Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE
NCT ID: NCT04505774
Last Updated: 2024-12-30
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE4
Total Enrollment
3591 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-09-04
Study Completion Date
2024-01-26
Brief Summary
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This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19 positive inpatients
Detailed Description
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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.).
Additional treatment strategies Data from the multiplatform randomized controlled trial (mpRCT) demonstrated that (1) therapeutic dose anticoagulation with heparin was not beneficial in improving clinical outcomes compared to standard of care prophylactic dose heparin in severely ill (ICU level of care) patients, and (2) therapeutic dose anticoagulation with heparin was beneficial in improving organ support free days compared to standard of care prophylactic dose heparin in moderately ill (hospitalized and not requiring organ support) patients. However, there remains significant residual risk for adverse clinical outcomes and excess mortality for severely ill as well as moderately ill patients.
Antithrombotic regimens that are shown to be efficacious will be combined in clinical practice with other agents to treat COVID-19 hospitalized patients. This adaptive platform trial will test other promising agents when added to proven therapies, such as heparin. The rationale and risks for each agent will be included in the arm-specific appendix. Two specific agents to be added as arms, effective October 2021, include the P-selectin inhibitor, Crizanlizumab as well as SGLT2 inhibitors. P-selectin may play a proximal role in the inflammatory and thrombotic cascade in patients with COVID-19 and P-selectin inhibition may be a effective in preventing downstream sequelae. In addition, SGLT-2 inhibitors have been shown to decrease capillary leak and may promote vascular integrity in COVID-19.
This platform trial will have multiple arms, which may be dropped or added as the platform trial progresses. Sample size will be flexible: the trial will be stopped for efficacy or futility based on pre-determined statistical thresholds as defined in the arm-specific appendices. Each arm will have an adaptive component for determinations of futility or success.
Randomization assignments are at the participant level, stratified by enrolling site and by ICU level of care vs non-ICU level of care and/or other arm-specific criteria.
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.).
Additional treatment strategies Data from the multiplatform randomized controlled trial (mpRCT) demonstrated that (1) therapeutic dose anticoagulation with heparin was not beneficial in improving clinical outcomes compared to standard of care prophylactic dose heparin in severely ill (ICU level of care) patients, and (2) therapeutic dose anticoagulation with heparin was beneficial in improving organ support free days compared to standard of care prophylactic dose heparin in moderately ill (hospitalized and not requiring organ support) patients. However, there remains significant residual risk for adverse clinical outcomes and excess mortality for severely ill as well as moderately ill patients.
Antithrombotic regimens that are shown to be efficacious will be combined in clinical practice with other agents to treat COVID-19 hospitalized patients. This adaptive platform trial will test other promising agents when added to proven therapies, such as heparin. The rationale and risks for each agent will be included in the arm-specific appendix. Two specific agents to be added as arms, effective October 2021, include the P-selectin inhibitor, Crizanlizumab as well as SGLT2 inhibitors. P-selectin may play a proximal role in the inflammatory and thrombotic cascade in patients with COVID-19 and P-selectin inhibition may be a effective in preventing downstream sequelae. In addition, SGLT-2 inhibitors have been shown to decrease capillary leak and may promote vascular integrity in COVID-19.
This platform trial will have multiple arms, which may be dropped or added as the platform trial progresses. Sample size will be flexible: the trial will be stopped for efficacy or futility based on pre-determined statistical thresholds as defined in the arm-specific appendices. Each arm will have an adaptive component for determinations of futility or success.
Randomization assignments are at the participant level, stratified by enrolling site and by ICU level of care vs non-ICU level of care and/or other arm-specific criteria.
Conditions
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Covid19
Keywords
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anti-coagulation
antithrombosis
anticoagulation
ACTIV
inpatient
heparin
p2y12
endothelial dysfunction
vascular integrity
P-selectin
crizanlizumab
SGLT-2 inhibitor
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
SEQUENTIAL
This is an adaptive design
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
There will be independent masked adjudicators.
Study Groups
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Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care.
1.0 - This arm was stopped in severe patients in December 2020 and results are published in PMID: 34351722 (NEJM, August, 2021) (see reference section for citation). This arm was stopped for moderate patients in January 2021.
Group Type
OTHER
theraputic heparin
Intervention Type
DRUG
increased dose of heparin above standard of care.
Prophylactic Dose Anticoagulation
Heparin standard of care
1.0 - this arm was stopped for all patients in January, 2021 and results are published in PMID: 34351721 (NEJM, August, 2021) (see reference section for citation)
Group Type
OTHER
prophylactic heparin
Intervention Type
DRUG
standard of care dose of heparin
Therapeutic Dose Anticoagulation + P2Y12 inhibitor
increased dose of heparin above standard of care with an added P2Y12 inhibitor
This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021 and results are published in PMID: PMID: 35040887 (JAMA, January, 2022) (see reference section for citation)
Group Type
OTHER
theraputic heparin
Intervention Type
DRUG
increased dose of heparin above standard of care.
P2Y12
Intervention Type
DRUG
added P2Y12 inhibitor
Prophylactic Dose Anticoagulation + P2Y12 inhibitor
Heparin standard of care with an added P2Y12 inhibitor
This Arm enrolled severe illness patients only. Enrollment of severe illness patients in the trial was ended per DSMB in June 2022.
Group Type
OTHER
prophylactic heparin
Intervention Type
DRUG
standard of care dose of heparin
P2Y12
Intervention Type
DRUG
added P2Y12 inhibitor
Standard of Care + Crizanlizumab
Standard of care plus crizanlizumab infusion
This arm will enroll moderate and severe illness patients
This arm was ended for all patients per the DSMB in September 2022.
Group Type
OTHER
Crizanlizumab Injection
Intervention Type
DRUG
crizanlizumab injection
Standard of Care + SGLT2 inhibitor
Standard of care plus SGLT2 inhibitor
This arm will enroll moderate and severe illness patients
This arm was ended in March 2023
Group Type
OTHER
SGLT2 inhibitor
Intervention Type
DRUG
sglt2 inhibitor
Standard of Care (SGLT2 arm)
Standard of care only
This arm will enroll moderate and severe illness patients
This arm was ended in March 2023
Group Type
OTHER
SGLT2 inhibitor
Intervention Type
DRUG
sglt2 inhibitor
Standard of Care (Criza)
Standard of care only This arm will enroll moderate and severe illness patients
This arm was ended for all patients per the DSMB in September 2022.
Group Type
OTHER
Crizanlizumab Injection
Intervention Type
DRUG
crizanlizumab injection
Interventions
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theraputic heparin
increased dose of heparin above standard of care.
Intervention Type
DRUG
prophylactic heparin
standard of care dose of heparin
Intervention Type
DRUG
P2Y12
added P2Y12 inhibitor
Intervention Type
DRUG
Crizanlizumab Injection
crizanlizumab injection
Intervention Type
DRUG
SGLT2 inhibitor
sglt2 inhibitor
Intervention Type
DRUG
Other Intervention Names
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unfractionated heparin
Enoxaparin
Dalteparin
Tinzaparin
Heparin
enoxaparin
dalteparin
Tinzaparin
Fondparinux
Heparin
Ticagrelor
Prasugrel
Clopidogrel
dapagliflozin
empagliflozin
canagliflozin
ertugliflozin
Eligibility Criteria
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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
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following -
* O2 supplementation \> 2 liters per minute
* BMI ≥ 35
* GFR ≤ 60
* History of Type 2 diabetes
* History of heart failure (regardless of ejection fraction)
* D dimer ≥ 2x the site's upper limit of normal (ULN)
* Troponin ≥ 2x the site's ULN
* BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
* CRP ≥50 mg/L
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following-
* O2 supplementation \> 2 liters per minute
* BMI ≥ 35
* GFR ≤ 60
* History of Type 2 diabetes
* History of heart failure (regardless of ejection fraction)
* D dimer ≥ 2x the site's upper limit of normal (ULN)
* Troponin ≥ 2x the site's ULN
* BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
* CRP ≥50 mg/L
* 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
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following -
* O2 supplementation \> 2 liters per minute
* BMI ≥ 35
* GFR ≤ 60
* History of Type 2 diabetes
* History of heart failure (regardless of ejection fraction)
* D dimer ≥ 2x the site's upper limit of normal (ULN)
* Troponin ≥ 2x the site's ULN
* BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
* CRP ≥50 mg/L
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following-
* O2 supplementation \> 2 liters per minute
* BMI ≥ 35
* GFR ≤ 60
* History of Type 2 diabetes
* History of heart failure (regardless of ejection fraction)
* D dimer ≥ 2x the site's upper limit of normal (ULN)
* Troponin ≥ 2x the site's ULN
* BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
* CRP ≥50 mg/L
Exclusion Criteria
* Imminent death
* Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
* Pregnancy
* Any condition that, in the opinion of the investigator, precludes the use of crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin\<4 g/dL)
* Open label treatment with crizanlizumab within the past three months
* Known hypersensitivity to any SGLT2 inhibitors
* Type 1 diabetes
* History of diabetic ketoacidosis
* eGFR \<20 and/or requirement for renal replacement therapy
* Open label treatment with any SGLT2 inhibitor
* 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.
* Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of patients not requiring ICU level of care and randomized to P2Y12 or standard care was stopped due to meeting a futility threshold. Enrollment continues for severely ill (ICU level of care) hospitalized COVID-19 patients.
* Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
* Pregnancy
* Any condition that, in the opinion of the investigator, precludes the use of crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin\<4 g/dL)
* Open label treatment with crizanlizumab within the past three months
* Known hypersensitivity to any SGLT2 inhibitors
* Type 1 diabetes
* History of diabetic ketoacidosis
* eGFR \<20 and/or requirement for renal replacement therapy
* Open label treatment with any SGLT2 inhibitor
* 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.
* Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of patients not requiring ICU level of care and randomized to P2Y12 or standard care was stopped due to meeting a futility threshold. Enrollment continues for severely ill (ICU level of care) hospitalized COVID-19 patients.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Sponsor Role
collaborator
Matthew Neal MD
OTHER
Sponsor Role
lead
Responsible Party
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Matthew Neal MD
MD
Responsibility Role
SPONSOR_INVESTIGATOR
Principal Investigators
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Judith Hochman, MD
Role: STUDY_CHAIR
NYU Langone Health
Scott Solomon, MD
Role: PRINCIPAL_INVESTIGATOR
Brigham and Women's Hospital
Mikhail Kosiborod, MD
Role: PRINCIPAL_INVESTIGATOR
Saint Lukes
Jeffrey Berger, MD
Role: PRINCIPAL_INVESTIGATOR
NYU Langone Health
MATTHEW D NEAL, MD
Role: STUDY_CHAIR
University of Pittsburgh
Locations
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University of Alabama
Birmingham, Alabama, United States
Site Status
University of Arizona
Tucson, Arizona, United States
Site Status
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Site Status
Kaiser Permanente Fontana
Fontana, California, United States
Site Status
Kaiser Permanente Los Angeles
Los Angeles, California, United States
Site Status
Smidt Heart Institute at Cedars-Sinai
Los Angeles, California, United States
Site Status
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
Site Status
UC San Diego Hillcrest
San Diego, California, United States
Site Status
Zuckerberg San Francisco General Hospital
San Francisco, California, United States
Site Status
UCSF San Francisco
San Francisco, California, United States
Site Status
Zuckerberg San Francisco General Hospital
San Francisco, California, United States
Site Status
Stanford University Medical Center
Stanford, California, United States
Site Status
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Torrance, California, United States
Site Status
Denver Health and Hospital Authority
Denver, Colorado, United States
Site Status
St. Mary's Hospital & Regional Medical Center
Grand Junction, Colorado, United States
Site Status
Saint Francis Hospital and Medical Center
Hartford, Connecticut, United States
Site Status
University of Florida
Gainesville, Florida, United States
Site Status
Memorial Hospital
Jacksonville, Florida, United States
Site Status
AdventHealth Tampa
Tampa, Florida, United States
Site Status
Emory
Atlanta, Georgia, United States
Site Status
Morehouse School of Medicine
Atlanta, Georgia, United States
Site Status
Queens Medical Center
Honolulu, Hawaii, United States
Site Status
Memorial Hospital
Belleville, Illinois, United States
Site Status
Cook County Health
Chicago, Illinois, United States
Site Status
University of Illinois at Chicago Health (UIH)
Chicago, Illinois, United States
Site Status
OSF Little Company of Mary Medical Center (OSF LCM)
Evergreen Park, Illinois, United States
Site Status
Indiana University Health Methodist Hospital
Indianapolis, Iowa, United States
Site Status
Kansas University Medical Center
Kansas City, Kansas, United States
Site Status
Ochsner Clinic Foundation
New Orleans, Louisiana, United States
Site Status
Boston University
Boston, Massachusetts, United States
Site Status
St Elizabeth's Medical Center
Brighton, Massachusetts, United States
Site Status
Baystate Medical Center
Springfield, Massachusetts, United States
Site Status
University of Massachusetts
Worcester, Massachusetts, United States
Site Status
University of Michigan
Ann Arbor, Michigan, United States
Site Status
Wayne State University
Detroit, Michigan, United States
Site Status
Hennepin County Medical Center
Minneapolis, Minnesota, United States
Site Status
University of Mississippi Medical Center
Jackson, Mississippi, United States
Site Status
Washington University School of Medicine, ACCS Research
St Louis, Missouri, United States
Site Status
University Medical Center of Southern Nevada
Las Vegas, Nevada, United States
Site Status
Cooper Health
Camden, New Jersey, United States
Site Status
Englewood Health
Englewood, New Jersey, United States
Site Status
Atlantic Health System
Morristown, New Jersey, United States
Site Status
Rutgers New Jersey Medical School
Newark, New Jersey, United States
Site Status
AtlantiCare Regional Medical Center
Pomona, New Jersey, United States
Site Status
Albany Medical College
Albany, New York, United States
Site Status
Mercy Hospital Buffalo
Buffalo, New York, United States
Site Status
VA New York Harbor Healthcare System
New York, New York, United States
Site Status
NYU Langone
New York, New York, United States
Site Status
Mt. Sinai Hospital
New York, New York, United States
Site Status
SUNY Upstate University Hospital
Syracuse, New York, United States
Site Status
Jacobi Medical Center
The Bronx, New York, United States
Site Status
Montefiore Medical Center
The Bronx, New York, United States
Site Status
Westchester Medical Center
Valhalla, New York, United States
Site Status
Duke University Hospital
Durham, North Carolina, United States
Site Status
Wake Forest
Winston-Salem, North Carolina, United States
Site Status
Cleveland Clinic Akron General
Akron, Ohio, United States
Site Status
University of Cincinnati Medical Center
Cincinnati, Ohio, United States
Site Status
The MetroHealth System
Cleveland, Ohio, United States
Site Status
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Site Status
Ohio State Universtiy Wexner Medical Center
Columbus, Ohio, United States
Site Status
Mercy Health St Vincent Medical Center
Toledo, Ohio, United States
Site Status
Ascension St. John Clinical Research Institute
Tulsa, Oklahoma, United States
Site Status
Oregon Health and Science University
Portland, Oregon, United States
Site Status
Geisinger Research
Danville, Pennsylvania, United States
Site Status
Doylestown Cardiology Associates
Doylestown, Pennsylvania, United States
Site Status
Penn State Health Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States
Site Status
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Site Status
Temple University
Philadelphia, Pennsylvania, United States
Site Status
UPMC Presbyterian
Pittsburgh, Pennsylvania, United States
Site Status
Rhode Island Hospital
Providence, Rhode Island, United States
Site Status
The Miriam Hospital
Providence, Rhode Island, United States
Site Status
Sarah Cannon and HCA Research Institute
Nashville, Tennessee, United States
Site Status
Skyline Medical Center
Nashville, Tennessee, United States
Site Status
University of Texas at Austin
Austin, Texas, United States
Site Status
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Site Status
Medical City Ft Worth
Fort Worth, Texas, United States
Site Status
Baylor Scott and White Medical Center - Temple
Temple, Texas, United States
Site Status
HCA Henrico Doctors Hospital
Richmond, Virginia, United States
Site Status
Swedish Hospital
Seattle, Washington, United States
Site Status
West Virginia University CTR
Morgantown, West Virginia, United States
Site Status
University of Wisconsin Hospital; Meriter Hospital (UW affiliated)
Madison, Wisconsin, United States
Site Status
Hospital Universitario Sao Francisco de Assis
Bragança Paulista, , Brazil
Site Status
União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS
Porto Alegre, , Brazil
Site Status
Centro de Estudos ClÃnicos do Hospital Cárdio Pulmonar
Salvador, , Brazil
Site Status
Fundação Faculdade Regional De Medicina De São José Do Rio Preto
São José do Rio Preto, , Brazil
Site Status
Instituto Dante Pazzanese de Cardiologia
São Paulo, , Brazil
Site Status
Instituto do Coração do Hospital das ClÃnicas da Faculdade de Medicina da USP-InCor-HCFMUSP
São Paulo, , Brazil
Site Status
Azienda Ospedaliero Sant Anna e San Sebastiano
Caserta, , Italy
Site Status
Maria Cecilia Hospital , Cotignola, Ravenna
Cotignola, , Italy
Site Status
Università degli Studi di Ferrara, Ferrara
Ferrara, , Italy
Site Status
Azienda Ospedaliero -Universitaria Careggi
Florence, , Italy
Site Status
Policlinico di Napoli, Napoli
Napoli, , Italy
Site Status
AOU Policlinico di Palermo, Palermo
Palermo, , Italy
Site Status
ASL-1 Imperiese, Sanremo
Sanremo, , Italy
Site Status
Hospital Universitario A Coruna
A Coruña, , Spain
Site Status
Hospital Virgen del Mar
AlmerÃa, , Spain
Site Status
Hospital Arnau de Vilanova
Lleida, , Spain
Site Status
Hospital Universitario La Paz
Madrid, , Spain
Site Status
Hospital Universitario Ramon Y Cajal
Madrid, , Spain
Site Status
Hospital ClÃnico Universitario de Salamanca
Salamanca, , Spain
Site Status
Hospital ClÃnico Universitario de Santiago de Compostela
Santiago de Compostela, , Spain
Site Status
Countries
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United States
Brazil
Italy
Spain
References
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Kosiborod MN, Esterline R, Furtado RHM, Oscarsson J, Gasparyan SB, Koch GG, Martinez F, Mukhtar O, Verma S, Chopra V, Buenconsejo J, Langkilde AM, Ambery P, Tang F, Gosch K, Windsor SL, Akin EE, Soares RVP, Moia DDF, Aboudara M, Hoffmann Filho CR, Feitosa ADM, Fonseca A, Garla V, Gordon RA, Javaheri A, Jaeger CP, Leaes PE, Nassif M, Pursley M, Silveira FS, Barroso WKS, Lazcano Soto JR, Nigro Maia L, Berwanger O. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021 Sep;9(9):586-594. doi: 10.1016/S2213-8587(21)00180-7. Epub 2021 Jul 21.
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ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Dzavik V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, Garcia-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Perez Gonzalez YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4.
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BACKGROUND
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Dzavik V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.
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BACKGROUND
Berger JS, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Cheng Y, McVerry BJ, Kim KS, Lopes RD, Atassi B, Berry S, Bochicchio G, de Oliveira Antunes M, Farkouh ME, Greenstein Y, Hade EM, Hudock K, Hyzy R, Khatri P, Kindzelski A, Kirwan BA, Baumann Kreuziger L, Lawler PR, Leifer E, Lopez-Sendon Moreno J, Lopez-Sendon J, Luther JF, Nigro Maia L, Quigley J, Sherwin R, Wahid L, Wilson J, Hochman JS, Neal MD; ACTIV-4a Investigators. Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2022 Jan 18;327(3):227-236. doi: 10.1001/jama.2021.23605.
