Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)

  • STATUS
    Recruiting
  • End date
    Jun 12, 2023
  • participants needed
    3000
  • sponsor
    Matthew Neal MD
Updated on 12 July 2022

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.

Details
Condition Covid19
Treatment SGLT2 inhibitor, theraputic heparin, prophylactic heparin, P2Y12, Crizanlizumab Injection
Clinical Study IdentifierNCT04505774
SponsorMatthew Neal MD
Last Modified on12 July 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

Imminent death
Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
Pregnancy
Inclusion Criteria for Arm E
Exclusion Criteria for Arm E
Exclusion criteria contained in the master protocol, and
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
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)
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