Covid-19 Associated Coagulopathy

Study Overview
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Brief Summary
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This prospective, randomized, open-label, multi-center interventional study is designed to compare the safety and efficacy of two LMWH dosing protocols in patients admitted to the University of Iowa Hospitals with COVID-19 who meet the modified ISTH Overt DIC criteria score ≥3. Patients will be randomized to standard prophylactic dose LMWH (standard of care arm) or intermediate-dose LMWH (intervention arm).

Detailed Description
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Potentially eligible patients will be identified by a healthcare professional per institutional policy on privacy. The healthcare professional will assess the eligibility of the patient by performing a chart review which will include laboratory results and weight as measured on admission to the hospital. After obtaining verbal consent from the patient to be contacted for the study, a member of the research staff will approach the patient to be part of the study. The research staff will obtain informed consent from the patient/LAR before collecting any data and performing any procedures. 5.2 Trial interventions As standard of care, hospitalized patients with confirmed COVID-19 will be monitored for coagulopathy. Daily blood tests for platelet count, prothrombin time, D-Dimer, and fibrinogen and weekly thromboelastography will be obtained, and a daily Modified ISTH Overt DIC score will be calculated (Exhibit 1). Only patients meeting all inclusion and exclusion criteria will be asked to participate in the trial. Patients will be randomized to one of two arms: Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30 kg/m2; 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2). Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI <30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30 kg/m2), with doses rounded up to the nearest dose syringe in hospitalized patients with laboratory confirmed SARS CoV-2 infection. 5.3 Dose Modifications Enoxaparin will be held if platelets decrease to <25,000/mm3. Enoxaparin will resume once platelets increase to ≥25,000/ mm3. Enoxaparin will be held if fibrinogen is <50 mg/dL. Enoxaparin will resume once fibrinogen increases to ≥50 mg/dL. Enoxaparin will be held if estimated Creatinine clearance < 15 ml/min calculated by the modified Cockcroft and Gault formula and resumed once the Creatinine Clearance is ≥15 ml/min. Enoxaparin will be held if there is a clinical suspicion for heparin induced thrombocytopenia. Enoxaparin dose will be reduced by 25% if Creatinine Clearance ≥15 and <30 ml/min calculated by the modified Cockcroft and Gault formula and increased once the estimated Creatinine Clearance is ≥30 ml/min in both the arms. All participating patients will continue the assigned doses of enoxaparin until hospital discharge or until a clinical event occurs requiring either discontinuation of anticoagulation therapy or full therapeutic dose anticoagulation therapy.

Official Title
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COVID-19-associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults With COVID-19

Conditions
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COVID 19 Associated Coagulopathy

Intervention / Treatment
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* Drug: Intermediate dose thromboprophylaxis
* Drug: Standard of Care thromboprophylaxis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Laboratory confirmed SARS-CoV-2 infection Age ≥18 years Requires hospital admission for further clinical management Modified ISTH Overt DIC score ≥ 3 Exclusion Criteria: Indication for full therapeutic-dose anticoagulation Acute venous thromboembolism (deep vein thrombosis or pulmonary embolism) within prior 3 months Acute cardiovascular event within prior 3 months Acute stroke (ischemic or hemorrhagic) within prior 3 months Active major bleeding Severe thrombocytopenia (<25,000/mm3) Increased risk of bleeding, as assessed by the investigator Acute or chronic renal insufficiency with Creatinine Clearance < 30 ml/min calculated by the modified Cockcroft and Gault formula Weight < 40 kg Known allergies to ingredients contained in enoxaparin, allergy to heparin products or history of heparin induced thrombocytopenia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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 is a multi-center, randomized, open-label study comparing standard prophylactic dose enoxaparin (40 mg SC daily or 30 or 40 mg SC twice daily if BMI ≥30kg/m2; standard of care arm) versus intermediate-dose enoxaparin (1 mg/kg SC daily or 0.5 mg/kg SC twice daily if BMI≥30kg/m2; intervention arm) in hospitalized patients with laboratory-confirmed SARS-CoV-2 infection.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care<br>1) Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30kg/m2). | Drug: Standard of Care thromboprophylaxis<br>* Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).<br>|
| Other: Interventional<br>2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2). | Drug: Intermediate dose thromboprophylaxis<br>* 2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).<br>* Other names: intermediate dose Enoxaparin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All-cause mortality | 30 Days post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Acute Kidney Injury | Defined as an estimated creatinine clearance <30 mL/min | 30 days post intervention | 
| Number of Participants With Arterial Thrombosis | Risk of ischemic stroke, myocardial infarction and/or limb ischemia | 30 Days post intervention | 
| Number of Participants With Venous Thrombosis | Those at risk of symptomatic venous thromboembolism, which is a blood clot in a vein. | 30 Days post intervention | 
| Number of Participants With Major Bleeding | Those at risk of ISTH defined major bleeding, such as fatal bleeding, or bleeding into a critical area or organ. | 30 Days post intervention | 
| Number of Participants With Minor Bleeding | Defined as a bleeding event that did not meet ISTH criteria for major bleeding. | 30 Days post intervention |