Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE

Covid19 Clinical Trial

— ACTIV-4A  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04505774
• Other study ID #: ACTIV-4 ACUTE
• Secondary ID: 1OT2HL156812-01
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: September 4, 2020
• Est. completion date: June 1, 2024

Study information

• Verified date: April 2024
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Other known NCT identifiers

• NCT04359277

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 3239
• Est. completion date: June 1, 2024
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID-19
• Covid19

Intervention

Drug:
• theraputic heparin
increased dose of heparin above standard of care.
• prophylactic heparin
standard of care dose of heparin
• P2Y12
added P2Y12 inhibitor
• Crizanlizumab Injection
crizanlizumab injection
• SGLT2 inhibitor
sglt2 inhibitor

Locations

Country	Name	City	State
Brazil	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
Italy	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
Spain	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
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Albany Medical College	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory	Atlanta	Georgia
United States	Morehouse School of Medicine	Atlanta	Georgia
United States	University of Texas at Austin	Austin	Texas
United States	Memorial Hospital	Belleville	Illinois
United States	University of Alabama	Birmingham	Alabama
United States	Boston University	Boston	Massachusetts
United States	St Elizabeth's Medical Center	Brighton	Massachusetts
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	Cooper Health	Camden	New Jersey
United States	Cook County Health	Chicago	Illinois
United States	University of Illinois at Chicago Health (UIH)	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	The MetroHealth System	Cleveland	Ohio
United States	Ohio State Universtiy Wexner Medical Center	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Geisinger Research	Danville	Pennsylvania
United States	Denver Health and Hospital Authority	Denver	Colorado
United States	Wayne State University	Detroit	Michigan
United States	Doylestown Cardiology Associates	Doylestown	Pennsylvania
United States	Duke University Hospital	Durham	North Carolina
United States	Englewood Health	Englewood	New Jersey
United States	OSF Little Company of Mary Medical Center (OSF LCM)	Evergreen Park	Illinois
United States	Kaiser Permanente Fontana	Fontana	California
United States	Medical City Ft Worth	Fort Worth	Texas
United States	University of Florida	Gainesville	Florida
United States	St. Mary's Hospital & Regional Medical Center	Grand Junction	Colorado
United States	Saint Francis Hospital and Medical Center	Hartford	Connecticut
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Queens Medical Center	Honolulu	Hawaii
United States	Indiana University Health Methodist Hospital	Indianapolis	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Memorial Hospital	Jacksonville	Florida
United States	Kansas University Medical Center	Kansas City	Kansas
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Kaiser Permanente Los Angeles	Los Angeles	California
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	Smidt Heart Institute at Cedars-Sinai	Los Angeles	California
United States	University of Wisconsin Hospital; Meriter Hospital (UW affiliated)	Madison	Wisconsin
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	West Virginia University CTR	Morgantown	West Virginia
United States	Atlantic Health System	Morristown	New Jersey
United States	Sarah Cannon and HCA Research Institute	Nashville	Tennessee
United States	Skyline Medical Center	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Mt. Sinai Hospital	New York	New York
United States	NYU Langone	New York	New York
United States	VA New York Harbor Healthcare System	New York	New York
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Temple University	Philadelphia	Pennsylvania
United States	UPMC Presbyterian	Pittsburgh	Pennsylvania
United States	AtlantiCare Regional Medical Center	Pomona	New Jersey
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	The Miriam Hospital	Providence	Rhode Island
United States	HCA Henrico Doctors Hospital	Richmond	Virginia
United States	Washington University School of Medicine, ACCS Research	Saint Louis	Missouri
United States	UC San Diego Hillcrest	San Diego	California
United States	UCSF San Francisco	San Francisco	California
United States	Zuckerberg San Francisco General Hospital	San Francisco	California
United States	Zuckerberg San Francisco General Hospital	San Francisco	California
United States	Swedish Hospital	Seattle	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Stanford University Medical Center	Stanford	California
United States	SUNY Upstate University Hospital	Syracuse	New York
United States	AdventHealth Tampa	Tampa	Florida
United States	Baylor Scott and White Medical Center - Temple	Temple	Texas
United States	Mercy Health St Vincent Medical Center	Toledo	Ohio
United States	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California
United States	University of Arizona	Tucson	Arizona
United States	Ascension St. John Clinical Research Institute	Tulsa	Oklahoma
United States	Westchester Medical Center	Valhalla	New York
United States	Wake Forest	Winston-Salem	North Carolina
United States	University of Massachusetts	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Matthew Neal MD	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Brazil,  Italy,  Spain, 

References & Publications (31)

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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. — View Citation

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Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17. — View Citation

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* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Primary Safety Endpoint of Major Bleeding	Major bleeding (as defined by the ISTH)	28 days from study enrollment
Other	Secondary Safety Endpoint of HIT	Confirmed heparin induced thrombocytopenia (HIT)	28 days from study enrollment
Primary	21 Day Organ Support (respiratory or vasopressor) Free Days	which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.	21 days from study enrollment
Secondary	Secondary Endpoint all cause mortality	Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)	28 days from study enrollment
Secondary	Other Platform Secondary Endpoints of Morbidity and Hospitalization	Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)	28 days from study enrollment
Secondary	Days free of death	Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.	28 days from enrollment
Secondary	Death Composite	Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.	28 days from enrollment
Secondary	Acute kidney injury	Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality	90 days from enrollment