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FREEDOM COVID-19 Anticoagulation Strategy (FREEDOM COVID)

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ClinicalTrials.gov Identifier: NCT04512079
Recruitment Status : Recruiting
First Posted : August 13, 2020
Last Update Posted : February 11, 2021
Sponsor:
Information provided by (Responsible Party):
Valentin Fuster, Icahn School of Medicine at Mount Sinai

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
COVID-19 SARS-CoV-2 Drug: Enoxaparin Drug: Apixaban Phase 4

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Study participants will be randomized in a 1:1:1 fashion to 1 of 3 arms:

  1. Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min)
  2. Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min)
  3. 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)
Primary Purpose: Treatment
Official Title: FREEDOM COVID Anticoagulation Strategy Randomized Trial
Actual Study Start Date : September 8, 2020
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Prophylactic Enoxaparin
Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min)
Drug: Enoxaparin
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)

Active Comparator: Full Dose Enoxaparin
Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min)
Drug: Enoxaparin
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)

Experimental: Apixaban
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
(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)




Primary Outcome Measures :
  1. Time to first event [ Time Frame: 30 days ]
    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.

  2. Number of in-hospital rate of BARC 3 or 5 [ Time Frame: 30 days ]

    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:

    1. Probable fatal bleeding
    2. Definite fatal bleeding (overt or autopsy or imaging confirmation)


Secondary Outcome Measures :
  1. Number of participants with Myocardial infarction [ Time Frame: 30 days after randomization ]
    Myocardial infarction (according to the 4th universal definition, types 1,2, and 3)

  2. Number of participants with Myocardial infarction [ Time Frame: 90 days after randomization ]
    Myocardial infarction (according to the 4th universal definition, types 1,2, and 3)

  3. Number of participants with Deep Vein Thrombosis [ Time Frame: 30 days after randomization ]
    Deep vein thrombosis with confirmation on imaging

  4. Number of participants with Deep Vein Thrombosis [ Time Frame: 90 days after randomization ]
    Deep vein thrombosis with confirmation on imaging

  5. Number of participants requiring Ventilation [ Time Frame: 30 after randomization ]
    Intubation and mechanical ventilation

  6. Number of participants requiring Ventilation [ Time Frame: 90 days after randomization ]
    Intubation and mechanical ventilation

  7. Number of All Death [ Time Frame: 30 days after randomization ]
    All-cause death

  8. Number of All Death [ Time Frame: 90 days after randomization ]
    All-cause death

  9. Cause of Death [ Time Frame: 30 days after randomization ]
    Cause of Death

  10. Cause of Death [ Time Frame: 90 days after randomization ]
    Cause of Death

  11. Number of participants with Stroke [ Time Frame: 30 days after randomization ]
    Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic)

  12. Number of participants with Stroke [ Time Frame: 90 days after randomization ]
    Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic)

  13. Number of participants with Pulmonary Emboli [ Time Frame: 30 days after randomization ]
    Pulmonary emboli confirmed by imaging or autopsy

  14. Number of participants with Pulmonary Emboli [ Time Frame: 90 days after randomization ]
    Pulmonary emboli confirmed by imaging or autopsy

  15. Number of participants with Systemic Thromboembolism [ Time Frame: 30 days after randomization ]
    Systemic thromboembolism confirmed by imaging or requiring surgical intervention

  16. Number of participants with Systemic Thromboembolism [ Time Frame: 90 days after randomization ]
    Systemic thromboembolism confirmed by imaging or requiring surgical intervention



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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):

    1. Fever >38 degrees Celsius
    2. O2 saturation ≤94
    3. 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:

    1. intracranial surgery or stroke within 3 months
    2. history of intracerebral arteriovenous malformation
    3. cerebral aneurysm or mass lesions of the central nervous system
    4. intracranial malignancy
    5. history of intracranial bleeding
    6. history of bleeding diatheses (e.g., hemophilia)
    7. history of gastrointestinal bleeding within previous 3 months
    8. thrombolysis within the previous 7 days
    9. presence of an epidural or spinal catheter
    10. recent major surgery <14 days
    11. uncontrolled hypertension (sBP > 200 mmHg or dBP > 120 mmHg)
    12. other physician-perceived contraindications to anticoagulation
    13. Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds
    14. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)
    15. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04512079


Contacts
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Contact: Debra Fitzpatrick, MS 212-659-9151 debra.fitzpatrick@mssm.edu

Locations
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Sponsors and Collaborators
Valentin Fuster
Investigators
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Principal Investigator: Valentin Fuster, MD,PhD Icahn School of Medicine at Mount Sinai
Principal Investigator: Anu Lala, MD Icahn School of Medicine at Mount Sinai
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Responsible Party: Valentin Fuster, Principal Investigator, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT04512079    
Other Study ID Numbers: GCO 20-2115
First Posted: August 13, 2020    Key Record Dates
Last Update Posted: February 11, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
Supporting Materials: Study Protocol
Time Frame: Beginning 9 months and ending 36 months following article publication.
Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. The type of analysis that will be conducted is for individual participant data meta-analysis. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Valentin Fuster, Icahn School of Medicine at Mount Sinai:
Randomization
Hospitalization
PCR or Antigen Positive Test
Abnormal Laboratory Maker
Anticoagulation
Apixaban
Additional relevant MeSH terms:
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Enoxaparin
Apixaban
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors