Clinical trial NCT04408235: High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy
Official title: Randomised Controlled Trial Comparing High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy Not Requiring Invasive Mechanical Ventilation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: COVID
Pneumonia, Viral
Coagulation Disorder
Keywords: COVID-19
PNEUMONIA
COAGULOPATHY
LOW-MOLECULAR WEIGHT HEPARIN
ENOXAPARIN
Lead sponsor: Azienda Ospedaliero-Universitaria di Modena
Sponsor class: OTHER
First posted: 2020-05-29
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a multicentre, randomised controlled, open label, investigator sponsored, two arms study.
Primary purpose: TREATMENT

Brief summary: Randomized, controlled study conducted in hospitalized patients with severe COViD-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation.

Aim of this study is to assess whether high doses of Low Molecular Weight Heparin (LMWH) (ie. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (ie, Enoxaparin 4000 IU once day) are:

1. More effective to prevent clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first, during hospital stay:

   1. Death
   2. Acute Myocardial Infarction \[AMI\]
   3. Objectively confirmed, symptomatic arterial or venous thromboembolism \[TE\]
   4. Need for either non-invasive - Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) - or invasive mechanical ventilation for patients who are in standard oxygen therapy by delivery interfaces at randomisation
   5. Need for invasive mechanical ventilation for patients who are in non-invasive mechanical ventilation at randomisation
2. Similar in terms of major bleeding risk during hospital stay

Detailed description: This is a multicentre, randomised controlled, open label, investigator sponsored, two arms study.

The study will involve 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Diseases Units, 1 Respiratory Diseases Unit.

Patients who satisfy all inclusion criteria and do not have any exclusion criteria and have signed written informed consent, will be randomly assigned to a Low-Dose LMWH group (Control Group) or High-Dose LMWH group (Intervention Group) in a 1:1 ratio.

Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 IU subcutaneously once day).

Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table.

The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group.

The treatments will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization).

Patients allocated to the two arms will maintain the doses of Enoxaparin, as stated in the protocol, until:

1. hospital discharge or
2. when at least one of the following events occurs:

   1. Acute Myocardial Infarction \[AMI\]
   2. Objectively confirmed, symptomatic arterial or venous thromboembolism \[TE\]
   3. Need for either non-invasive - Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) - or invasive mechanical ventilation for patients, who are in standard oxygen therapy by delivery interfaces at randomisation
   4. Need for invasive mechanical ventilation for patients, who are in non-invasive mechanical ventilation at randomisation
   5. Major bleeding
   6. Any adverse events and clinical condition requiring interruption of the scheduled intervention according to the judgement of the physician in charge
   7. Death

The decision about what type and dose of antithrombotic treatment to administer, after the interruption of assigned dose of Enoxaparin, will be left to clinical judgement of the physicians in charge.

Any information about the type and dose of antithrombotic treatments administered after the interruption of the assigned dose of Enoxaparin will be collected until the hospital discharge or death.

Each patient will be followed-up until hospital discharge. Information about the status (dead/alive) of patients who are discharged from hospital before 30 days will be sought on Day 30 from randomisation.

Eligibility criteria: Inclusion Criteria (all required):

* Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material)
* Severe pneumonia defined by the presence of at least one of the following criteria:

  1. Respiratory Rate ≥25 breaths /min
  2. Arterial oxygen saturation≤93% at rest on ambient air
  3. PaO2/FiO2 ≤300 mmHg
* Coagulopathy, defined by the presence of at least one of the following criteria:

  1. D-dimer \>4 times the upper level of normal reference range
  2. Sepsis-Induced Coagulopathy (SIC) score \>4
* No need for invasive mechanical ventilation

Exclusion Criteria:

* Invasive mechanical ventilation
* Thrombocytopenia (platelet count \< 80.000 mm3)
* Coagulopathy: INR \>1.5, aPTT ratio \> 1.4
* Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation \< 30 ml/min)
* Known hypersensitivity to enoxaparin
* History of heparin induced thrombocytopenia
* Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations)
* Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves).
* Concomitant double antiplatelet therapy
* Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed
* Pregnancy or breastfeeding or positive pregnancy test
* Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition)
* Lack or withdrawal of informed consent

Primary outcomes:
measure: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first:
timeFrame: through study completion, up to 30 days
Secondary outcomes:
measure: Any of the following events occurring within the hospital stay
timeFrame: through study completion, up to 30 days
measure: Mortality at 30 days
timeFrame: 30 days
Other outcomes:
Locations:
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria
Study officials:
affiliation: Azienda Ospedaliero-Universitaria di Modena
name: Marco Marietta, MD
role: PRINCIPAL_INVESTIGATOR
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