Clinical trial NCT04505774: Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE
Official title: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Covid19
Keywords: anti-coagulation
antithrombosis
anticoagulation
ACTIV
inpatient
heparin
p2y12
endothelial dysfunction
vascular integrity
P-selectin
crizanlizumab
SGLT-2 inhibitor
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2020-08-10
Enrollment: 3591
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an adaptive design
Primary purpose: TREATMENT

Brief summary: 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: 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.

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:

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.

Primary outcomes:
measure: 21 Day Organ Support (Respiratory or Vasopressor) Free Days
timeFrame: 21 days from study enrollment
Secondary outcomes:
measure: Death Within 28 Days
timeFrame: 28 days from enrollment
measure: Acute Kidney Injury
timeFrame: 90 days from enrollment
measure: Major Thrombotic Event or in Hospital Death
timeFrame: 28 days
measure: Any Thrombotic Event or in Hospital Death
timeFrame: 28 days
measure: Any Renal Replacement Therapy
timeFrame: 28 days
measure: Days Free of Organ Support and Renal Replacement Therapy
timeFrame: 28 days
measure: Ventilator Free Days up to Day 28
timeFrame: 28 days
measure: Days Free of Vasopressors
timeFrame: 28 days
measure: Progression to Intubation or Death
timeFrame: 28 days
measure: Survival Until Discharge
timeFrame: 28 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Fontana
country: United States
facility: Kaiser Permanente Fontana
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles
state: California
city: Los Angeles
country: United States
facility: Smidt Heart Institute at Cedars-Sinai
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: San Diego
country: United States
facility: UC San Diego Hillcrest
state: California
city: San Francisco
country: United States
facility: Zuckerberg San Francisco General Hospital
state: California
city: San Francisco
country: United States
facility: UCSF San Francisco
state: California
city: San Francisco
country: United States
facility: Zuckerberg San Francisco General Hospital
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Torrance
country: United States
facility: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
state: California
city: Denver
country: United States
facility: Denver Health and Hospital Authority
state: Colorado
city: Grand Junction
country: United States
facility: St. Mary's Hospital & Regional Medical Center
state: Colorado
city: Hartford
country: United States
facility: Saint Francis Hospital and Medical Center
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Memorial Hospital
state: Florida
city: Tampa
country: United States
facility: AdventHealth Tampa
state: Florida
city: Atlanta
country: United States
facility: Emory
state: Georgia
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Honolulu
country: United States
facility: Queens Medical Center
state: Hawaii
city: Belleville
country: United States
facility: Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Cook County Health
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Health (UIH)
state: Illinois
city: Evergreen Park
country: United States
facility: OSF Little Company of Mary Medical Center (OSF LCM)
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Hospital
state: Iowa
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Brighton
country: United States
facility: St Elizabeth's Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine, ACCS Research
state: Missouri
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Camden
country: United States
facility: Cooper Health
state: New Jersey
city: Englewood
country: United States
facility: Englewood Health
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Pomona
country: United States
facility: AtlantiCare Regional Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Mercy Hospital Buffalo
state: New York
city: New York
country: United States
facility: VA New York Harbor Healthcare System
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate University Hospital
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest
state: North Carolina
city: Akron
country: United States
facility: Cleveland Clinic Akron General
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: The MetroHealth System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State Universtiy Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: Mercy Health St Vincent Medical Center
state: Ohio
city: Tulsa
country: United States
facility: Ascension St. John Clinical Research Institute
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Danville
country: United States
facility: Geisinger Research
state: Pennsylvania
city: Doylestown
country: United States
facility: Doylestown Cardiology Associates
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Skyline Medical Center
state: Tennessee
city: Austin
country: United States
facility: University of Texas at Austin
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Medical City Ft Worth
state: Texas
city: Temple
country: United States
facility: Baylor Scott and White Medical Center - Temple
state: Texas
city: Richmond
country: United States
facility: HCA Henrico Doctors Hospital
state: Virginia
city: Seattle
country: United States
facility: Swedish Hospital
state: Washington
city: Morgantown
country: United States
facility: West Virginia University CTR
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital; Meriter Hospital (UW affiliated)
state: Wisconsin
city: Braganca Paulista
country: Brazil
facility: Hospital Universitario Sao Francisco de Assis
city: Porto Alegre
country: Brazil
facility: União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS
city: Salvador
country: Brazil
facility: Centro de Estudos Clínicos do Hospital Cárdio Pulmonar
city: São José do Rio Preto
country: Brazil
facility: Fundação Faculdade Regional De Medicina De São José Do Rio Preto
city: São Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
city: São Paulo
country: Brazil
facility: Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP
city: Caserta
country: Italy
facility: Azienda Ospedaliero Sant Anna e San Sebastiano
city: Cotignola
country: Italy
facility: Maria Cecilia Hospital , Cotignola, Ravenna
city: Ferrara
country: Italy
facility: Università degli Studi di Ferrara, Ferrara
city: Firenze
country: Italy
facility: Azienda Ospedaliero -Universitaria Careggi
city: Napoli
country: Italy
facility: Policlinico di Napoli, Napoli
city: Palermo
country: Italy
facility: AOU Policlinico di Palermo, Palermo
city: Sanremo
country: Italy
facility: ASL-1 Imperiese, Sanremo
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruna
city: Almeria
country: Spain
facility: Hospital Virgen del Mar
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
Study officials:
affiliation: NYU Langone Health
name: Judith Hochman, MD
role: STUDY_CHAIR
affiliation: Brigham and Women's Hospital
name: Scott Solomon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Saint Lukes
name: Mikhail Kosiborod, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU Langone Health
name: Jeffrey Berger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: MATTHEW D NEAL, MD
role: STUDY_CHAIR
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