Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19

Study Overview
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Brief Summary
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In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19. The first randomization entails open-label assignment to intermediate versus standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate dose compared with standard prophylactic dose anticoagulation will have a superior efficacy with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be double-blind assignment of the included patients to atorvastatin 20mg daily versus matching placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the composite of VTE, need for ECMO, or all-cause mortality.

Detailed Description
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Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the most common form of thrombotic involvement. Existing studies, depending on the type of outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85% of patients with COVID-19. However, the optimal antithrombotic regimen in these patients remains uncertain. Although many clinicians continue to consider standard-dose prophylactic anticoagulation, other believe that more intense anticoagulation may reduce the thrombotic events, and improve outcomes. However, limited high-quality data exist to inform clinical practice and the existing guidelines recommendations are mostly based on expert opinion and consensus. In addition, exuberant inflammatory response is known to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects, prove beneficial in patients with severe COVID-19. This study plans to investigate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design. First, patients will be assessed for the eligibility criteria for the anticoagulation hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose prophylactic anticoagulation. These patients will subsequently be assessed for eligibility for the second randomization, and if meeting the criteria, will be assigned to atorvastatin 20mg/d or matching placebo.

Official Title
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Intermediate-dose Versus Standard Prophylactic Anticoagulation In cRitically-ill pATIents With COVID-19: An opeN Label Randomized Controlled Trial---A Randomized Trial of Atorvastatin vs. Placebo In Critically-ill Patients With COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Drug: intermediate dose Enoxaparin/ unfractionated heparin
* Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin
* Drug: Atorvastatin 20mg
* Drug: Matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Anticoagulation Hypothesis Adult patients (≥18 years), with polymerase chain reaction (PCR)-confirmed COVID-19 admitted to ICU within 7 days of initial hospitalization , who do not have another firm indication for anticoagulation (such as mechanical valve, high-risk atrial fibrillation (AF), VTE, or left ventricle (LV) thrombus),who are not enrolled in another blinded randomized trial, and are willing to participate in the study and provide informed consent . Estimated survival of at least 24 hours at the discretion of enrolling physician Exclusion Criteria for Anticoagulation Hypothesis Weight <40 Kilogram (kg) Overt bleeding at the day of enrollment Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A) Platelet count <50,000/Fl Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients <50 years) Patients on Extracorporeal Membrane Oxygenation (ECMO) History of heparin induced thrombocytopenia or immune thrombocytopenia Ischemic stroke within the past 2 weeks Craniotomy/major neurosurgery within the past 3 months Major head or spinal trauma in the past 30 days Known brain metastases or vascular malformations (aneurysm) Presence of an epidural, spinal or pericardial catheter Major surgery other than neurosurgery within 14 days prior to enrollment Coexistence of severe obesity (weight >120 kg or BMI>35 kg/m2 along with severe renal insufficiency defined as creatinine clearance (CrCl) <30 mL/sec) Allergic reaction to study medications Lack or withdrawal of informed consent Inclusion Criteria for the Statin Randomization Patients enrolled for the anticoagulation randomization Willingness to participation in the study and providing informed consent Exclusions Criteria for the Statin Randomization Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis) Routine use of statins prior to the index hospitalization Previous documented statin intolerance

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: Factorial Assignment
Interventional Model Description: 1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermediate dose anticoagulation<br>Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula. | Drug: intermediate dose Enoxaparin/ unfractionated heparin<br>* Intermediate dose anticoagulation according to creatinine clearance and weight<br>* Other names: Intermediate dose anticoagulation;|
| Active Comparator: Standard Prophylaxis<br>Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula. | Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin<br>* Standard prophylaxis anticoagulation according to creatinine clearance and weight<br>* Other names: Standard dose prophylaxis anticoagulation;|
| Experimental: Atorvastatin 20<br>Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm | Drug: Atorvastatin 20mg<br>* Statin<br>* Other names: Statin;|
| Placebo Comparator: Atorvastatin 20 mg Matched placebo<br>Matching placebo will be used for the control arm | Drug: Matched placebo<br>* Matched placebo to atorvastatin 20 mg<br>* Other names: Statin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality | composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. | 30 days from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of all-cause mortality | Patient status regarding to being alive or dead at the end of 30-day follow up | 30 days from enrollment | 
| Rate of objectively-confirmed VTE | Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan | 30 days from enrollment | 
| Ventilator free days | Difference between days of ICU stay and days on invasive mechanical ventilation | 30 days from enrollment | 
| Rate of major bleeding | According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding) | 30 days from enrollment | 
| Rate of clinically-relevant non-major bleeding | Clinically-significant bleeding, not fulfilling criteria for major bleeding) | 30 days from enrollment | 
| Rate of severe thrombocytopenia | Platelet count <20.000 | 30 days from enrollment | 
| Rate of rise in liver enzymes | Increase liver function tests 3 times greater than upper limit of normal | 30 days from enrollment | 
| Clinically-diagnosed myopathy | Assessed by clinical and biomarker tests according to the treating physicians. | 30 days from enrollment | 
| Objectively-confirmed arterial thrombosis | Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography) | 30 days from enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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statin, anticoagulation