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Analysis of the Coagulopathy Developed by COVID-19 Infected Patients (COVID-TGT)

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ClinicalTrials.gov Identifier: NCT04356950
Recruitment Status : Active, not recruiting
First Posted : April 22, 2020
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Nīmes

Study Description
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Brief Summary:
Increased D-dimers at admission of COVID-19 infected patients entering hospital due to a severe disease is a risk factor for death. Understanding this acquired coagulopathy is a prerequisite before specific interventional studies. The study investigators aim to apply a normalized and automated thrombin generation test (TGT), developed for testing the thrombotic risk (triggered by 5 pM Tissue Factor, with a purified thrombomodulin (TM) challenge) and to study its association with survival.

Condition or disease Intervention/treatment
Sepsis Blood Coagulation Disorders Thrombin Disseminated Intravascular Coagulation COVID-19 Other: Thrombin generation test assay Other: Fibrin generation markers assays

Detailed Description:

Accumulating data describe, in COVID-19 severely infected patients necessitating hospitalized medical support, the development of an acquired coagulopathy, from a sepsis-induced coagulopathy to an overt-DIC, which is a strong risk factor for death. Understanding this coagulopathy is a prerequisite before specific interventional studies. Conventional coagulation tests, like prothrombin time PT and aPTT, only reflect 5% of the total thrombin generation and are insensitive to the patients' natural anticoagulants. The investigators thus wish to analyze the coagulopathy of SARS-CoV-2 using a global analytical test reflecting the full complexity of thrombin generation then inhibition, the thrombin generation test (TGT), in its version designed to analyze the thrombotic risk (initiation by an intermediate concentration of human Tissue: 5 pM), in its fully automated and standardized technical version. This test analyzes not only the generation of thrombin and its various informative phases (initiation phase, propagation phase culminating at the peak of formation, inhibition phase with natural anticoagulants) but also the capacity for an exogenous addition of purified thrombomodulin (TM), which quantifies the anticoagulant activity of the patient's protein C activated by thrombin, to inhibit this generation of thrombin.

The aim is to assay this TGT version in a centralized way, on the patients' plasma obtained at hospital admission, just after checking the positive COVID-19 testing , together with the traditional blood tests including platelet counts, PT, D-dimers (DDi) and soluble fibrin monomers (FMs). The various quantitative biological parameters describing the results of the TGT assay, together with relevant covariates, will be tested using multivariate analysis for their capacity to be risk factors for clinically-relevant qualitative outcomes.

Study Design
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Study Type : Observational
Actual Enrollment : 175 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Analysis of the Coagulopathy Developed by COVID-19 Infected Patients: Thrombin Generation Potential in COVID-19 Infected Patients
Actual Study Start Date : April 28, 2020
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Intervention Details:
  • Other: Thrombin generation test assay
    lag time, initial velocity, time-to-peak, thrombin peak, total thrombin generation time, extrinsic thrombin potential (ETP). Crude quantitative values and relative values (%, by reference to the one obtained with an invariant reference plasma). Both without the addition of purified thrombomodulin (TM-) and with the addition of purified thrombomodulin (TM+). The ability of TM to inhibit thrombin generation will be calculated as follows: [ETP (%)(TM+) / ETP (%)(TM-)].
  • Other: Fibrin generation markers assays
    D-dimers (coagulation plus fibrinolysis), soluble fibrin monomers (coagulation only)

Outcome Measures
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Primary Outcome Measures :
  1. 28-day survival rate [ Time Frame: 1 month ]
    Death yes/no during hopstilization, 28 days after admittence

  2. Absolute thrombin generation test latent period [ Time Frame: Day 0 ]
    Seconds; without (TM-) and with (TM+) purified thrombomodulin

  3. Relative thrombin generation test latent period compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin

  4. Absolute thrombin generation test initial velocity [ Time Frame: Day 0 ]
    nmol/s; without (TM-) and with (TM+) purified thrombomodulin