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BACKGROUND
Kosiborod MN, Windsor SL, Vardeny O, Berger JS, Reynolds HR, Boumakis S, Althouse AD, Solomon SD, Bhatt AS, Peikert A, Luther JF, Leifer ES, Kindzelski AL, Cushman M, Ng Gong M, Kornblith LZ, Khatri P, Kim KS, Baumann Kreuziger L, Javaheri A, Carpio C, Wahid L, Lopez-Sendon Moreno J, Alonso A, Ho MQ, Lopez-Sendon J, Lopes RD, Curtis JL, Kirwan BA, Geraci MW, Neal MD, Hochman JS; ACTIV-4a Investigators. Effect of sodium-glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial. Lancet Diabetes Endocrinol. 2024 Oct;12(10):725-734. doi: 10.1016/S2213-8587(24)00218-3. Epub 2024 Sep 6.
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DERIVED
Greenstein YY, Hubel K, Froess J, Wisniewski SR, Venugopal V, Lai YH, Berger JS, Chang SY, Colovos C, Shah F, Kornblith LZ, Lawler PR, Gaddh M, Guerrero RM, Nkemdirim W, Lopes RD, Reynolds HR, Amigo JS, Wahid L, Zahra A, Goligher EC, Zarychanski R, Leifer E, Huang DT, Neal MD, Hochman JS, Cushman M, Gong MN. Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life. Chest. 2024 Apr;165(4):785-799. doi: 10.1016/j.chest.2023.11.019. Epub 2023 Nov 17.
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Fischer AL, Messer S, Riera R, Martimbianco ALC, Stegemann M, Estcourt LJ, Weibel S, Monsef I, Andreas M, Pacheco RL, Skoetz N. Antiplatelet agents for the treatment of adults with COVID-19. Cochrane Database Syst Rev. 2023 Jul 25;7(7):CD015078. doi: 10.1002/14651858.CD015078.
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Solomon SD, Lowenstein CJ, Bhatt AS, Peikert A, Vardeny O, Kosiborod MN, Berger JS, Reynolds HR, Mavromichalis S, Barytol A, Althouse AD, Luther JF, Leifer ES, Kindzelski AL, Cushman M, Gong MN, Kornblith LZ, Khatri P, Kim KS, Baumann Kreuziger L, Wahid L, Kirwan BA, Geraci MW, Neal MD, Hochman JS; ACTIV4a Investigators. Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial. Circulation. 2023 Aug;148(5):381-390. doi: 10.1161/CIRCULATIONAHA.123.065190. Epub 2023 Jun 25.
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DERIVED
Berger JS, Neal MD, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Althouse AD, Lawler PR, McVerry BJ, Kim KS, Baumann Kreuziger L, Solomon SD, Kosiborod MN, Berry SM, Bochicchio GV, Contoli M, Farkouh ME, Froess JD, Gandotra S, Greenstein Y, Hade EM, Hanna N, Hudock K, Hyzy RC, Ibanez Estellez F, Iovine N, Khanna AK, Khatri P, Kirwan BA, Kutcher ME, Leifer E, Lim G, Lopes RD, Lopez-Sendon JL, Luther JF, Nigro Maia L, Quigley JG, Wahid L, Wilson JG, Zarychanski R, Kindzelski A, Geraci MW, Hochman JS; ACTIV-4a Investigators. Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2314428. doi: 10.1001/jamanetworkopen.2023.14428.
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Goligher EC, Lawler PR, Jensen TP, Talisa V, Berry LR, Lorenzi E, McVerry BJ, Chang CH, Leifer E, Bradbury C, Berger J, Hunt BJ, Castellucci LA, Kornblith LZ, Gordon AC, McArthur C, Webb S, Hochman J, Neal MD, Zarychanski R, Berry S, Angus DC; REMAP-CAP, ATTACC, and ACTIV-4a Investigators. Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19. JAMA. 2023 Apr 4;329(13):1066-1077. doi: 10.1001/jama.2023.3651.
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Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
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DERIVED
Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.
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DERIVED
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
ACTIV-4 ACUTE
Identifier Type: -
Identifier Source: org_study_id
NCT04359277
Identifier Type: -
Identifier Source: nct_alias