Purpose

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

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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.

Study Design

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

Arm Groups

ArmDescriptionAssigned Intervention
Other
Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care. 1.0 - This arm was stopped in severe patients in December 2020 1.1 - this arm was stopped for moderate patients in June 2021
  • Drug: theraputic heparin
    increased dose of heparin above standard of care.
    Other names:
    • unfractionated heparin
    • Enoxaparin
    • Dalteparin
    • Tinzaparin
    • Heparin
Other
Prophylactic Dose Anticoagulation
Heparin standard of care 1.0 - this arm was stopped for all patients in January, 2021. 1.1 - this arm was reinstated for severe patients.
  • Drug: prophylactic heparin
    standard of care dose of heparin
    Other names:
    • enoxaparin
    • dalteparin
    • Tinzaparin
    • Fondparinux
    • Heparin
Other
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.
  • Drug: theraputic heparin
    increased dose of heparin above standard of care.
    Other names:
    • unfractionated heparin
    • Enoxaparin
    • Dalteparin
    • Tinzaparin
    • Heparin
  • Drug: P2Y12
    added P2Y12 inhibitor
    Other names:
    • Ticagrelor
    • Prasugrel
    • Clopidogrel
Other
Prophylactic Dose Anticoagulation + P2Y12 inhibitor
Heparin standard of care with an added P2Y12 inhibitor This Arm enrolled severe illness patients only.
  • Drug: prophylactic heparin
    standard of care dose of heparin
    Other names:
    • enoxaparin
    • dalteparin
    • Tinzaparin
    • Fondparinux
    • Heparin
  • Drug: P2Y12
    added P2Y12 inhibitor
    Other names:
    • Ticagrelor
    • Prasugrel
    • Clopidogrel
Other
Standard of Care + Crizanlizumab
Standard of care plus crizanlizumab infusion This arm will enroll moderate and severe illness patients
  • Drug: Crizanlizumab Injection
    crizanlizumab injection
Other
Standard of Care + SGLT2 inhibitor
Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients
  • Drug: SGLT2 inhibitor
    sglt2 inhibitor
    Other names:
    • dapagliflozin
    • empagliflozin
    • canagliflozin
    • ertugliflozin

Recruiting Locations

University of Alabama
Birmingham, Alabama 35233
Contact:
Shetal Gandotra

University of Arizona
Tucson, Arizona 85719
Contact:
Bellal Joseph

University of Arkansas for Medical Sciences
Little Rock, Arkansas 72205
Contact:
Srikanth Vallurupalli

Kaiser Permanente Fontana
Fontana, California 92335
Contact:
Conrad Liang

Kaiser Permanente Los Angeles
Los Angeles, California 90027
Contact:
Zahra Ajani

Smidt Heart Institute at Cedars-Sinai
Los Angeles, California 90048
Contact:
Oren Friedman

Ronald Reagan UCLA Medical Center
Los Angeles, California 90095
Contact:
George Lim

UC San Diego Hillcrest
San Diego, California 92103
Contact:
Todd Constantini

Zuckerberg San Francisco General Hospital
San Francisco, California 94110
Contact:
Lucy Kornblith

UCSF San Francisco
San Francisco, California 94143
Contact:
Michael Matthay

Zuckerberg San Francisco General Hospital
San Francisco, California 94410
Contact:
Lucy Kornblith

Stanford University Medical Center
Stanford, California 94305
Contact:
Jennifer Wilson

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Torrance, California 90502
Contact:
Janine Vintch

Denver Health and Hospital Authority
Denver, Colorado 80401
Contact:
Mitchell Cohen

St. Mary's Hospital & Regional Medical Center
Grand Junction, Colorado 81501
Contact:
Logan McDaneld

Saint Francis Hospital and Medical Center
Hartford, Connecticut 06105
Contact:
Sudhanshu Mulay

University of Florida
Gainesville, Florida 32608
Contact:
Marie-Carmelle Elie

Memorial Hospital
Jacksonville, Florida 32216
Contact:
Mohannad Bisharat

AdventHealth Tampa
Tampa, Florida 33613
Contact:
Octavio Cosme

Emory
Atlanta, Georgia 30308
Contact:
Manila Gaddh

Morehouse School of Medicine
Atlanta, Georgia 30310
Contact:
Melvin Echols

Queens Medical Center
Honolulu, Hawaii 96813
Contact:
Stephanie Guo

Memorial Hospital
Belleville, Illinois 62226
Contact:
Omar Almousalli

Cook County Health
Chicago, Illinois 60612
Contact:
Saurabh Malhotra

University of Illinois at Chicago Health (UIH)
Chicago, Illinois 60612
Contact:
John Quigley

OSF Little Company of Mary Medical Center (OSF LCM)
Evergreen Park, Illinois 60805
Contact:
M. Bassel Atassi

Indiana University Health Methodist Hospital
Indianapolis, Iowa 46202
Contact:
Rajat Kapoor

Kansas University Medical Center
Kansas City, Kansas 66160
Contact:
Lewis Satterwhite

Ochsner Clinic Foundation
New Orleans, Louisiana 70121
Contact:
Mark Effron

Boston University
Boston, Massachusetts 02118
Contact:
Naomi Hamburg

St Elizabeth's Medical Center
Brighton, Massachusetts 02135
Contact:
Michael Johnstone

