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

May 27, 2020 updated by: Marco Marietta, Azienda Ospedaliero-Universitaria di Modena

Randomised Controlled Trial Comparing High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy Not Requiring Invasive Mechanical Ventilation

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Modena, Italy, 41124
        • Azienda Ospedaliero-Universitaria
        • Contact:
        • Principal Investigator:
          • Marco Marietta, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • Inhixa®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
through study completion, up to 30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
through study completion, up to 30 days
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.
30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliero-Universitaria di Modena

Investigators

  • Principal Investigator: Marco Marietta, MD, Azienda Ospedaliero-Universitaria di Modena

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

June 1, 2020

Primary Completion (ANTICIPATED)

June 1, 2021

Study Completion (ANTICIPATED)

June 1, 2021

Study Registration Dates

First Submitted

May 26, 2020

First Submitted That Met QC Criteria

May 27, 2020

First Posted (ACTUAL)

May 29, 2020

Study Record Updates

Last Update Posted (ACTUAL)

May 29, 2020

Last Update Submitted That Met QC Criteria

May 27, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT N°: 2020-001972-13

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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