  5. Relative thrombin generation test initial velocity compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin

  6. Relative thrombin generation test peak thrombin compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin

  7. Absolute thrombin generation test peak thrombin [ Time Frame: Day 0 ]
    nmol/L; without (TM-) and with (TM+) purified thrombomodulin

  8. Absolute thrombin generation test peak thrombin time [ Time Frame: Day 0 ]
    Seconds; without (TM-) and with (TM+) purified thrombomodulin

  9. Relative thrombin generation test peak thrombin time compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin

  10. Absolute thrombin generation test total thrombin generation time [ Time Frame: Day 0 ]
    seconds; without (TM-) and with (TM+) purified thrombomodulin

  11. Relative thrombin generation test total thrombin generation time compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin

  12. Absolute thrombin generation test endogenous thrombin potential [ Time Frame: Day 0 ]
    Seconds; without (TM-) and with (TM+) purified thrombomodulin

  13. Relative thrombin generation test endogenous thrombin potential compared to reference plasma [ Time Frame: Day 0 ]
    %; without (TM-) and with (TM+) purified thrombomodulin


Secondary Outcome Measures :
  1. 3-month survival rate [ Time Frame: 3 months ]
    Death yes/no

  2. Transfer to intensive care unit during hospitalization [ Time Frame: 3 months ]
    Yes/no

  3. Thrombotic complication during hospitalization [ Time Frame: 3 months ]
    Yes/no (deep vein thrombosis, pulmonary embolism, atherothrombosis flare, arterial thrombosis)

  4. Plasma concentrations of D-dimers [ Time Frame: Day 0 ]
    µg / L, assayed by automated enzyme linked fluorescent assay (Vidas® D-dimers Exclusion ™ II)

  5. Plasma concentrations of soluble fibrin monomers [ Time Frame: Day 0 ]
    mg / L, measured by automated immunoagglutination (STA®-Liatest® FM)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Consecutive patients hospitalized for SARS-CoV-2 infection with symptomatology / severity requiring hospital treatment.
Criteria

Inclusion Criteria:

  • Patient with SARS-CoV-2 infection entering hospitalization with or without resuscitation
  • The patient (or their carer) must have given their free and informed consent and signed the consent form
  • The patient must be a member or beneficiary of a health insurance plan

Exclusion Criteria:

  • Pregnant or breastfeeding patient
  • It is impossible to give the subject informed information
  • The patient is under safeguard of justice or state guardianship
  • Thrombotic events during treatment: flare-up of venous thromboembolism, flare-up of atherothrombosis.
  • Long-term anticoagulant treatment (anti-vitamin K, direct oral anticoagulant).
  • Chronic anti-aggregation treatment.
  • Pre-existing constitutive or acquired known coagulation pathology: hemorrhagic diseases (thrombocytopenia, thrombocytopathy, hemophilia, von Willebrand's disease, hemorrhagiparous factor deficiency), and for thrombophilia (deficits in antithrombin, protein C or S , Factor V Leiden or Prothrombin 20201A mutation).
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT04356950


Locations
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France
CHU de Bordeaux
Bordeaux, France
CHU de Limoges
Limoges, France
CHU de Montpellier
Montpellier, France
CHU de Nimes
Nîmes, France
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nīmes
Investigators
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Principal Investigator: Jean-Christophe Gris CHU Nimes
More Information
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Responsible Party: Centre Hospitalier Universitaire de Nīmes
ClinicalTrials.gov Identifier: NCT04356950    
Other Study ID Numbers: PHRC-I/2020/JCG-01
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Hospitalier Universitaire de Nīmes:
coagulation
survival
thrombin generation test
Additional relevant MeSH terms:
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Hemostatic Disorders
Blood Coagulation Disorders
Disseminated Intravascular Coagulation
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
 Hemorrhagic Disorders
Thrombophilia
Thrombin
Hemostatics
Coagulants