Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial

Study Overview
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Brief Summary
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This is a multicenter, open-label, 2x2 factorial, randomized-controlled trial in critically-ill patients with novel coronavirus disease 2019 (COVID-19) evaluating the efficacy and safety of full-dose vs. standard prophylactic dose anticoagulation and of antiplatelet vs. no antiplatelet therapy for prevention of venous and arterial thrombotic events.

Official Title
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A Multicenter, Randomized-Controlled Trial to Evaluate the Efficacy and Safety of Antithrombotic Therapy for Prevention of Arterial and Venous Thrombotic Complications in Critically-Ill COVID-19 Patients

Conditions
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COVID-19, Venous Thromboembolism, Arterial Thrombosis

Intervention / Treatment
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* Drug: Unfractionated Heparin IV
* Drug: Enoxaparin 1 mg/kg
* Drug: Clopidogrel
* Drug: Unfractionated heparin SC
* Drug: Enoxaparin 40 Mg/0.4 mL Injectable Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years (male or female) Acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Currently admitted to an intensive care unit (ICU) Key Exclusion Criteria: Ongoing (>48 hours) or planned full-dose (therapeutic) anticoagulation for any indication Ongoing or planned treatment with dual antiplatelet therapy Contraindication to antithrombotic therapy or high risk of bleeding due to conditions including, but not limited to, any of the following: History of intracranial hemorrhage, known CNS tumor or CNS vascular abnormality Active or recent major bleeding within the past 30 days with untreated source Platelet count <70,000 or known functional platelet disorder Fibrinogen <200 mg/dL International normalized ratio (INR) >1.9 History of heparin-induced thrombocytopenia Ischemic stroke within the past 2 weeks Patients who meet the following criterion are excluded from the second randomization (antiplatelet therapy vs. no antiplatelet therapy): 1. Ongoing or planned antiplatelet therapy, including aspirin monotherapy

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Full-dose anticoagulation + antiplatelet therapy<br>• Full-dose anticoagulation: Unfractionated heparin IV continuous targeting aPTT of 1.5-2.5X control, or Enoxaparin 1 mg/kg SC Q12h • Anti-platelet therapy: Clopidogrel 300 mg PO x1, followed by clopidogrel 75 mg PO QD | Drug: Unfractionated Heparin IV<br>* Unfractionated heparin IV targeting an aPTT of 1.5-2.5 times the control<br>Drug: Enoxaparin 1 mg/kg<br>* Enoxaparin 1 mg/kg SC Q12h<br>Drug: Clopidogrel<br>* Clopidogrel 300 mg PO x1, then clopidogrel 75 mg PO QD<br>|
| Experimental: Full-dose anticoagulation + no antiplatelet therapy<br>• Full-dose anticoagulation: Unfractionated heparin IV continuous targeting aPTT of 1.5-2.5X control, or Enoxaparin 1 mg/kg SC Q12h | Drug: Unfractionated Heparin IV<br>* Unfractionated heparin IV targeting an aPTT of 1.5-2.5 times the control<br>Drug: Enoxaparin 1 mg/kg<br>* Enoxaparin 1 mg/kg SC Q12h<br>|
| Experimental: Prophylactic anticoagulation + antiplatelet therapy<br>• Standard prophylactic anticoagulation: Enoxaparin 40 mg SC QD or Unfractionated heparin 5,000 IU SC TID • Antiplatelet therapy: Clopidogrel 300 mg PO x1, followed by clopidogrel 75 mg PO QD | Drug: Clopidogrel<br>* Clopidogrel 300 mg PO x1, then clopidogrel 75 mg PO QD<br>Drug: Unfractionated heparin SC<br>* Unfractionated heparin 5,000 IU SC TID<br>Drug: Enoxaparin 40 Mg/0.4 mL Injectable Solution<br>* Enoxaparin 40 mg SC QD<br>|
| Active Comparator: Prophylactic anticoagulation + no antiplatelet therapy<br>• Standard prophylactic anticoagulation: Enoxaparin 40 mg SC QD or Unfractionated heparin 5,000 IU SC TID | Drug: Unfractionated heparin SC<br>* Unfractionated heparin 5,000 IU SC TID<br>Drug: Enoxaparin 40 Mg/0.4 mL Injectable Solution<br>* Enoxaparin 40 mg SC QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint: Venous or arterial thrombotic events | Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT | 28 days or until hospital discharge, whichever earlier | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key secondary endpoint: Clinically evident venous or arterial thrombotic events | Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia | 28 days or until hospital discharge, whichever earlier |