Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Drug: theraputic heparin
* Drug: prophylactic heparin
* Drug: P2Y12
* Drug: Crizanlizumab Injection
* Drug: SGLT2 inhibitor


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an adaptive design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Therapeutic Dose Anticoagulation<br>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. | Drug: theraputic heparin<br>* increased dose of heparin above standard of care.<br>* Other names: Heparin;|
| Other: Prophylactic Dose Anticoagulation<br>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) | Drug: prophylactic heparin<br>* standard of care dose of heparin<br>* Other names: Heparin;|
| Other: Therapeutic Dose Anticoagulation + P2Y12 inhibitor<br>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) | Drug: theraputic heparin<br>* increased dose of heparin above standard of care.<br>* Other names: Heparin;Drug: P2Y12<br>* added P2Y12 inhibitor<br>* Other names: Clopidogrel;|
| Other: Prophylactic Dose Anticoagulation + P2Y12 inhibitor<br>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. | Drug: prophylactic heparin<br>* standard of care dose of heparin<br>* Other names: Heparin;Drug: P2Y12<br>* added P2Y12 inhibitor<br>* Other names: Clopidogrel;|
| Other: Standard of Care + Crizanlizumab<br>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. | Drug: Crizanlizumab Injection<br>* crizanlizumab injection<br>|
| Other: Standard of Care + SGLT2 inhibitor<br>Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients This arm was ended in March 2023 | Drug: SGLT2 inhibitor<br>* sglt2 inhibitor<br>* Other names: ertugliflozin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-coagulation, antithrombosis, anticoagulation, ACTIV, inpatient, heparin, p2y12, endothelial dysfunction, vascular integrity, P-selectin, crizanlizumab, SGLT-2 inhibitor