FREEDOM COVID-19 Anticoagulation Strategy

Study Overview
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Brief Summary
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Coronavirus Disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to unprecedented morbidity and mortality in the modern era. To date, nearly 13 million people have contracted COVID-19, leading to more than 550,000 deaths worldwide. As the number of affected individuals continues to climb, effective strategies for treatment and prevention of the disease are of paramount importance. SARS-CoV-2 is understood to directly invade cells via the human angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed predominantly in the lungs but also throughout the cardiovascular system. Thus, while acute respiratory distress syndrome remains a feared complication, new thromboembolic disease has emerged as a common and potentially catastrophic manifestation of COVID-19.

Detailed Description
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This is a Prospective, multi-center, open label, randomized controlled comparative safety and effectiveness trial with objectives: 1. To determine the effectiveness of enoxaparin and apixaban in patients hospitalized (but not yet intubated) with confirmed COVID-19 and 2. To determine the safety of enoxaparin and apixaban in patients hospitalized (but not yet intubated) with confirmed COVID-19. Observational analyses have suggested potential benefit for in-hospital use of anticoagulation. Yet, due to a lack of rigorous evidence for optimal anticoagulation regimens, practice patterns among hospitalized patients with COVID-19 vary significantly. Specifically, the choice of anticoagulant, dosing, and duration of treatment are not well understood. A preliminary analysis of approximately 2700 patients admitted to the Mount Sinai Health System (MSHS) in New York, demonstrated an association between in-hospital administration of therapeutic Anticoagulation (AC) and improved survival compared to no or prophylactic dose AC. A subsequent analysis under review of a larger 4400 patient cohort with longer follow up demonstrated similar associations with reduction in the risk of mortality and risk of intubation. Further analyses suggest more pronounced benefit with therapeutic as opposed to prophylactic doses. Bleeding rates were generally low overall, but higher among patients on therapeutic anticoagulation. Finally, though exploratory in nature, a potential signal for benefit was observed for patients on novel oral anticoagulant therapy (primarily apixaban) at therapeutic doses compared to low molecular weight heparin. Ultimately, randomized controlled trials are needed to elucidate the optimal anticoagulation regimen to improve outcomes in patients hospitalized with COVID-19.

Official Title
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FREEDOM COVID Anticoagulation Strategy Randomized Trial

Conditions
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COVID-19, SARS-CoV-2

Intervention / Treatment
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* Drug: Enoxaparin
* Drug: Apixaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalization within the prior 24 hours for either confirmed (based on PCR or antigen positive test for SARS-CoV-2) or suspected COVID-19 based on 3 criteria (all 3 must be present for suspected cases): Fever >38 degrees Celsius O2 saturation ≤94 Abnormal laboratory marker (at least 1): i. d-dimer ≥1.0 μg /mL ii. CRP >2 mg/L iii. Ferritin >300 μg /L iv. Lymphopenia <1500 cells /m3 Patient or legal guardian provides written informed consent Exclusion Criteria: Age <18 years Mechanical ventilation on admission or high likelihood for the need for invasive mechanical ventilation within 24 hours of admission Anticipated duration of hospital stay <72 hours Treatment with therapeutic dose UFH or LMWH, vitamin K antagonists, or NOACs within seven days Active bleeding Risk factors for bleeding, including: intracranial surgery or stroke within 3 months history of intracerebral arteriovenous malformation cerebral aneurysm or mass lesions of the central nervous system intracranial malignancy history of intracranial bleeding history of bleeding diatheses (e.g., hemophilia) history of gastrointestinal bleeding within previous 3 months thrombolysis within the previous 7 days presence of an epidural or spinal catheter recent major surgery <14 days uncontrolled hypertension (sBP > 200 mmHg or dBP > 120 mmHg) other physician-perceived contraindications to anticoagulation Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur) current treatment with antithrombotics or antiplatelet agents including but not limited to ticagrelor, prasugrel, and aspirin> 100mg, or non-steroidal anti-inflammatory drugs (e.g. ibuprofen, naproxen, etc.) due to increased risk of bleeding, unless such agents can be permanently discontinued (aspirin <= 100mg and clopidogrel <=75mg is permitted) Acute or subacute bacterial endocarditis History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity Patients with non-COVID-19 related clinical condition for which life expectancy is <6 months Pregnancy (women of childbearing potential are required to have a negative pregnancy test prior to enrollment) Active enrollment in other trials related to anticoagulation Patients has end stage kidney disease (ESKD) on chronic dialysis Patient is a member of a vulnerable population: In the judgment of the investigator the patient is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy. This may include: Individuals with mental disability, persons in nursing homes, children, impoverished persons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations also may include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the Sponsor, members of the armed forces, and persons kept in detention.

