Anti-thrombotics for Adults Hospitalized With COVID-19 (ACTIV-4)
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|ClinicalTrials.gov Identifier: NCT04505774|
Recruitment Status : Recruiting
First Posted : August 10, 2020
Last Update Posted : January 5, 2021
|Condition or disease||Intervention/treatment||Phase|
|Covid19||Drug: theraputic heparin Drug: prophylactic heparin||Phase 4|
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.).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||2000 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||This is an adaptive design|
|Masking:||None (Open Label)|
|Masking Description:||There will be independent masked adjudicators.|
|Official Title:||A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults With COVID-19|
|Actual Study Start Date :||September 4, 2020|
|Estimated Primary Completion Date :||March 2021|
|Estimated Study Completion Date :||December 2021|
Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care.
Drug: theraputic heparin
increased dose of heparin above standard of care.
Prophylactic Dose Anticoagulation
Heparin standard of care
Drug: prophylactic heparin
standard of care dose of heparin
- 21 Day Organ Support (respiratory or vasopressor) Free Days [ Time Frame: 21 days from study enrollment ]which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.
- Key Platform Secondary Thrombotic Endpoint [ Time Frame: 28 days from study enrollment ]Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first
- Other Platform Secondary Endpoints of Morbidity and Hospitalization [ Time Frame: 28 days from study enrollment ]Acute kidney injury defined by KDIGO criteria, Individual endpoints comprising the key secondary endpoint, death during hospitalization, 28 Day Ventilator-Free Days, 28 Day Vasopressor Free Days, 28 Day Renal Replacement Free Days, WHO clinical scale, 28 Day Hospital Free Days, 28 day organ support free days.
- All cause mortality [ Time Frame: 90 days from enrollment ]Any mortality of patients enrolled within 90 days.
- Primary Safety Endpoint of Major Bleeding [ Time Frame: 28 days from study enrollment ]Major bleeding (as defined by the ISTH)
- Secondary Safety Endpoint of HIT [ Time Frame: 28 days from study enrollment ]Confirmed heparin induced thrombocytopenia (HIT)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04505774
|Contact: Judith Hochman, MD||212-263-6927||Judith.Hochman@nyulangone.org|
|Contact: Matthew Neal, MDfirstname.lastname@example.org|
|Study Chair:||Judith Hochman, MD||New York University - Grossman School of Medicine|