Clinical trial NCT04646655: Enoxaparin at Prophylactic or Therapeutic Doses in COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Thrombosis
Keywords: COVID.19
Thrombosis
Enoxaparin
Outcome
Respiratory failure
D-dimer
Venous compression ultrasound
Lead sponsor: ASST Fatebenefratelli Sacco
Sponsor class: OTHER
Collaborators: name: Massimo Arquati
name: Riccardo Colombo
name: Umberto Russo
name: Manuela Nebuloni
name: Spinello Antinori
First posted: 2020-11-30
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mortality rate
timeFrame: 30 days from enrollment
measure: Progression of respiratory failure
timeFrame: 30 days from enrollment
measure: Progression of respiratory failure
timeFrame: 30 days from enrollment
measure: Progression of respiratory failure
timeFrame: 30 days from enrollment
measure: Number of major bleeding episodes
timeFrame: up to 6 months from randomization
Secondary outcomes:
measure: Respiratory function improvement
timeFrame: at 72 hours
measure: Respiratory function improvement
timeFrame: 1 week from randomization
measure: Number of major cardiovascular events
timeFrame: 6 months from randomization
measure: Deep Vein Thrombosis
timeFrame: 6 months from randomization
Other outcomes:
Locations:
city: Milan
country: Italy
facility: ASST Fatebenefratelli Sacco
Study officials:
affiliation: ASST Fatebenefratelli Sacco
name: Maddalena A Wu, M.D.
role: PRINCIPAL_INVESTIGATOR
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