Weight-Adjusted vs Fixed Low Doses of Low Molecular Weight Heparin For Venous Thromboembolism Prevention in COVID-19

Study Overview
=================
Brief Summary
-----------------
Worldwide observational studies indicate a significant prothrombogenic effect associated with SARS-CoV-2 infection with a high incidence of venous thromboembolism (VTE), notably life-threatening pulmonary embolism. According to recommendations for acute medical illnesses, all COVID-19 hospitalized patients should be given VTE prophylaxis such as a low molecular weight heparin (LMWH). A standard prophylactic dose (eg. Enoxaparin 4000IU once daily) could be insufficient in obese patients and VTE has been reported in patients treated with a standard prophylactic dose. In COVID-19 patients, guidelines from several international societies confirm the existence of an hypercoagulability and the importance of thromboprophylaxis but the optimal dose is unknown and comparative studies are needed. In view of these elements, carrying out a trial comparing various therapeutic strategies for the prevention of VTE in hospitalized patients with COVID-19 constitutes a health emergency. Thus, we hypothesize that an increased prophylactic dose of weight-adjusted LMWH would be greater than a lower prophylactic dose of LMWH to reduce the risk of life-threatening VTE in hospitalized patients. The benefit-risk balance of this increase dose will be carefully evaluated because of bleeding complications favored by possible renal / hepatic dysfunctions, drug interactions or invasive procedures in COVID-19 patients. This multicenter randomized (1:1) open-label controlled trial will randomize hospitalized adults with COVID-19 infection to weight-adjusted prophylactic dose vs. lower prophylactic dose of LMWH.

Official Title
-----------------
Effectiveness of Weight-adjusted Prophylactic Low Molecular Weight Heparin Doses Compared With Lower Fixed Prophylactic Doses to Prevent Venous Thromboembolism in COVID-2019. The Multicenter Randomized Controlled Open-label Trial COVI-DOSE

Conditions
-----------------
COVID, Thrombosis, Pulmonary Embolism, Deep Vein Thrombosis

Intervention / Treatment
-----------------
* Drug: Enoxaparin
* Drug: Enoxaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patient hospitalized for a probable/confirmed COVID-19 infection (confirmed by serology/polymerase chain reaction or by radiologic signs of COVID-19 pneumonia in the setting of clinical and laboratory abnormalities suggestive of a SARS-CoV-2 infection) Signed informed consent Patient affiliated to the Social Security Exclusion Criteria: Renal insufficiency with a GFR<15 mL/min/1.73m² Acute kidney injury KDIGO3 Prophylactic dose of low molecular weight heparin for more than 3 days Curative dose of low molecular weight heparin for more than 1 day Recurrent catheter/hemodialysis access thromboses ECMO required in the next 24h Contraindication to low molecular weight heparin High bleeding risk (e.g. uncontrolled severe systemic hypertension, recent major bleeding, disseminated intravascular coagulopathy, thrombocytopenia < 75G/L) History of heparin-induced thrombocytopenia Contraindication to blood-derived products Impossibility to perform a doppler ultrasound of the lower limbs (e.g. above the knee amputation, severe burn injuries) Expected death in the next 48h Vulnerable subjects according to articles L. 1121-5, L. 1121-7 et L1121-8 of French Public Health Code

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter randomized (1:1) controlled open-label trial, stratified on disease severity (admission to ICU or not)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Prophylactic Dose of Low Molecular Weight Heparin<br>Enoxaparin, Tinzaparin, Nadroparin, Dalteparin | Drug: Enoxaparin<br>* For example (Enoxaparin): From 4000IU once a day in patients admitted in medical ward to 4000IU twice a day in patients admitted in the ICU. In patients with severe renal insufficiency (GFR=15-30 mL/min/1.73m²), LMWH doses will be reduced by 50%.<br>* Other names: Dalteparin;|
| Experimental: Weight-Adjusted Prophylactic Dose Low Molecular Weight Heparin<br>Enoxaparin, Tinzaparin, Nadroparin, Dalteparin | Drug: Enoxaparin<br>* For example (Enoxaparin): 4000IU twice a day in patients <50kg 5000IU twice a day in patients 50-70kg 6000IU twice a day in patients 70-100kg 7000IU twice a day in patients above 100kg<br>* Other names: Dalteparin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous thromboembolism | Risk of deep vein thrombosis or pulmonary embolism or venous thromboembolism-related death | hospitalization stay (up to 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major bleeding | Risk of major bleeding defined by the ISTH | hospitalization stay (up to 28 days) | 
| Major Bleeding and Clinically Relevant Non-Major Bleeding | Risk of Major Bleeding and Clinically Relevant Non-Major Bleeding Defined by the ISTH | hospitalization stay (up to 28 days) | 
| Net Clinical Benefit | Risk of Venous Thromboembolism and Major Bleeding | hospitalization stay (up to 28 days) and 60 days | 
| Venous Thromboembolism at other sites | Risk of venous thrombosis at other sites: e.g. superficial vein, catheters, hemodialysis access, ECMO, splanchnic, encephalic, upper limb | hospitalization stay (up to 28 days) | 
| Arterial Thrombosis | Risk of arterial thrombosis at any sites | hospitalization stay (up to 28 days) | 
| All-Cause Mortality | Risk of all-cause mortality | hospitalization stay (up to 28 days) and 60 days | 
| Factors associated with the risk of venous thromboembolism | Identification of associations between the risk of venous thromboembolism and clinical (eg. past medical history of thrombosis, cardiovascular risk factors, treatments, severity of COVID-19) and laboratory variables (e.g. D-dimers, fibrinogen, CRP) collected in the eCRF | hospitalization stay (up to 28 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID, Thrombosis, Venous Thromboembolism, Pulmonary Embolism, Deep Vein Thrombosis, Low Molecular Weight Heparin