Baystate Medical Center
Springfield, Massachusetts 01199
Contact:
Mark Tidswell

University of Massachusetts
Worcester, Massachusetts 01655
Contact:
Alonso Alvaro

University of Michigan
Ann Arbor, Michigan 48109
Contact:
Robert Hyzy

Wayne State University
Detroit, Michigan 48201
Contact:
Robert Sherwin

Hennepin County Medical Center
Minneapolis, Minnesota 55415
Contact:
Matt Prekker

University of Mississippi Medical Center
Jackson, Mississippi 39216
Contact:
Matthew Kutcher

Washington University School of Medicine, ACCS Research
Saint Louis, Missouri 63110
Contact:
Grant Bochicchio

University Medical Center of Southern Nevada
Las Vegas, Nevada 89102
Contact:
Chowdhury Ahsan

Cooper Health
Camden, New Jersey 08103
Contact:
Nitin Puri

Englewood Health
Englewood, New Jersey 07631
Contact:
Ashwin Jathavedam

Atlantic Health System
Morristown, New Jersey 07960
Contact:
Eric Whitman

Rutgers New Jersey Medical School
Newark, New Jersey 07103
Contact:
Yonatan Greenstein

AtlantiCare Regional Medical Center
Pomona, New Jersey 08240
Contact:
Anthony Macchiavelli

Albany Medical College
Albany, New York 12208
Contact:
Mandeep Sidhu

Jacobi Medical Center
Bronx, New York 10461
Contact:
Eleonora Gashi

Montefiore Medical Center
Bronx, New York 10461
Contact:
Michelle Gong

Mercy Hospital Buffalo
Buffalo, New York 14220
Contact:
Raed Alnaji

VA New York Harbor Healthcare System
New York, New York 10010
Contact:
Binita Shah

NYU Langone
New York, New York 10016
Contact:
Jeffrey Berger, MD
212-263-0855
Jeffrey.Berger@nyulangone.org

Mt. Sinai Hospital
New York, New York 10029
Contact:
Lynne Richardson

SUNY Upstate University Hospital
Syracuse, New York 13210
Contact:
Julius Gene Latorre

Westchester Medical Center
Valhalla, New York 10595
Contact:
Stephen Pan

Duke University Hospital
Durham, North Carolina 27704
Contact:
Lana Wahid

Wake Forest
Winston-Salem, North Carolina 27157
Contact:
Ashish Khanna

Cleveland Clinic Akron General
Akron, Ohio 44307
Contact:
Lokesh Venkatashaiah

University of Cincinnati Medical Center
Cincinnati, Ohio 45219
Contact:
Kristin Hudock

The MetroHealth System
Cleveland, Ohio 44109
Contact:
Vidya Krishnan

Cleveland Clinic Foundation
Cleveland, Ohio 44195
Contact:
Abhijit Duggal

Ohio State Universtiy Wexner Medical Center
Columbus, Ohio 43210
Contact:
Matthew Exline

Mercy Health St Vincent Medical Center
Toledo, Ohio 43608
Contact:
Salil Avasthi

Ascension St. John Clinical Research Institute
Tulsa, Oklahoma 74104
Contact:
Nicholas Hanna

Oregon Health and Science University
Portland, Oregon 97239
Contact:
Akram Kahn

Geisinger Research
Danville, Pennsylvania 17822
Contact:
Parth Rao

Doylestown Cardiology Associates
Doylestown, Pennsylvania 18901
Contact:
Joseph McGarvey

Penn State Health Milton S. Hershey Medical Center
Hershey, Pennsylvania 17033
Contact:
Steven Moore

Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania 19104
Contact:
Allyson Pishko

Temple University
Philadelphia, Pennsylvania 19141
Contact:
Michael Bromberg

UPMC Presbyterian
Pittsburgh, Pennsylvania 15260
Contact:
David Huang

Rhode Island Hospital
Providence, Rhode Island 02903
Contact:
Ralph Rogers

The Miriam Hospital
Providence, Rhode Island 02906
Contact:
Ralph Rogers

Sarah Cannon and HCA Research Institute
Nashville, Tennessee 37203
Contact:
Andrew Goodman

Skyline Medical Center
Nashville, Tennessee 37207
Contact:
John Witt

University of Texas at Austin
Austin, Texas 78701
Contact:
Hemali Patel

University of Texas Southwestern Medical Center
Dallas, Texas 75390
Contact:
Ambarish Pandey

Medical City Ft Worth
Fort Worth, Texas 76104
Contact:
Ranjit Nair

Baylor Scott and White Medical Center - Temple
Temple, Texas 76508
Contact:
Robert Widmer

HCA Henrico Doctors Hospital
Richmond, Virginia 23229
Contact:
Amish Shah

Swedish Hospital
Seattle, Washington 98122
Contact:
David Wilson

West Virginia University CTR
Morgantown, West Virginia 26506
Contact:
Sunil Sharma

University of Wisconsin Hospital; Meriter Hospital (UW affiliated)
Madison, Wisconsin 53715
Contact:
John Sheehan

More Details

NCT ID
NCT04505774
Status
Recruiting
Sponsor
Matthew Neal MD

Study Contact

Judith Hochman, MD
212-263-6927
Judith.Hochman@nyulangone.org

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.). 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.