A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to (SARS-CoV-2) COVID-19 Pandemic

Study Overview
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Brief Summary
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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
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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: All-cause death Composite outcome of ICU admission or all-cause death Composite outcome of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation Number of participants who received red blood cell transfusion (≥1 unit) Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate Renal replacement therapy; Number of hospital-free days alive Number of ICU-free days alive Number of ventilator-free days alive Number of organ support-free days alive Number of participants with venous thromboembolism Number of participants with arterial thromboembolism Number of participants with heparin induced thrombocytopenia 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.

Official Title
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Utilização da Enoxaparina em Dose Anticoagulante em Pacientes Hospitalizados Com síndrome respiratória Aguda Grave Por COVID-19

Conditions
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Anticoagulants and Bleeding Disorders, COVID, Coronavirus Infection, Severe Acute Respiratory Syndrome, Thromboembolism, Venous

Intervention / Treatment
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* Drug: Therapeutic anticoagulation


Participation Criteria
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Eligibility Criteria
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The inclusion criteria are: 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; admitted to hospital for COVID-19; 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; ≥18 years of age; informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin <80 g/L in the last 72 hours; platelet count <50 x 10^9/L in the last 72 hours; known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 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); 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); patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; 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). imminent death according to the judgement of the most responsible physician enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic anticoagulation<br>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<br>* 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.<br>|
| No Intervention: Standard care<br>Administration 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 the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause death | All-cause death | Up to 28 days | 
| Composite outcome of ICU admission or all-cause death | Composite outcome of ICU admission or all-cause death | Up to 28 days | 
| Composite outcome of mechanical ventilation or all-cause death | Composite outcome of mechanical ventilation or all-cause death | Up to 28 days | 
| Major bleeding | Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation | Up to 28 days | 
| Red blood cell transfusion | Red Blood Cell transfusion (greater than or equal to 1 unit) | Up to 28 days | 
| 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 | Up to 28 days | 
| Renal replacement therapy | Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis | Up to 28 days | 
| Hospital-free days alive up to day 28 | Hospital-free days alive up to day 28 | Up to 28 days | 
| ICU-free days alive up to day 28 | ICU-free days alive up to day 28 | Up to 28 days | 
| Ventilator-free days alive up to day 28 | Ventilator-free days alive up to day 28 | Up to 28 days | 
| Organ support-free days alive up to day 28 | Organ support-free days alive up to day 28 | Up to 28 days | 
| Venous thromboembolism | Venous thromboembolism | Up to 28 days | 
| Arterial thromboembolism | Arterial thromboembolism | Up to 28 days | 
| Heparin induced thrombocytopenia | Heparin induced thrombocytopenia | Up to 28 days | 
| Changes in D-dimer up to day 3 | D-dimer | Up to day 3 |