This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic strategies for prevention of adverse outcomes in COVID-19 positive inpatients



Eligible Ages
Over 18 Years
Eligible Genders
Accepts Healthy Volunteers

Inclusion Criteria

  • ≥ 18 years of age - Hospitalized for COVID-19 - Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test - Expected to require hospitalization for > 72 hours

Exclusion Criteria

  • Imminent death - Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization - Pregnancy - Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment of patients requiring ICU level of care into the therapeutic anti-coagulation arm was stopped due to meeting a futility threshold and a potential for harm for this sub-group could not be excluded. Enrollment continues for moderately ill hospitalized COVID-19 patients.

Study Design

Phase 4
Study Type
Intervention Model
Single Group Assignment
Intervention Model Description
This is an adaptive design
Primary Purpose
None (Open Label)
Masking Description
There will be independent masked adjudicators.

Arm Groups

ArmDescriptionAssigned Intervention
Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care.
  • Drug: theraputic heparin
    increased dose of heparin above standard of care.
    Other names:
    • unfractionated heparin
    • Enoxaparin
    • Dalteparin
    • Tinzaparin
    • Heparin
Prophylactic Dose Anticoagulation
Heparin standard of care
  • Drug: prophylactic heparin
    standard of care dose of heparin
    Other names:
    • enoxaparin
    • dalteparin
    • Tinzaparin
    • Fondparinux
    • Heparin

Recruiting Locations

Boston University
Boston, Massachusetts 02118
Naomi Hamburg

More Details

Matthew Neal MD

Study Contact

Judith Hochman, MD

Detailed Description

The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious coronavirus disease 2019 (COVID-19), has resulted in a global pandemic. The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. The risk of thrombotic complications is increased, even as compared to other viral respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as induction of procoagulant factors associated with COVID-19 has been proposed to contribute to thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are at increased risk for arterial and vein thromboembolism, with high rates observed despite thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across multiple organ beds consistent with an early hypercoagulable state. Notably, in COVID-19, data in the U.K. and U.S. document that infection and outcomes of infection are worse in African and Hispanic descent persons than in other groups. The reasons for this are uncertain. Viral Infection and Thrombosis A large body of literature links inflammation and coagulation; altered hemostasis is a known complication of respiratory viral infections. Procoagulant markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in viral infections upregulate expression of tissue factor, markers of thrombin generation, platelet activation, and down-regulate natural anticoagulant proteins C and S. Studies have demonstrated significant risk of deep venous thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) associated with viral respiratory infections. In a series of patients with fatal influenza H1N1, 75% had pulmonary thrombi on autopsy (a rate considerably higher than reported on autopsy studies among the general intensive care unit population). Incidence ratio for acute myocardial infarction in the context of Influenza A is over 10. Severe acute respiratory syndrome coronavirus-1 (SARS CoV-1) and influenza have been associated with disseminated intravascular coagulation (DIC), endothelial damage, DVT, PE, and large artery ischemic stroke. Patients with Influenza H1N1 and acute respiratory distress syndrome (ARDS) had a 23.3-fold higher risk for pulmonary embolism, and a 17.9-fold increased risk for deep vein thrombosis. Compared to those treated with systemic anticoagulation, those without treatment were 33 times more likely to suffer a VTE. Thrombosis, both microvascular and macrovascular, is a prominent feature in multiple organs at autopsy in fatal cases of COVID-19. Thrombosis may thus contribute to respiratory failure, renal failure, and hepatic injury in COVID-19. The number of megakaryocytes in tissues is higher than in other forms of ARDS, and thrombi are platelet-rich based on specific staining. Thrombotic stroke has been reported in young COVID-19 patients with no cardiovascular risk factors. Both arterial and venous thrombotic events have been seen in increasing numbers of hospitalized patients infected with COVID-19. The incidence of thrombosis has ranged from 10 to 30% in hospitalized patients; however, this varies by type of thrombosis captured (arterial or vein) and severity of illness (ICU level care, requiring mechanical ventilation, etc.).


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