Hospitalier Universitaire de Saint Etienne

Pfizer

Ecole Normale Supérieure des Mines de Saint-Etienne

Investigators

• Principal Investigator: Brigitte TARDY-PONCET, MD; CHU SAINT-ETIENNE

More Information

• Responsible Party: Centre Hospitalier Universitaire de Saint Etienne
• ClinicalTrials.gov Identifier: NCT02300519
• Other Study ID Numbers: 1408185; 2014-A01734-43 ( Other Identifier: ANSM - FRANCE )
• First Posted: November 25, 2014
• Last Update Posted: August 13, 2015
• Last Verified: August 2015

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:

Haemophilia; numerical models; thrombin generation; volunteers; endogenous thrombin potential

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked