Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE

Phase 4

Completed

Conditions: Covid19

Interventions: Drug: prophylactic heparin
Drug: theraputic heparin
Drug: SGLT2 inhibitor
Drug: Crizanlizumab Injection
Drug: P2Y12

Registration Number: NCT04505774

Lead Sponsor: Matthew Neal MD

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3591

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Prophylactic Dose Anticoagulation	prophylactic heparin	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)
Therapeutic Dose Anticoagulation + P2Y12 inhibitor	theraputic heparin	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)
Therapeutic Dose Anticoagulation + P2Y12 inhibitor	P2Y12	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)
Prophylactic Dose Anticoagulation + P2Y12 inhibitor	P2Y12	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 + SGLT2 inhibitor	SGLT2 inhibitor	Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients This arm was ended in March 2023
Standard of Care (SGLT2 arm)	SGLT2 inhibitor	Standard of care only This arm will enroll moderate and severe illness patients This arm was ended in March 2023
Standard of Care + Crizanlizumab	Crizanlizumab Injection	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 (Criza)	Crizanlizumab Injection	Standard of care only This arm will enroll moderate and severe illness patients This arm was ended for all patients per the DSMB in September 2022.
Therapeutic Dose Anticoagulation	theraputic heparin	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.
Prophylactic Dose Anticoagulation + P2Y12 inhibitor	prophylactic heparin	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.

Primary Outcome Measures

Name	Time	Method
21 Day Organ Support (Respiratory or Vasopressor) Free Days	21 days from study enrollment	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. This outcome variable was designed to exceed day 21 on the IQR. It goes above 21 days because it include baseline day 0 in their design.

Secondary Outcome Measures

Name	Time	Method
Acute Kidney Injury	90 days from enrollment	Acute Kidney Injury Acute kidney injury after enrollment is defined by KDIGO criteria for Acute Kidney Injury in the setting of not meeting these criteria upon enrollment: Modified Stages: ∙ Stage 2: Serum Cr 2.0-2.9 times baseline ∙ Stage 3: Serum Cr ≥ 3.0 times baseline, OR Increase in serum creatinine to ≥ 4.0mg/dl, OR Initiation of renal replacement therapy
Major Thrombotic Event or in Hospital Death	28 days	A composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke during hospitalization or at 28 days after enrollment (whichever is earlier) - "major thrombotic events or death"
Any Thrombotic Event or in Hospital Death	28 days	A composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, DVT, or ischemic stroke during hospitalization or at 28 days after enrollment (whichever is earlier)
Any Renal Replacement Therapy	28 days
Days Free of Organ Support and Renal Replacement Therapy	28 days	This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Ventilator Free Days up to Day 28	28 days	This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Days Free of Vasopressors	28 days	This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Progression to Intubation or Death	28 days	analysis completed on the Heparin protocol
Survival Until Discharge	28 days
Death Within 28 Days	28 days from enrollment

Trial Locations

Locations (99): University of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Arizona
🇺🇸
Tucson, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Fontana
🇺🇸
Fontana, California, United States
Kaiser Permanente Los Angeles
🇺🇸
Los Angeles, California, United States
Smidt Heart Institute at Cedars-Sinai
🇺🇸
Los Angeles, California, United States
Ronald Reagan UCLA Medical Center
🇺🇸
Los Angeles, California, United States
UC San Diego Hillcrest
🇺🇸
San Diego, California, United States
Zuckerberg San Francisco General Hospital
🇺🇸
San Francisco, California, United States
UCSF San Francisco
🇺🇸
San Francisco, California, United States
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University of Alabama
🇺🇸Birmingham, Alabama, United States