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COVID-19Phase 3NCT04362085

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

A Phase 3 study testing Therapeutic Anticoagulation in people with COVID-19, run by Unity Health Toronto at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
COVID-19
What is being tested?
Therapeutic Anticoagulation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
465 participants
Where
1 siteCanada
Study dates
11 May 2020to 14 Oct 2021
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • St. Michael's Hospital

    Toronto, Ontario

Other trials in Canada

About this study

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)

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.

Read the 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.

Conditions
COVID-19
Being tested
Therapeutic Anticoagulation
Keywords
coagulopathy, anticoagulation
Medical subject headings
COVID-19, Hemostatic Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Therapeutic AnticoagulationDrug

    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 groups in NCT04362085
Study groupRoleWhat they receive
Therapeutic AnticoagulationExperimentalTherapeutic 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.
Receives: Drug: Therapeutic Anticoagulation
Standard CareNo interventionAdministration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days.

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

    Measured: Up to 28 days

Secondary outcomes (15)

  1. All-cause Death

    All-cause death

    Measured: Up to 28 days

  2. Composite Outcome of ICU Admission or All-cause Death

    Composite outcome of ICU admission or all-cause death

    Measured: Up to 28 days

  3. Composite Outcome of Mechanical Ventilation or All-cause Death

    Composite outcome of mechanical ventilation or all-cause death

    Measured: Up to 28 days

  4. Major Bleeding

    Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation

    Measured: Up to 28 days

  5. Red Blood Cell Transfusion

    Red Blood Cell transfusion (greater than or equal to 1 unit)

    Measured: Up to 28 days

  6. Transfusion of Platelets, Frozen Plasma, Prothrombin Complex Concentrate, Cryoprecipiate and/or Fibrinogen Concentrate

    Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate

    Measured: Up to 28 days

  7. Renal Replacement Therapy

    Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis

    Measured: Up to 28 days

  8. Hospital-free Days Alive up to Day 28

    Hospital-free days alive up to day 28

    Measured: Up to 28 days

  9. ICU-free Days Alive up to Day 28

    ICU-free days alive up to day 28

    Measured: Up to 28 days

  10. Ventilator-free Days Alive up to Day 28

    Ventilator-free days alive up to day 28

    Measured: Up to 28 days

  11. Organ Support-free Days Alive up to Day 28

    Organ support-free days alive up to day 28

    Measured: Up to 28 days

  12. Venous Thromboembolism

    Venous thromboembolism

    Measured: Up to 28 days

  13. Arterial Thromboembolism

    Arterial thromboembolism

    Measured: Up to 28 days

  14. Heparin Induced Thrombocytopenia

    Heparin induced thrombocytopenia

    Measured: Up to 28 days

  15. Changes in D-dimer

    Geometric mean ratio defined as ratio of geometric means of D-dimer ratios (D-dimer×ULN) of day 2 ±24 hours post-randomisation, adjusted for baseline geometric means of D-dimer ratios using analysis of covariance.

    Measured: Up to day 3

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Apr 2020
  2. Study start11 May 2020
  3. Primary completion10 May 2021
  4. Study completion14 Oct 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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)
Enrolment
465 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04362085
Sponsor's protocol ID
RAPID COVID-COAG
Status last verified
Aug 2024
First submitted
20 Apr 2020
Last updated
30 Jan 2025
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19: a rapid review. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.

    PubMed 35244208

  • Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Ainle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci LA, James PD, Lillicrap D, Carrier M, Beckett A, Colovos C, Jayakar J, Arsenault MP, Wu C, Doyon K, Andreou ER, Dounaevskaia V, Tseng EK, Lim G, Fralick M, Middeldorp S, Lee AYY, Zuo F, da Costa BR, Thorpe KE, Negri EM, Cushman M, Juni P; RAPID trial investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021 Oct 14;375:n2400. doi: 10.1136/bmj.n2400.

    PubMed 34649864

  • Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Ni Ainle F, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci L, James PD, Lillicrap D, Carrier M, Beckett A, Colovos C, Jayakar J, Arsenault MP, Wu C, Doyon K, Andreou ER, Dounaevskaia V, Tseng EK, Lim G, Fralick M, Middeldorp S, Lee AYY, Zuo F, da Costa BR, Thorpe KE, Negri EM, Cushman M, Juni P; RAPID Trial investigators. Heparin for Moderately Ill Patients with Covid-19. medRxiv [Preprint]. 2021 Jul 12:2021.07.08.21259351. doi: 10.1101/2021.07.08.21259351.

    PubMed 34268513

  • Sholzberg M, Tang GH, Negri E, Rahhal H, Kreuziger LB, Pompilio CE, James P, Fralick M, AlHamzah M, Alomran F, Tseng E, Lim G, Lillicrap D, Carrier M, Ainle FN, Beckett A, da Costa BR, Thorpe K, Middeldorp S, Lee A, Cushman M, Juni P. Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Mar 10;22(1):202. doi: 10.1186/s13063-021-05076-0.

    PubMed 33691765

  • Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.

    PubMed 33502773

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Therapeutic Anticoagulation in people with COVID-19, run by Unity Health Toronto at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days. (time frame: Up to 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04362085, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2025.

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