FREEDOM COVID-19 Anticoagulation Strategy

• Sponsor: Valentin Fuster (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04512079
• Collaborator: (none)
• Enrollment: 3,600
• Locations: 21
• Arms: 3
• Anticipated Duration (Months): 21.7
• Patients Per Site: 171.4
• Patients Per Site Per Month: 7.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Anticipated 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: 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)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)
• Primary Purpose: Treatment
• Official Title: FREEDOM COVID Anticoagulation Strategy Randomized Trial
• Actual Study Start Date: Sep 8, 2020
• Anticipated Primary Completion Date: Jul 1, 2022
• Anticipated Study Completion Date: Jul 1, 2022

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. Time to first event [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 [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: Probable fatal bleeding Definite fatal bleeding (overt or autopsy or imaging confirmation)

Secondary Outcome Measures

1. Number of participants with Myocardial infarction [30 days after randomization]

   Myocardial infarction (according to the 4th universal definition, types 1,2, and 3)

2. Number of participants with Myocardial infarction [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 [30 days after randomization]

   Deep vein thrombosis with confirmation on imaging

4. Number of participants with Deep Vein Thrombosis [90 days after randomization]

   Deep vein thrombosis with confirmation on imaging

5. Number of participants requiring Ventilation [30 after randomization]

   Intubation and mechanical ventilation

6. Number of participants requiring Ventilation [90 days after randomization]

   Intubation and mechanical ventilation

7. Number of All Death [30 days after randomization]

   All-cause death

8. Number of All Death [90 days after randomization]

   All-cause death

9. Cause of Death [30 days after randomization]

   Cause of Death

10. Cause of Death [90 days after randomization]

    Cause of Death

11. Number of participants with Stroke [30 days after randomization]

    Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic)

12. Number of participants with Stroke [90 days after randomization]

    Stroke confirmed by imaging or autopsy (all, ischemic and hemorrhagic)

13. Number of participants with Pulmonary Emboli [30 days after randomization]

    Pulmonary emboli confirmed by imaging or autopsy

14. Number of participants with Pulmonary Emboli [90 days after randomization]

    Pulmonary emboli confirmed by imaging or autopsy

15. Number of participants with Systemic Thromboembolism [30 days after randomization]

    Systemic thromboembolism confirmed by imaging or requiring surgical intervention

16. Number of participants with Systemic Thromboembolism [90 days after randomization]

    Systemic thromboembolism confirmed by imaging or requiring surgical intervention

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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):

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
2	Instituto do Coração - INCOR	São Paulo		Brazil
3	Instituto Prevent Senior - IPS	São Paulo		Brazil
4	Clínica de la Costa	Barranquilla		Colombia
5	Clínica Shaio	Bogotá		Colombia
6	Fundación Cardioinfantil	Bogotá		Colombia
7	Fundacion Oftalmológica de Santander - Foscal	Bucaramanga		Colombia
8	Centro Médico Imbanaco	Cali		Colombia
9	CardioVid	Medellín		Colombia
10	Eternal Heart Care Centre and Research Ins Pvt Ltd.	Jaipur		India
11	Jaipur National University	Jaipur		India
12	Sawai Mann Singh Hospital	Jaipur		India
13	Jaslok Hospital & Research Center	Mumbai		India
14	Saifee Hospital	Mumbai		India
15	Sengupta Hospital & Research Institute	Nagpur		India
16	D Y Patil University School of Medicine & D Y Patil Hospital	Navi Mumbai		India
17	Hospital Cardiológica Aguascalientes	Aguascalientes		Mexico
18	Centro Médico Nacional 20 de Noviembre	Mexico City		Mexico
19	Christus Muguerza Hospital Alta Especialidad	Monterrey		Mexico
20	Centro de Estudios Clinicos de Querétaro S.C.	Santiago de Querétaro		Mexico
21	Centro Medico Hospital del Prado	Tijuana		Mexico

Sponsors and Collaborators

• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• 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: Aug 13, 2020
• Last Update Posted: Jan 20, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Valentin Fuster, Principal Investigator, Icahn School of Medicine at Mount Sinai: Randomization; Hospitalization; PCR or Antigen Positive Test; Abnormal Laboratory Maker; Anticoagulation; Apixaban
• Additional relevant MeSH terms: COVID-19; Enoxaparin; Apixaban

Study Results

No Results Posted as of Jan 20, 2022