FREEDOM COVID-19 Anticoagulation Strategy (FREEDOM COVID)

FREEDOM COVID Anticoagulation Strategy Randomized Trial

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV-2
• Intervention / Treatment: Drug: Enoxaparin; Drug: Apixaban

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.

• Study Type: Interventional
• Enrollment (Actual): 3460
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil
    • Instituto do Coração - InCor
  • São Paulo, Brazil
    • Instituto Prevent Senior - IPS
• Colombia
  • Barranquilla, Colombia
    • Clinica de la Costa
  • Bogotá, Colombia
    • Fundacion Cardioinfantil
  • Bogotá, Colombia
    • Clínica SHAIO
  • Bucaramanga, Colombia
    • Fundacion Oftalmologica De Santander - Foscal
  • Cali, Colombia
    • Centro Medico Imbanaco
  • Medellín, Colombia
    • CardioVid
• India
  • Jaipur, India
    • Eternal Heart Care Centre and Research Ins Pvt Ltd.
  • Jaipur, India
    • Jaipur National University
  • Jaipur, India
    • Sawai Mann Singh Hospital
  • Mumbai, India
    • Saifee Hospital
  • Mumbai, India
    • Jaslok Hospital & Research Center
  • Nagpur, India
    • Sengupta Hospital & Research Institute
  • Navi Mumbai, India
    • D Y Patil University School of Medicine & D Y Patil Hospital
• Mexico
  • Aguascalientes, Mexico
    • Hospital Cardiológica Aguascalientes
  • Mexico City, Mexico
    • Centro Médico Nacional 20 de Noviembre
  • Monterrey, Mexico
    • Christus Muguerza Hospital Alta Especialidad
  • Santiago de Querétaro, Mexico
    • Centro de Estudios Clínicos de Querétaro S.C.
  • Tijuana, Mexico
    • Centro Medico Hospital del Prado
• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Valentin Fuster
• Investigators: 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

Publications and helpful links

General Publications

• Farkouh ME, Stone GW, Lala A, Bagiella E, Moreno PR, Nadkarni GN, Ben-Yehuda O, Granada JF, Dressler O, Tinuoye EO, Granada C, Bustamante J, Peyra C, Godoy LC, Palacios IF, Fuster V. Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week. J Am Coll Cardiol. 2022 Mar 8;79(9):917-928. doi: 10.1016/j.jacc.2021.12.023.

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2020
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): March 16, 2023
• Last Update Submitted That Met QC Criteria: March 15, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Anticoagulation; Randomization; Apixaban; Hospitalization; PCR or Antigen Positive Test; Abnormal Laboratory Maker
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban; Enoxaparin
• Other Study ID Numbers: GCO 20-2115

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No