FREEDOM COVID-19 Anticoagulation Strategy

NCT ID: NCT04512079

Last Updated: 2023-03-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 3460 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-08
• Study Completion Date: 2022-12-30

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.

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.

Conditions

COVID-19; SARS-CoV-2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Prophylactic Enoxaparin

Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl \<30 mL/min)

Group Type: ACTIVE_COMPARATOR

Enoxaparin

Intervention Type: DRUG

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)

Full Dose Enoxaparin

Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl \<30 mL/min)

Group Type: ACTIVE_COMPARATOR

Enoxaparin

Intervention Type: DRUG

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

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)

Group Type: EXPERIMENTAL

Apixaban

Intervention Type: DRUG

(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)

Interventions

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)

Intervention Type: 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)

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Valentin Fuster

OTHER

Sponsor Role: lead

Responsible Party

Valentin Fuster

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Valentin Fuster, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Anu Lala, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Instituto do Coração - INCOR

São Paulo, , Brazil

Instituto Prevent Senior - IPS

São Paulo, , Brazil

Clínica de la Costa

Barranquilla, , Colombia

Clínica Shaio

Bogotá, , Colombia

Fundación Cardioinfantil

Bogotá, , Colombia

Fundacion Oftalmológica de Santander - Foscal

Bucaramanga, , Colombia

Centro Médico Imbanaco

Cali, , Colombia

CardioVid

Medellín, , Colombia

Eternal Heart Care Centre and Research Ins Pvt Ltd.

Jaipur, , India

Jaipur National University

Jaipur, , India

Sawai Mann Singh Hospital

Jaipur, , India

Jaslok Hospital & Research Center

Mumbai, , India

Saifee Hospital

Mumbai, , India

Sengupta Hospital & Research Institute

Nagpur, , India

D Y Patil University School of Medicine & D Y Patil Hospital

Navi Mumbai, , India

Hospital Cardiológica Aguascalientes

Aguascalientes, , Mexico

Centro Médico Nacional 20 de Noviembre

Mexico City, , Mexico

Christus Muguerza Hospital Alta Especialidad

Monterrey, , Mexico

Centro de Estudios Clinicos de Querétaro S.C.

Querétaro City, , Mexico

Centro Medico Hospital del Prado

Tijuana, , Mexico

Countries

United States; Brazil; Colombia; India; Mexico

References

Stone GW, Farkouh ME, Lala A, Tinuoye E, Dressler O, Moreno PR, Palacios IF, Goodman SG, Esper RB, Abizaid A, Varade D, Betancur JF, Ricalde A, Payro G, Castellano JM, Hung IFN, Nadkarni GN, Giustino G, Godoy LC, Feinman J, Camaj A, Bienstock SW, Furtado RHM, Granada C, Bustamante J, Peyra C, Contreras J, Owen R, Bhatt DL, Pocock SJ, Fuster V; FREEDOM COVID Anticoagulation Strategy Randomized Trial Investigators. Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19. J Am Coll Cardiol. 2023 May 9;81(18):1747-1762. doi: 10.1016/j.jacc.2023.02.041. Epub 2023 Mar 6.

Reference Type: DERIVED

PMID: 36889611 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35241226 (View on PubMed)

Other Identifiers

GCO 20-2115

Identifier Type: -

Identifier Source: org_study_id