Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy (COVID-19 HD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04408235
Recruitment Status : Not yet recruiting
First Posted : May 29, 2020
Last Update Posted : May 29, 2020
Sponsor:
Information provided by (Responsible Party):
Marco Marietta, Azienda Ospedaliero-Universitaria di Modena

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

Condition or disease Intervention/treatment Phase
COVID Pneumonia, Viral Coagulation Disorder Drug: Enoxaparin Phase 3

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a multicentre, randomised controlled, open label, investigator sponsored, two arms study.
Masking: Single (Investigator)
Masking Description: Randomisation will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75/≥75 years); 3) BMI (<30/≥30); 4) Co-morbidities (0-1/>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment.
Primary Purpose: Treatment
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
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Low-Dose LMWH
Enoxaparin 4000 IU daily
Drug: Enoxaparin
Low-Dose LMWH: enoxaparin 4000 IU daily; High dose LMWH: 70 IU/kg twice daily
Other Name: Inhixa®

Experimental: High-Dose LMWH
Enoxaparin 70 IU/kg twice daily
Drug: Enoxaparin
Low-Dose LMWH: enoxaparin 4000 IU daily; High dose LMWH: 70 IU/kg twice daily
Other Name: Inhixa®




Primary Outcome Measures :
  1. Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: [ Time Frame: through study completion, up to 30 days ]
    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


Secondary Outcome Measures :
  1. Any of the following events occurring within the hospital stay [ Time Frame: through study completion, up to 30 days ]
    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
    6. Improvement of laboratory parameters of disease severity, including:

      • D-dimer level
      • Plasma fibrinogen levels
      • Mean Platelet Volume
      • Lymphocyte/Neutrophil ratio
      • IL-6 plasma levels

  2. Mortality at 30 days [ Time Frame: 30 days ]
    Information about patients' status will be sought in those who are discharged before 30 days on Day 30 from randomisation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04408235


Contacts
Layout table for location contacts
Contact: Marco Marietta, MD 0594224640 ext +39 marco.marietta@unimore.it
Contact: Pasquale Mighali 0594225868 ext +39 mighali.pasquale@aou.mo.it

Locations
Layout table for location information
Italy
Azienda Ospedaliero-Universitaria
Modena, Italy, 41124
Contact: Pasquale Mighali    0594225868 ext +39    mighali.pasquale@policlinico.mo.it   
Principal Investigator: Marco Marietta, MD         
Sponsors and Collaborators
Azienda Ospedaliero-Universitaria di Modena
Investigators
Layout table for investigator information
Principal Investigator: Marco Marietta, MD Azienda Ospedaliero-Universitaria di Modena
Publications:

Layout table for additonal information
Responsible Party: Marco Marietta, Head, Hemostasis and Thrombosis Unit, Azienda Ospedaliero-Universitaria di Modena
ClinicalTrials.gov Identifier: NCT04408235    
Other Study ID Numbers: EudraCT N°: 2020-001972-13
First Posted: May 29, 2020    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Marco Marietta, Azienda Ospedaliero-Universitaria di Modena:
COVID-19
PNEUMONIA
COAGULOPATHY
LOW-MOLECULAR WEIGHT HEPARIN
ENOXAPARIN
Additional relevant MeSH terms:
Layout table for MeSH terms
Pneumonia, Viral
Pneumonia
Hemostatic Disorders
Blood Coagulation Disorders
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders
Virus Diseases
Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action