EMOS-COVID: Enoxaparin at Prophylactic or Therapeutic Doses in COVID-19

Sponsor

ASST Fatebenefratelli Sacco (Other)

Overall Status

Recruiting

CT.gov ID

NCT04646655

Collaborator

Massimo Arquati (Other), Riccardo Colombo (Other), Umberto Russo (Other), Manuela Nebuloni (Other), Spinello Antinori (Other)

300

Enrollment

Location

Arms

31.1

Anticipated Duration (Months)

9.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Covid19 Thrombosis	Drug: Enoxaparin	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 27, 2020

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Feb 28, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Enoxaparin at prophylactic dose Enoxaparin at prophylactic dose: standard 4.000 IU QD via subcutaneous injection (6000 IU if body weight>100 kg)	Drug: Enoxaparin subcutaneous injections Other Names: Clexane
Experimental: Enoxaparin at therapeutic dose 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 subcutaneous injections Other Names: Clexane

Arm

Intervention/Treatment

Active Comparator: Enoxaparin at prophylactic dose

Enoxaparin at prophylactic dose: standard 4.000 IU QD via subcutaneous injection (6000 IU if body weight>100 kg)

Drug: Enoxaparin

subcutaneous injections

Other Names:

Clexane

Experimental: Enoxaparin at therapeutic dose

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

subcutaneous injections

Other Names:

Clexane

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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