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

• ClinicalTrials.gov Identifier: NCT04356950
• Recruitment Status: Recruiting
• First Posted: April 22, 2020
• Last Update Posted: December 2, 2020
• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Information provided by (Responsible Party): Centre Hospitalier Universitaire de Nīmes

Tracking Information

• First Submitted Date: April 16, 2020
• First Posted Date: April 22, 2020
• Last Update Posted Date: December 2, 2020
• Actual Study Start Date: April 28, 2020
• Estimated Primary Completion Date: April 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2020)

• 28-day survival rate [ Time Frame: 1 month ]
  Death yes/no during hopstilization, 28 days after admittence
• Absolute thrombin generation test latent period [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test latent period compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test initial velocity [ Time Frame: Day 0 ]
  nmol/s; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test initial velocity compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test peak thrombin compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test peak thrombin [ Time Frame: Day 0 ]
  nmol/L; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test peak thrombin time [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test peak thrombin time compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test total thrombin generation time [ Time Frame: Day 0 ]
  seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test total thrombin generation time compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test endogenous thrombin potential [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test endogenous thrombin potential compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin

Original Primary Outcome Measures (submitted: April 20, 2020)

• Survival rate during hospitalization [ Time Frame: 3 months ]
  % patients surviving hospitalization
• Absolute thrombin generation test latent period [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test latent period compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test initial velocity [ Time Frame: Day 0 ]
  nmol/s; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test initial velocity compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test peak thrombin compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test peak thrombin [ Time Frame: Day 0 ]
  nmol/L; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test peak thrombin time [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test peak thrombin time compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test total thrombin generation time [ Time Frame: Day 0 ]
  seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test total thrombin generation time compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin
• Absolute thrombin generation test endogenous thrombin potential [ Time Frame: Day 0 ]
  Seconds; without (TM-) and with (TM+) purified thrombomodulin
• Relative thrombin generation test endogenous thrombin potential compared to reference plasma [ Time Frame: Day 0 ]
  %; without (TM-) and with (TM+) purified thrombomodulin

Current Secondary Outcome Measures (submitted: April 27, 2020)

• 3-month survival rate [ Time Frame: 3 months ]
  Death yes/no
• Transfer to intensive care unit during hospitalization [ Time Frame: 3 months ]
  Yes/no
• Thrombotic complication during hospitalization [ Time Frame: 3 months ]
  Yes/no (deep vein thrombosis, pulmonary embolism, atherothrombosis flare, arterial thrombosis)
• Plasma concentrations of D-dimers [ Time Frame: Day 0 ]
  µg / L, assayed by automated enzyme linked fluorescent assay (Vidas® D-dimers Exclusion ™ II)
• Plasma concentrations of soluble fibrin monomers [ Time Frame: Day 0 ]
  mg / L, measured by automated immunoagglutination (STA®-Liatest® FM)

Original Secondary Outcome Measures (submitted: April 20, 2020)

• Transfer to intensive care unit during hospitalization [ Time Frame: 3 months ]
  Yes/no
• Thrombotic complication during hospitalization [ Time Frame: 3 months ]
  Yes/no (deep vein thrombosis, pulmonary embolism, atherothrombosis flare, arterial thrombosis)
• Plasma concentrations of D-dimers [ Time Frame: Day 0 ]
  µg / L, assayed by automated enzyme linked fluorescent assay (Vidas® D-dimers Exclusion ™ II)
• Plasma concentrations of soluble fibrin monomers [ Time Frame: Day 0 ]
  mg / L, measured by automated immunoagglutination (STA®-Liatest® FM)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Analysis of the Coagulopathy Developed by COVID-19 Infected Patients
• Official Title: Analysis of the Coagulopathy Developed by COVID-19 Infected Patients: Thrombin Generation Potential in COVID-19 Infected Patients
• 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.

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 Type: Observational
• Study Design: Observational Model: Other; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Consecutive patients hospitalized for SARS-CoV-2 infection with symptomatology / severity requiring hospital treatment.

Condition

• Sepsis
• Blood Coagulation Disorders
• Thrombin
• Disseminated Intravascular Coagulation
• COVID-19

Intervention

• 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)

• Study Groups/Cohorts: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 20, 2020): 175
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2022
• Estimated Primary Completion Date: April 2022 (Final data collection date for primary outcome measure)

Eligibility 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jean-Christophe Gris; 04 66 68 32 11; jean.christophe.gris@chu-nimes.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04356950
• Other Study ID Numbers: PHRC-I/2020/JCG-01
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Centre Hospitalier Universitaire de Nīmes
• Study Sponsor: Centre Hospitalier Universitaire de Nīmes
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jean-Christophe Gris; CHU Nimes

• PRS Account: Centre Hospitalier Universitaire de Nīmes
• Verification Date: December 2020