FREEDOM COVID-19 Anticoagulation Strategy

COVID-19 Clinical Trial

— FREEDOM COVID  

Official title:

FREEDOM COVID Anticoagulation Strategy Randomized Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04512079
• Other study ID #: GCO 20-2115
• Status: Completed
• Phase: Phase 4
• Start date: September 8, 2020
• Est. completion date: December 30, 2022

Study information

• Verified date: March 2023
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3460
• Est. completion date: December 30, 2022
• Est. primary completion date: December 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID-19
• SARS-CoV-2

Intervention

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)
• 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)

Locations

Country	Name	City	State
Brazil	Instituto do Coração - INCOR	São Paulo
Brazil	Instituto Prevent Senior - IPS	São Paulo
Colombia	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
India	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
Mexico	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.	Santiago de Querétaro
Mexico	Centro Medico Hospital del Prado	Tijuana
United States	Icahn School of Medicine at Mount Sinai	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Valentin Fuster

Countries where clinical trial is conducted

United States,  Brazil,  Colombia,  India,  Mexico, 

Outcome

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