Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)
Covid19
About this trial
This is an interventional treatment trial for Covid19 focused on measuring anti-coagulation, antithrombosis, anticoagulation, ACTIV, inpatient, heparin, p2y12, endothelial dysfunction, vascular integrity, P-selectin, crizanlizumab, SGLT-2 inhibitor
Eligibility Criteria
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:
- Age ≥ 65 years or
≥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:
- Age ≥ 65 years or
≥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.
Sites / Locations
- University of Alabama
- University of Arizona
- University of Arkansas for Medical Sciences
- Kaiser Permanente Fontana
- Kaiser Permanente Los Angeles
- Smidt Heart Institute at Cedars-Sinai
- Ronald Reagan UCLA Medical Center
- UC San Diego Hillcrest
- Zuckerberg San Francisco General Hospital
- UCSF San Francisco
- Zuckerberg San Francisco General Hospital
- Stanford University Medical Center
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Denver Health and Hospital Authority
- St. Mary's Hospital & Regional Medical Center
- Saint Francis Hospital and Medical Center
- University of Florida
- Memorial Hospital
- AdventHealth Tampa
- Emory
- Morehouse School of Medicine
- Queens Medical Center
- Memorial Hospital
- Cook County Health
- University of Illinois at Chicago Health (UIH)
- OSF Little Company of Mary Medical Center (OSF LCM)
- Indiana University Health Methodist Hospital
- Kansas University Medical Center
- Ochsner Clinic Foundation
- Boston University
- St Elizabeth's Medical Center
- Baystate Medical Center
- University of Massachusetts
- University of Michigan
- Wayne State University
- Hennepin County Medical Center
- University of Mississippi Medical Center
- Washington University School of Medicine, ACCS Research
- University Medical Center of Southern Nevada
- Cooper Health
- Englewood Health
- Atlantic Health System
- Rutgers New Jersey Medical School
- AtlantiCare Regional Medical Center
- Albany Medical College
- Jacobi Medical Center
- Montefiore Medical Center
- Mercy Hospital Buffalo
- VA New York Harbor Healthcare System
- NYU Langone
- Mt. Sinai Hospital
- SUNY Upstate University Hospital
- Westchester Medical Center
- Duke University Hospital
- Wake Forest
- Cleveland Clinic Akron General
- University of Cincinnati Medical Center
- The MetroHealth System
- Cleveland Clinic Foundation
- Ohio State Universtiy Wexner Medical Center
- Mercy Health St Vincent Medical Center
- Ascension St. John Clinical Research Institute
- Oregon Health and Science University
- Geisinger Research
- Doylestown Cardiology Associates
- Penn State Health Milton S. Hershey Medical Center
- Hospital of the University of Pennsylvania
- Temple University
- UPMC Presbyterian
- Rhode Island Hospital
- The Miriam Hospital
- Sarah Cannon and HCA Research Institute
- Skyline Medical Center
- University of Texas at Austin
- University of Texas Southwestern Medical Center
- Medical City Ft Worth
- Baylor Scott and White Medical Center - Temple
- HCA Henrico Doctors Hospital
- Swedish Hospital
- West Virginia University CTR
- University of Wisconsin Hospital; Meriter Hospital (UW affiliated)
- Hospital Universitario Sao Francisco de Assis
- União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS
- Centro de Estudos Clínicos do Hospital Cárdio Pulmonar
- Fundação Faculdade Regional De Medicina De São José Do Rio Preto
- Instituto Dante Pazzanese de Cardiologia
- Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP
- Azienda Ospedaliero Sant Anna e San Sebastiano
- Maria Cecilia Hospital , Cotignola, Ravenna
- Università degli Studi di Ferrara, Ferrara
- Azienda Ospedaliero -Universitaria Careggi
- Policlinico di Napoli, Napoli
- AOU Policlinico di Palermo, Palermo
- ASL-1 Imperiese, Sanremo
- Hospital Universitario A Coruna
- Hospital Virgen del Mar
- Hospital Arnau de Vilanova
- Hospital Universitario La Paz
- Hospital Universitario Ramon Y Cajal
- Hospital Clínico Universitario de Salamanca
- Hospital Clínico Universitario de Santiago de Compostela
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Other
Other
Other
Other
Other
Other
Therapeutic Dose Anticoagulation
Prophylactic Dose Anticoagulation
Therapeutic Dose Anticoagulation + P2Y12 inhibitor
Prophylactic Dose Anticoagulation + P2Y12 inhibitor
Standard of Care + Crizanlizumab
Standard of Care + SGLT2 inhibitor
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.
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)
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)
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.
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.
Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients This arm was ended in March 2023