Enoxaparin at Prophylactic or Therapeutic Doses in COVID-19

Study Overview
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Brief Summary
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SINGLE CENTER PHASE III INTERVENTIONAL RANDOMIZED CONTROLLED TRIAL comparing efficacy and safety of enoxaparin at prophylactic dose (standard treatment) and enoxaparin at therapeutic dose (OFF-LABEL treatment) in 300 COVID-19 infected patients with moderate-severe respiratory failure (PaO2/FiO2<250) and/or increased D-dimer levels enrolled in different Units (Infectious disease, Internal Medicine, Emergency Medicine, Pneumology) of Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco (ASST-FBF-SACCO).

Detailed Description
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Patients with COVID-19 are at high risk of developing a venous thromboembolism (VTE) and it is essential that effective thromboprophylaxis with parenteral drugs (LMWH, UFH) is considered for all patients admitted to hospital especially in case of severe pneumonia. The aim of the study is the evaluation of efficacy and safety of enoxaparin at prophylactic dose (standard treatment) as compared to enoxaparin at therapeutic dose (OFF-LABEL treatment) in 300 COVID-19 infected patients with moderate-severe respiratory failure (PaO2/FiO2<250) and/or increased D-dimer levels. After the admission to different Units (Infectious disease, Internal Medicine, Emergency Medicine, Pneumology), enoxaparin at prophylactic dose (standard of care) will be prescribed to all patients. The randomization of the single patient will be made when the the inclusion criteria (PaO2/FiO2 <250 and/or D-dimer >2000 ng/) will be satisfied. Patients with increased bleeding risk will be excluded (exclusion criteria). Patients will be divided into two arms: arm A: enoxaparin at prophylactic dose (standard 4.000 IU; 6000 UI if body weight>100 kg) arm B: enoxaparin at therapeutic dose (70 U/Kg b.i.d. every 12 h) In both arms, enoxaparin treatment will be monitored clinically and with first and second line laboratory tests Venous compression ultrasound (CUS) will be performed at admission and after 7 days in case of a first negative exam and elevated D-Dimer levels, to rule out deep vein thrombosis. Enoxaparin at prophylactic dose (4000 IU) will be maintained in all patients for 4 weeks after discharge.

Official Title
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Enoxaparin at Prophylactic or Therapeutic Doses With Monitoring of Outcomes in Subjects Infected With COVID-19: a Pilot Study on 300 Cases Enrolled at ASST-FBF-Sacco

Conditions
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Covid19, Thrombosis

Intervention / Treatment
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* Drug: Enoxaparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COVID-19 related pneumonia with moderate-severe respiratory failure (PaO2/FiO2<250) and/or markedly increased D-dimer level (>2000 ng/mL) Signed informed consent Exclusion Criteria: age < 18 and > 80 yrs history of bleeding (peptic ulcer, esophageal varices, cerebral aneurysm, cancer at high risk of bleeding, cirrhosis, hemorrhagic stroke < 1 year) thrombocytopenia (<100 x109/L) anemia (Hb < 8 g/dl) coagulation abnormalities (PT e/o aPTT > 1.5; fibrinogen < 150 mg/dl) consumption coagulopathy (ISTH criteria) [15, 16] deep vein thrombosis or pulmonary embolism dual antiplatelet therapy ongoing anticoagulant therapy allergic reaction to LMWH previous heparin-induced thrombocytopenia major surgery < 1 month; neurosurgery <3 months; eye surgery <3 months pregnancy arterial hypertension (SBPS>160 mm Hg; DBP>100 mm Hg) renal failure (creatinine clearance 30 ml/min) ICU admission or endotracheal intubation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enoxaparin at prophylactic dose<br>Enoxaparin at prophylactic dose: standard 4.000 IU QD via subcutaneous injection (6000 IU if body weight>100 kg) | Drug: Enoxaparin<br>* subcutaneous injections<br>* Other names: Clexane;|
| Experimental: Enoxaparin at therapeutic dose<br>Enoxaparin at therapeutic dose : 70 U/Kg b.i.d. (every 12 h) In order to easily calculate the correct therapeutic dose of enoxaparin for each patient, a simplified categorization will be applied, as follows: weight < 65 Kg: 4.000 IU b.i.d. (every 12 h) weight ≥ 65 Kg: 6.000 IU b.i.d. (every 12 h) weight ≥ 100 Kg: 8.000 IU b.i.d. (every 12 h) The most appropriate dose will be evaluated in patients with creatinine clearance between 30 and 50 ml/min | Drug: Enoxaparin<br>* subcutaneous injections<br>* Other names: Clexane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate | Mortality registered during the time frame | 30 days from enrollment | 
| Progression of respiratory failure | Progression of respiratory failure defined as duration of continuous positive pressure ventilation (CPAP) | 30 days from enrollment | 
| Progression of respiratory failure | Progression of respiratory failure defined as percentage of patients admitted to ICU | 30 days from enrollment | 
| Progression of respiratory failure | Progression of respiratory failure defined as percentage of patients undergoing oro-tracheal intubation | 30 days from enrollment | 
| Number of major bleeding episodes | Major bleeding (ISTH criteria) and/or clinically relevant non-major bleeding | up to 6 months from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory function improvement | Amelioration of the respiratory function defined as a PaO2/FiO2 increase > 300 and / or respiratory rate (RR) < 20 breaths per min | at 72 hours | 
| Respiratory function improvement | Amelioration of the respiratory function defined as a PaO2/FiO2 increase > 300 and / or respiratory rate (RR) < 20 breaths per min | 1 week from randomization | 
| Number of major cardiovascular events | numbers of myocardial infarction and stroke within the time frame | 6 months from randomization | 
| Deep Vein Thrombosis | Numbers of Deep Vein Thrombosis at CUS examination within the time frame | 6 months from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID.19, Thrombosis, Enoxaparin, Outcome, Respiratory failure, D-dimer, Venous compression ultrasound