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: Study participants will be randomized in a 1:1:1 fashion to 1 of 3 arms: Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min) Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min) Apixaban (5 mg Q12h; 2.5 mg Q12h for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prophylactic Enoxaparin<br>Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min) | Drug: Enoxaparin<br>* Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min) Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min)<br>|
| Active Comparator: Full Dose Enoxaparin<br>Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min) | Drug: Enoxaparin<br>* Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min) Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min)<br>|
| Experimental: Apixaban<br>Apixaban (5 mg Q12h; 2.5 mg Q12h for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL) | Drug: Apixaban<br>* (5 mg Q12h; 2.5 mg Q12h for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first event | The time to first event rate within 30 days of randomization of the composite of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism (including pulmonary emboli) confirmed by imaging or requiring surgical intervention OR ischemic stroke confirmed by imaging. | 30 days | 
| Number of in-hospital rate of BARC 3 or 5 | Number of in-hospital rate of BARC 3 or 5 bleeding (binary). BARC Type 3: a. Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding b. Overt bleeding plus hemoglobin drop < 5 g/dL (provided hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision. BARC Type 5: Probable fatal bleeding Definite fatal bleeding (overt or autopsy or imaging confirmation) | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Myocardial infarction | Myocardial infarction (according to the 4th universal definition, types 1,2, and 3) | 30 days after randomization | 
| Number of participants with Myocardial infarction | Myocardial infarction (according to the 4th universal definition, types 1,2, and 3) | 90 days after randomization | 
| Number of participants with Deep Vein Thrombosis | Deep vein thrombosis with confirmation on imaging | 30 days after randomization | 
| Number of participants with Deep Vein Thrombosis | Deep vein thrombosis with confirmation on imaging | 90 days after randomization | 
| Number of participants requiring Ventilation | Intubation and mechanical ventilation | 30 after randomization | 
| Number of participants requiring Ventilation | Intubation and mechanical ventilation | 90 days after randomization | 
| Number of All Death | All-cause death | 30 days after randomization | 
| Number of All Death | All-cause death | 90 days after randomization | 
| Cause of Death | Cause of Death | 30 days after randomization | 
| Cause of Death | Cause of Death | 90 days after randomization | 
| Number of participants with Stroke | Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic) | 30 days after randomization | 
| Number of participants with Stroke | Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic) | 90 days after randomization | 
| Number of participants with Pulmonary Emboli | Pulmonary emboli confirmed by imaging or autopsy | 30 days after randomization | 
| Number of participants with Pulmonary Emboli | Pulmonary emboli confirmed by imaging or autopsy | 90 days after randomization | 
| Number of participants with Systemic Thromboembolism | Systemic thromboembolism confirmed by imaging or requiring surgical intervention | 30 days after randomization | 
| Number of participants with Systemic Thromboembolism | Systemic thromboembolism confirmed by imaging or requiring surgical intervention | 90 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomization, Hospitalization, PCR or Antigen Positive Test, Abnormal Laboratory Maker, Anticoagulation, Apixaban