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
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.
Drug: theraputic heparin
increased dose of heparin above standard of care.
Other Name: Array
Drug: prophylactic heparin
standard of care dose of heparin
Other Name: Array
Drug: P2Y12
added P2Y12 inhibitor
Other Name: Array
Drug: Crizanlizumab Injection
crizanlizumab injection
Drug: SGLT2 inhibitor
sglt2 inhibitor
Other Name: Array
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
Inclusion Criteria for Arm E
Inclusion criteria contained in the master protocol in addition to the following:
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 for Arm E
- Exclusion criteria contained in the master protocol, and
- 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
Inclusion Criteria for Arm F
Inclusion criteria contained in the master protocol in addition to the following:
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 for Arm F
In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion
criteria are as follows:
- 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.
University of Alabama
Birmingham, Alabama, United States
University of Arizona
Tucson, Arizona, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Kaiser Permanente Fontana
Fontana, California, United States
Kaiser Permanente Los Angeles
Los Angeles, California, United States
Smidt Heart Institute at Cedars-Sinai
Los Angeles, California, United States
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
UC San Diego Hillcrest
San Diego, California, United States
Zuckerberg San Francisco General Hospital
San Francisco, California, United States
UCSF San Francisco
San Francisco, California, United States
Zuckerberg San Francisco General Hospital
San Francisco, California, United States
Stanford University Medical Center
Stanford, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Torrance, California, United States
Denver Health and Hospital Authority
Denver, Colorado, United States
St. Mary's Hospital & Regional Medical Center
Grand Junction, Colorado, United States
Saint Francis Hospital and Medical Center
Hartford, Connecticut, United States
University of Florida
Gainesville, Florida, United States
Memorial Hospital
Jacksonville, Florida, United States
AdventHealth Tampa
Tampa, Florida, United States
Emory
Atlanta, Georgia, United States
Morehouse School of Medicine
Atlanta, Georgia, United States
Queens Medical Center
Honolulu, Hawaii, United States
Memorial Hospital
Belleville, Illinois, United States
Cook County Health
Chicago, Illinois, United States
University of Illinois at Chicago Health (UIH)
Chicago, Illinois, United States
OSF Little Company of Mary Medical Center (OSF LCM)
Evergreen Park, Illinois, United States
Indiana University Health Methodist Hospital
Indianapolis, Iowa, United States
Kansas University Medical Center
Kansas City, Kansas, United States
Ochsner Clinic Foundation
New Orleans, Louisiana, United States
Boston University
Boston, Massachusetts, United States
St Elizabeth's Medical Center
Brighton, Massachusetts, United States
Baystate Medical Center
Springfield, Massachusetts, United States
University of Massachusetts
Worcester, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Wayne State University
Detroit, Michigan, United States
Hennepin County Medical Center
Minneapolis, Minnesota, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
Washington University School of Medicine, ACCS Research
Saint Louis, Missouri, United States
University Medical Center of Southern Nevada
Las Vegas, Nevada, United States
Cooper Health
Camden, New Jersey, United States
Englewood Health
Englewood, New Jersey, United States
Atlantic Health System
Morristown, New Jersey, United States
Rutgers New Jersey Medical School
Newark, New Jersey, United States
AtlantiCare Regional Medical Center
Pomona, New Jersey, United States
Albany Medical College
Albany, New York, United States
Jacobi Medical Center
Bronx, New York, United States
Montefiore Medical Center
Bronx, New York, United States
Mercy Hospital Buffalo
Buffalo, New York, United States
VA New York Harbor Healthcare System
New York, New York, United States
NYU Langone
New York, New York, United States
Mt. Sinai Hospital
New York, New York, United States
SUNY Upstate University Hospital
Syracuse, New York, United States
Westchester Medical Center
Valhalla, New York, United States
Duke University Hospital
Durham, North Carolina, United States
Wake Forest
Winston-Salem, North Carolina, United States
Cleveland Clinic Akron General
Akron, Ohio, United States
University of Cincinnati Medical Center
Cincinnati, Ohio, United States
The MetroHealth System
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Ohio State Universtiy Wexner Medical Center
Columbus, Ohio, United States
Mercy Health St Vincent Medical Center
Toledo, Ohio, United States
Ascension St. John Clinical Research Institute
Tulsa, Oklahoma, United States
Oregon Health and Science University
Portland, Oregon, United States
Geisinger Research
Danville, Pennsylvania, United States
Doylestown Cardiology Associates
Doylestown, Pennsylvania, United States
Penn State Health Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Temple University
Philadelphia, Pennsylvania, United States
UPMC Presbyterian
Pittsburgh, Pennsylvania, United States
Rhode Island Hospital
Providence, Rhode Island, United States
The Miriam Hospital
Providence, Rhode Island, United States
Sarah Cannon and HCA Research Institute
Nashville, Tennessee, United States
Skyline Medical Center
Nashville, Tennessee, United States
University of Texas at Austin
Austin, Texas, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Medical City Ft Worth
Fort Worth, Texas, United States
Baylor Scott and White Medical Center - Temple
Temple, Texas, United States
HCA Henrico Doctors Hospital
Richmond, Virginia, United States
Swedish Hospital
Seattle, Washington, United States
West Virginia University CTR
Morgantown, West Virginia, United States
University of Wisconsin Hospital; Meriter Hospital (UW affiliated)
Madison, Wisconsin, United States
Hospital Universitario Sao Francisco de Assis
Braganca Paulista, Brazil
União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS
Porto Alegre, Brazil
Centro de Estudos Clínicos do Hospital Cárdio Pulmonar
Salvador, Brazil
Fundação Faculdade Regional De Medicina De São José Do Rio Preto
São José do Rio Preto, Brazil
Instituto Dante Pazzanese de Cardiologia
São Paulo, Brazil
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP
São Paulo, Brazil
Azienda Ospedaliero Sant Anna e San Sebastiano
Caserta, Italy
Maria Cecilia Hospital , Cotignola, Ravenna
Cotignola, Italy
Università degli Studi di Ferrara, Ferrara
Ferrara, Italy
Azienda Ospedaliero -Universitaria Careggi
Firenze, Italy
Policlinico di Napoli, Napoli
Napoli, Italy
AOU Policlinico di Palermo, Palermo
Palermo, Italy
ASL-1 Imperiese, Sanremo
Sanremo, Italy
Hospital Universitario A Coruna
A Coruna, Spain
Hospital Virgen del Mar
Almeria, Spain
Hospital Arnau de Vilanova
Lleida, Spain
Hospital Universitario La Paz
Madrid, Spain
Hospital Universitario Ramon Y Cajal
Madrid, Spain
Hospital Clínico Universitario de Salamanca
Salamanca, Spain
Hospital Clínico Universitario de Santiago de Compostela
Santiago de Compostela, Spain