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

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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

Tracking Information
First Submitted Date  ICMJE May 26, 2020
First Posted Date  ICMJE May 29, 2020
Last Update Posted Date May 29, 2020
Estimated Study Start Date  ICMJE June 2020
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
  • 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
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy
Official Title  ICMJE Randomised Controlled Trial Comparing High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy Not Requiring Invasive Mechanical Ventilation
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • COVID
  • Pneumonia, Viral
  • Coagulation Disorder
Intervention  ICMJE Drug: Enoxaparin
Low-Dose LMWH: enoxaparin 4000 IU daily; High dose LMWH: 70 IU/kg twice daily
Other Name: Inhixa®
Study Arms  ICMJE
  • Active Comparator: Low-Dose LMWH
    Enoxaparin 4000 IU daily
    Intervention: Drug: Enoxaparin
  • Experimental: High-Dose LMWH
    Enoxaparin 70 IU/kg twice daily
    Intervention: Drug: Enoxaparin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 27, 2020)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marco Marietta, MD 0594224640 ext +39 marco.marietta@unimore.it
Contact: Pasquale Mighali 0594225868 ext +39 mighali.pasquale@aou.mo.it
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04408235
Other Study ID Numbers  ICMJE EudraCT N°: 2020-001972-13
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Marco Marietta, Azienda Ospedaliero-Universitaria di Modena
Study Sponsor  ICMJE Azienda Ospedaliero-Universitaria di Modena
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marco Marietta, MD Azienda Ospedaliero-Universitaria di Modena
PRS Account Azienda Ospedaliero-Universitaria di Modena
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP