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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04362085
Recruitment Status : Completed
First Posted : April 24, 2020
Last Update Posted : October 26, 2021
Sponsor:
Collaborators:
University of Vermont Medical Center
University of Sao Paulo
Hôpital Charles Lemoyne
William Osler Health System
MOUNT SINAI HOSPITAL
Trillium Health Partners
St. Joseph's Health Centre
The Ottawa Hospital
Hopital du Sacre-Coeur de Montreal
Michael Garron Hospital
University of Alberta
Southlake Regional Health Centre
Hospital Maisonneuve-Rosemont
Queen Elizabeth II Health Sciences Centre
Foothills Medical Centre
Rockyview General Hospital
Peter Lougheed Centre
Mater Misericordiae University Hospital
King Saud University Medical City
King Fahad Medical City
King Faisal Specialist Hospital
Versiti
Barnes-Jewish Hospital
Al Ain Hospital
Information provided by (Responsible Party):
Unity Health Toronto

Tracking Information
First Submitted Date  ICMJE April 20, 2020
First Posted Date  ICMJE April 24, 2020
Last Update Posted Date October 26, 2021
Actual Study Start Date  ICMJE May 11, 2020
Actual Primary Completion Date May 10, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2021)
  • All-cause death [ Time Frame: Up to 28 days ]
    All-cause death
  • Composite outcome of ICU admission or all-cause death [ Time Frame: Up to 28 days ]
    Composite outcome of ICU admission or all-cause death
  • Composite outcome of mechanical ventilation or all-cause death [ Time Frame: Up to 28 days ]
    Composite outcome of mechanical ventilation or all-cause death
  • Major bleeding [ Time Frame: Up to 28 days ]
    Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
  • Red blood cell transfusion [ Time Frame: Up to 28 days ]
    Red Blood Cell transfusion (greater than or equal to 1 unit)
  • Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate [ Time Frame: Up to 28 days ]
    Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
  • Renal replacement therapy [ Time Frame: Up to 28 days ]
    Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis
  • Hospital-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Hospital-free days alive up to day 28
  • ICU-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    ICU-free days alive up to day 28
  • Ventilator-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Ventilator-free days alive up to day 28
  • Organ support-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Organ support-free days alive up to day 28
  • Venous thromboembolism [ Time Frame: Up to 28 days ]
    Venous thromboembolism
  • Arterial thromboembolism [ Time Frame: Up to 28 days ]
    Arterial thromboembolism
  • Heparin induced thrombocytopenia [ Time Frame: Up to 28 days ]
    Heparin induced thrombocytopenia
  • Changes in D-dimer up to day 3 [ Time Frame: Up to day 3 ]
    D-dimer
Original Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
  • All-cause death [ Time Frame: Up to 28 days ]
    All-cause death
  • Composite outcome of ICU admission or all-cause death [ Time Frame: Up to 28 days ]
    Composite outcome of ICU admission or all-cause death
  • Major bleeding [ Time Frame: Up to 28 days ]
    Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
  • 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)
  • 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
  • Number of hospital-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Hospital-free days alive up to day 28
  • Number of ICU-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    ICU-free days alive up to day 28
  • Number of ventilator-free days alive up to day 28 [ Time Frame: Up to 28 days ]
    Ventilator-free days alive up to day 28
  • Number of participants with venous thromboembolism [ Time Frame: Up to 28 days ]
    Venous thromboembolism
  • Number of participants with arterial thromboembolism [ Time Frame: Up to 28 days ]
    Arterial thromboembolism
  • Number of participants with heparin induced thrombocytopenia [ Time Frame: Up to 28 days ]
    Heparin induced thrombocytopenia
  • Changes in D-dimer up to day 3 [ Time Frame: Up to day 3 ]
    D-dimer
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care
Official Title  ICMJE 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)
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 admitted for COVID-19 with an elevated D-dimer.
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 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 between study arms up to day 28 include:

  1. All-cause death
  2. Composite outcome of ICU admission or all-cause death
  3. Composite outcome of mechanical ventilation or all-cause death
  4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
  5. Number of participants who received red blood cell transfusion (≥1 unit)
  6. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
  7. Renal replacement therapy;
  8. Number of hospital-free days alive
  9. Number of ICU-free days alive
  10. Number of ventilator-free days alive
  11. Number of organ support-free days alive
  12. Number of participants with venous thromboembolism
  13. Number of participants with arterial thromboembolism
  14. Number of participants with heparin induced thrombocytopenia
  15. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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, 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
Condition  ICMJE COVID-19
Intervention  ICMJE 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, Enoxaparin or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Therapeutic Anticoagulation
  • No Intervention: Standard Care
    Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.
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 Completed
Actual Enrollment  ICMJE
 (submitted: May 12, 2021)
465
Original Estimated Enrollment  ICMJE
 (submitted: April 23, 2020)
462
Actual Study Completion Date  ICMJE October 14, 2021
Actual Primary Completion Date May 10, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.Positive test prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission;
  2. admitted to hospital for COVID-19;
  3. one D-dimer value above ULN (5 days (i.e. 120 hours) of hospital admission) and either: a) D-Dimer ≥2 times ULN; or b) D-dimer above ULN and oxygen saturation ≤ 93% on room air;
  4. ≥18 years of age;
  5. informed consent from the patient (or legally authorized substitute decision maker).

The exclusion criteria are:

  1. pregnancy;
  2. hemoglobin <80 g/L in the last 72 hours;
  3. platelet count <50 x 10^9/L in the last 72 hours;
  4. known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  5. known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  6. 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);
  7. 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);
  8. patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely;
  9. known bleeding within the last 30 days requiring emergency room presentation or hospitalization;
  10. known history of a bleeding disorder of an inherited or active acquired bleeding disorder;
  11. known history of heparin-induced thrombocytopenia;
  12. known allergy to UFH or LMWH;
  13. admitted to the intensive care unit at the time of screening;
  14. 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).
  15. imminent death according to the judgement of the most responsible physician
  16. enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04362085
Other Study ID Numbers  ICMJE RAPID COVID-COAG
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Unity Health Toronto
Study Sponsor  ICMJE Unity Health Toronto
Collaborators  ICMJE
  • University of Vermont Medical Center
  • University of Sao Paulo
  • Hôpital Charles Lemoyne
  • William Osler Health System
  • MOUNT SINAI HOSPITAL
  • Trillium Health Partners
  • St. Joseph's Health Centre
  • The Ottawa Hospital
  • Hopital du Sacre-Coeur de Montreal
  • Michael Garron Hospital
  • University of Alberta
  • Southlake Regional Health Centre
  • Hospital Maisonneuve-Rosemont
  • Queen Elizabeth II Health Sciences Centre
  • Foothills Medical Centre
  • Rockyview General Hospital
  • Peter Lougheed Centre
  • Mater Misericordiae University Hospital
  • King Saud University Medical City
  • King Fahad Medical City
  • King Faisal Specialist Hospital
  • Versiti
  • Barnes-Jewish Hospital
  • Al Ain Hospital
Investigators  ICMJE
Principal Investigator: Michelle Sholzberg, MD, FRCPC Unity Health Toronto
Principal Investigator: Peter Jüni, MD, FESC Unity Health Toronto
Principal Investigator: Mary Cushman, MD University of Vermont Medical Center, Vermont
PRS Account Unity Health Toronto
Verification Date October 2021

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