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

Evaluation of the Concentration-effect Relationship of Enoxaparin for Thromboembolic Prevention in COVID-19 Intensive Unit Care Patients.

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.

Study Overview

• Status: Withdrawn
• Conditions: Sars-CoV2
• Intervention / Treatment: Drug: Lovenox 40 MG in 0.4 mL Prefilled Syringe; Device: Ultrasound of the lower limbs

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.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Montélimar, France
    • Groupement Hospitalier des Portes de Province
  • Roanne, France
    • Centre hospitalier de Roanne
  • Saint-Étienne, France
    • CHU de Saint-Etienne
  • Saint-Étienne, France
    • Clinique Mutualiste

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of anti-Xa activity	Measure of anti-Xa activity by chromogenic method.	Up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of hemorrhagic risk	Hemorrhagic risk is composite of : Major haemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) definition; clinically significant haemorrhage	Up to 1 month
Venous thromboembolic events	Venous thromboembolic events is composite of: symptomatic or symptomatic proximal deep vein thrombosis; asymptomatic or symptomatic pulmonary embolism	Up to 1 month
Analysis individual patient characteristics by the biomarker of Kidney function	Rate of creatinine.	Up to 1 month
Analysis individual patient characteristics by the biomarker of inflammation	Biomarker of inflammation is composite of C-reactive protein (CRP) and inflammatory cytokines.	Up to 1 month
Analysis individual patient characteristics by the biomarker of coagulation	Biomarker of coagulation is composite of fibrinogen and D-Dimers.	Up to 1 month
Demographic characteristics	Analysis of weight, age, sex, height, presence of a high thrombotic risk factor (history of venous thrombotics, active cancer, invasive mechanical ventilation).	Up to 1 month

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: CHU Saint-Etienne - Laboratoire de Pharmacologie - Toxicologie - Gaz du sang
• Investigators: Principal Investigator: Paul ZUFFEREY, MD, CHU Saint-Etienne

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2020
• Primary Completion (Actual): July 10, 2020
• Study Completion (Actual): July 10, 2020

Study Registration Dates

• First Submitted: July 22, 2020
• First Submitted That Met QC Criteria: August 19, 2020
• First Posted (Actual): August 20, 2020

Study Record Updates

• Last Update Posted (Actual): August 20, 2020
• Last Update Submitted That Met QC Criteria: August 19, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: intensive care unit; pharmacokinetics; enoxaparin; SARS-Co-V-2; Lovenox
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: 20CH089; 2020-001823-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No