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Concentration-effect Relationship of Enoxaparin for Thromboembolic Prevention (COV-ENOX)

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ClinicalTrials.gov Identifier: NCT04520620
Recruitment Status : Withdrawn (End of the COVID 19 epidemic in the region and decision to participate in a national study on the same subject (COVI-DOSE).)
First Posted : August 20, 2020
Last Update Posted : August 20, 2020
Sponsor:
Collaborator:
CHU Saint-Etienne - Laboratoire de Pharmacologie - Toxicologie - Gaz du sang
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Saint Etienne

Brief Summary:

Patients with COVID-19 have special demographic characteristics including thromboembolic risk factors .

The pharmacokinetics of enoxaparin administered subcutaneously in the intensive care unit patient are not described.

Finally, given the lack of knowledge on the pharmacokinetic/pharmacodynamic properties of enoxaparin in intensive care unit patients infected with SARS-CoV-2, we propose to conduct a prospective multicenter cohort study to collect the biological data necessary for its study.


Condition or disease Intervention/treatment Phase
Sars-CoV2 Drug: Lovenox 40 MG in 0.4 mL Prefilled Syringe Device: Ultrasound of the lower limbs Phase 4

Detailed Description:

D-dimers greater than 1 μg/mL are a prognostic factor for 28-day mortality (odds ratio=18, 2-128). The use of preventive doses of enoxaparin (4,000 to 6,000 anti-Xa per day) or unfractionated heparin (10,000 to 15,000 IU per day) has been associated with a reduction in mortality of approximately one-third in patients with D-dimer levels greater than 3 μg/mL or those with sepsis-induced coagulopathy (SIC (sepsis-induced coagulopathy) score > 4)

For the intensive care unit patient, the preventive enoxaparin dosages were increased to 4,000 anti-Xa IU twice daily and to 6,000 anti-Xa IU twice daily if the patient weighs more than 120 kg. Curative treatment is even proposed in cases of marked inflammatory syndrome and/or hypercoagulability (e.g. fibrinogen > 8 g/L or D-Dimer > 3 μg/mL or 3000 ng/mL) even without symptomatic thrombosis.

Given the lack of data on the use of these high "prophylactic" doses of enoxaparin, it is proposed that anti-Xa activity be monitored after the 3rd injection, and then regularly in the event of renal failure (because LMWHs are renally eliminated), to look for overdosage exposing a higher risk of bleeding. It is also proposed to regularly monitor (at least every 48 hours) the hemostasis of patients in search of multivisceral failure, or of coagulopathy of consumption which will require a re-evaluation of the heparin therapy dosage, these events being associated with an increased risk of haemorrhage.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of the Concentration-effect Relationship of Enoxaparin for Thromboembolic Prevention in COVID-19 Intensive Unit Care Patients.
Actual Study Start Date : May 2, 2020
Actual Primary Completion Date : July 10, 2020
Actual Study Completion Date : July 10, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: enoxaparin treatment

Patients infected by SARS-CoV-2 in intensive care unit with enoxaparin treatment will be included.

They will have enoxaparin pharmacokinetic and ultrasound of the lower limbs at 7, 14 and 21 days after inclusion.

Drug: Lovenox 40 MG in 0.4 mL Prefilled Syringe

Patients with a high thrombotic risk:

In patients with a BMI included between < 30 kg/m² and > 30 kg/m² without added thrombotic risk factor:

  • Enoxaparin 40 milligrams, (4,000 IU) twice daily subcutaneously (SC) for the entire duration of the intensive care hospitalization
  • if weight > 120 kg, enoxaparin 60 milligrams (6000 IU) twice daily subcutaneously for the entire duration of the intensive care hospitalization

Patients with a very high thrombotic risk:

In patients with a BMI > 30 kg/m2 with added thrombotic risk factor (active cancer, recent personal history of thromboembolic event), or if iterative or unusual catheter thromboses, or if marked inflammatory syndrome and/or hypercoagulability (e.g. fibrinogen > 8 g/L or D-Dimer > 3 μg/ml or 3000 ng/ml)

* Enoxaparin sodium curative at a dose of 100 IU/kg/12h subcutaneously (SC) not to exceed a dose of 100 mg/12 hours

Other Name: enoxaparin

Device: Ultrasound of the lower limbs
A 4-point compression ultrasound will be performed. In case of suspicion, an angiologist will perform to check the absence of legs thrombosis.




Primary Outcome Measures :
  1. Measure of anti-Xa activity [ Time Frame: Up to 1 month ]
    Measure of anti-Xa activity by chromogenic method.


Secondary Outcome Measures :
  1. Analysis of hemorrhagic risk [ Time Frame: Up to 1 month ]

    Hemorrhagic risk is composite of :

    • Major haemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) definition
    • clinically significant haemorrhage

  2. Venous thromboembolic events [ Time Frame: Up to 1 month ]

    Venous thromboembolic events is composite of:

    • symptomatic or symptomatic proximal deep vein thrombosis
    • asymptomatic or symptomatic pulmonary embolism

  3. Analysis individual patient characteristics by the biomarker of Kidney function [ Time Frame: Up to 1 month ]
    Rate of creatinine.

  4. Analysis individual patient characteristics by the biomarker of inflammation [ Time Frame: Up to 1 month ]
    Biomarker of inflammation is composite of C-reactive protein (CRP) and inflammatory cytokines.

  5. Analysis individual patient characteristics by the biomarker of coagulation [ Time Frame: Up to 1 month ]
    Biomarker of coagulation is composite of fibrinogen and D-Dimers.

  6. Demographic characteristics [ Time Frame: Up to 1 month ]
    Analysis of weight, age, sex, height, presence of a high thrombotic risk factor (history of venous thrombotics, active cancer, invasive mechanical ventilation).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged > 18 ans
  • SARS-CoV-2 infected intensive care unit patients
  • Diagnosis of SARS-CoV-2 respiratory infection was made with a nasopharyngeal swab or a deep respiratory specimen.
  • Patient receiving enoxaparin treatment as part of care or as part of a clinical trial for the prevention or treatment of thromboembolic venous disease.
  • Patient affiliated or entitled to a social security scheme

Exclusion Criteria:

  • Creatinine clearance according to Cockcroft and Gault <30ml/min.
  • Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWHs)
  • History of immune-mediated heparin-induced thrombocytopenia (HIT) in the last 100 days or in the presence of circulating antibodies
  • Active clinically significant bleeding or a condition associated with a high risk of bleeding, such as a recent hemorrhagic stroke, gastrointestinal ulcer, the presence of a malignant tumour at high risk of bleeding, recent brain, spinal or ophthalmologic surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysm or major intrarachidian or intracerebral vascular abnormalities.
  • Spinal, epidural or locoregional anaesthesia or anaesthesia when enoxaparin sodium is used for curative treatment within the previous 24 hours

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): NCT04520620


Locations
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France
Groupement Hospitalier des portes de Province
Montélimar, France
Centre Hospitalier de Roanne
Roanne, France
CHU de Saint-Etienne
Saint-Étienne, France
Clinique Mutualiste
Saint-Étienne, France
Sponsors and Collaborators
Centre Hospitalier Universitaire de Saint Etienne
CHU Saint-Etienne - Laboratoire de Pharmacologie - Toxicologie - Gaz du sang
Investigators
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Principal Investigator: Paul ZUFFEREY, MD CHU SAINT-ETIENNE
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Responsible Party: Centre Hospitalier Universitaire de Saint Etienne
ClinicalTrials.gov Identifier: NCT04520620    
Other Study ID Numbers: 20CH089
2020-001823-15 ( EudraCT Number )
First Posted: August 20, 2020    Key Record Dates
Last Update Posted: August 20, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Saint Etienne:
enoxaparin
intensive care unit
pharmacokinetics
SARS-Co-V-2
Lovenox
Additional relevant MeSH terms:
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Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action