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Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care

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ClinicalTrials.gov Identifier: NCT04362085
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : May 15, 2020
Sponsor:
Collaborator:
University of Vermont Medical Center
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto

Brief Summary:
Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic multi-centre open-label randomized controlled trial to determine the effect of therapeutic anticoagulation compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer (≥2X upper limit of normal {ULN}).

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Therapeutic Anticoagulation Phase 3

Detailed Description:

2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation, with low molecular weight heparin or unfractionated heparin (high dose nomogram), compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer (≥2 times the ULN) on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Eligible participants will be randomized to one of two treatment regimens, receiving either therapeutic anticoagulation or standard care until discharged from hospital, death or day 28.

The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.

Key secondary outcomes include:

  1. All-cause death
  2. Composite outcome of ICU admission or all-cause death
  3. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
  4. Number of participants who received red blood cell transfusion
  5. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
  6. Number of hospital-free days alive up to day 28
  7. Number of ICU-free days alive up to day 28
  8. Number of ventilator-free days alive up to day 28
  9. Number of participants with venous thromboembolism
  10. Number of participants with arterial thromboembolism
  11. Number of participants with heparin induced thrombocytopenia
  12. Changes in D-dimer up to day 3

The treatment arm is therapeutic anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin, or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to the center-specific protocol. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. The standard care arm is the administration of LMWH, UFH or fondaparinux at thromboprophylactic doses in the absence of contraindication.

No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through standard of care) up to and including day 3 after randomization for all participants in both study arms. In those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance. All laboratory results will be collected from standard of care from admission to hospital discharge, death or 28 days, where available. An optional biobanking component will collect blood at baseline and 2 follow up time points.

This study will immediately impact the clinical care of patients with severe COVID-19 internationally, whether the findings are positive or negative, as COVID-19 coagulopathy is a highly prevalent complication of severe COVID-19 and may precede the respiratory manifestations that characterize it.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 462 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a 2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation on the composite outcome of ICU admission, invasive mechanical ventilation and/or death in hospitalized patients with COVID-19.
Masking: None (Open Label)
Masking Description: Blinding of participants, clinical research staff, and clinicians is not possible due to the nature of the intervention. However, the biostatisticians will be blinded at the data analysis phase.
Primary Purpose: Treatment
Official Title: Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG)
Actual Study Start Date : May 11, 2020
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Therapeutic Anticoagulation
Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement.
Drug: Therapeutic Anticoagulation
The choice of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) will be at the clinician's discretion. LMWH options include: Tinzaparin 175 U/kg once per day, Enoxaparin 1.5 mg/kg once per day or 1 mg/kg twice per day or Dalteparin 200 U/kg once per day or 100 U/kg twice per day. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.

No Intervention: Standard Care
In Canada and the US, administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.



Primary Outcome Measures :
  1. Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days. [ Time Frame: Up to 28 days ]
    Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.


Secondary Outcome Measures :
  1. All-cause death [ Time Frame: Up to 28 days ]
    All-cause death

  2. Composite outcome of ICU admission or all-cause death [ Time Frame: Up to 28 days ]
    Composite outcome of ICU admission or all-cause death

  3. Major bleeding [ Time Frame: Up to 28 days ]
    Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation

  4. Number of participants who received red blood cell transfusion [ Time Frame: Up to 28 days ]
    Red Blood Cell transfusion (greater than or equal to 1 unit)

  5. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate. [ Time Frame: Up to 28 days ]
    Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate

  6. Number of hospital-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Hospital-free days alive up to day 28

  7. Number of ICU-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    ICU-free days alive up to day 28

  8. Number of ventilator-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Ventilator-free days alive up to day 28

  9. Number of participants with venous thromboembolism [ Time Frame: Up to 28 days ]
    Venous thromboembolism

  10. Number of participants with arterial thromboembolism [ Time Frame: Up to 28 days ]
    Arterial thromboembolism

  11. Number of participants with heparin induced thrombocytopenia [ Time Frame: Up to 28 days ]
    Heparin induced thrombocytopenia

  12. Changes in D-dimer up to day 3 [ Time Frame: Up to day 3 ]
    D-dimer



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

The inclusion criteria are:

  1. Laboratory confirmed diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification;
  2. Admitted to hospital;
  3. One D-dimer value ≥2 times ULN (within 72 hours of hospital admission);
  4. ≥18 years of age;
  5. Informed consent from the patient (or legally authorized substitute decision maker).

The exclusion criteria are:

  1. pregnancy;
  2. body mass index <18.5 kg/m2 or ≥40kg/m2;
  3. hemoglobin <80 g/L in the last 72 hours;
  4. platelet count <50 x 109/L in the last 72 hours;
  5. known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  6. known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  7. patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration);
  8. patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban);
  9. patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely;
  10. known bleeding within the last 30 days requiring emergency room presentation or hospitalization;
  11. known history of a bleeding disorder of an inherited or active acquired bleeding disorder;
  12. known history of heparin-induced thrombocytopenia;
  13. known allergy to UFH or LMWH;
  14. admitted to the intensive care unit at the time of screening;
  15. treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion).

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): NCT04362085


Contacts
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Contact: Michelle Sholzberg, MD, FRCPC 416-864-5389 Michelle.Sholzberg@unityhealth.to

Locations
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Canada, Ontario
St. Michael's Hospital Recruiting
Toronto, Ontario, Canada
Contact: Michelle Sholzberg         
Sponsors and Collaborators
St. Michael's Hospital, Toronto
University of Vermont Medical Center
Investigators
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Principal Investigator: Michelle Sholzberg, MD, FRCPC St. Michael's Hospital, Toronto
Principal Investigator: Peter Jüni, MD, FESC St. Michael's Hospital, Toronto
Principal Investigator: Mary Cushman, MD University of Vermont Medical Center, Vermont
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Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT04362085    
Other Study ID Numbers: RAPID COVID-COAG
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Michael's Hospital, Toronto:
coagulopathy
anticoagulation
Additional relevant MeSH terms:
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Hemostatic Disorders
Blood Coagulation Disorders
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders