Clinical trial NCT04512079: FREEDOM COVID-19 Anticoagulation Strategy
Official title: FREEDOM COVID Anticoagulation Strategy Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
SARS-CoV-2
Keywords: Randomization
Hospitalization
PCR or Antigen Positive Test
Abnormal Laboratory Maker
Anticoagulation
Apixaban
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
First posted: 2020-08-13
Enrollment: 3460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Time to first event
timeFrame: 30 days
measure: Number of in-hospital rate of BARC 3 or 5
timeFrame: 30 days
Secondary outcomes:
measure: Number of participants with Myocardial infarction
timeFrame: 30 days after randomization
measure: Number of participants with Myocardial infarction
timeFrame: 90 days after randomization
measure: Number of participants with Deep Vein Thrombosis
timeFrame: 30 days after randomization
measure: Number of participants with Deep Vein Thrombosis
timeFrame: 90 days after randomization
measure: Number of participants requiring Ventilation
timeFrame: 30 after randomization
measure: Number of participants requiring Ventilation
timeFrame: 90 days after randomization
measure: Number of All Death
timeFrame: 30 days after randomization
measure: Number of All Death
timeFrame: 90 days after randomization
measure: Cause of Death
timeFrame: 30 days after randomization
measure: Cause of Death
timeFrame: 90 days after randomization
measure: Number of participants with Stroke
timeFrame: 30 days after randomization
measure: Number of participants with Stroke
timeFrame: 90 days after randomization
measure: Number of participants with Pulmonary Emboli
timeFrame: 30 days after randomization
measure: Number of participants with Pulmonary Emboli
timeFrame: 90 days after randomization
measure: Number of participants with Systemic Thromboembolism
timeFrame: 30 days after randomization
measure: Number of participants with Systemic Thromboembolism
timeFrame: 90 days after randomization
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: São Paulo
country: Brazil
facility: Instituto do Coração - INCOR
city: São Paulo
country: Brazil
facility: Instituto Prevent Senior - IPS
city: Barranquilla
country: Colombia
facility: Clínica de la Costa
city: Bogotá
country: Colombia
facility: Clínica Shaio
city: Bogotá
country: Colombia
facility: Fundación Cardioinfantil
city: Bucaramanga
country: Colombia
facility: Fundacion Oftalmológica de Santander - Foscal
city: Cali
country: Colombia
facility: Centro Médico Imbanaco
city: Medellín
country: Colombia
facility: CardioVid
city: Jaipur
country: India
facility: Eternal Heart Care Centre and Research Ins Pvt Ltd.
city: Jaipur
country: India
facility: Jaipur National University
city: Jaipur
country: India
facility: Sawai Mann Singh Hospital
city: Mumbai
country: India
facility: Jaslok Hospital & Research Center
city: Mumbai
country: India
facility: Saifee Hospital
city: Nagpur
country: India
facility: Sengupta Hospital & Research Institute
city: Navi Mumbai
country: India
facility: D Y Patil University School of Medicine & D Y Patil Hospital
city: Aguascalientes
country: Mexico
facility: Hospital Cardiológica Aguascalientes
city: Mexico City
country: Mexico
facility: Centro Médico Nacional 20 de Noviembre
city: Monterrey
country: Mexico
facility: Christus Muguerza Hospital Alta Especialidad
city: Santiago de Querétaro
country: Mexico
facility: Centro de Estudios Clinicos de Querétaro S.C.
city: Tijuana
country: Mexico
facility: Centro Medico Hospital del Prado
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Valentin Fuster, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Anu Lala, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.