COVID-19 Antithrombotic Rivaroxaban Evaluation

Study Overview
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Brief Summary
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There are several ways in which the COVID-19 pandemic may affect the prevention and management of thrombotic and thromboembolic disease, either direct effect or the indirect effects of infection, such as through severe illness and hypoxia, may predispose patients to thrombotic events. The severe inflammatory response, critical illness, and underlying traditional risk factors may all predispose to thrombotic events. Therefore, considering the high-risk profile of cardiovascular comorbidities in patients with COVID-19, it is scientifically relevant to evaluate the use of anticoagulants as an adjunctive treatment in the context of COVID-19. Indeed, it will be tested the hypothesis that the use of moderate dose of rivaroxaban has a beneficial effect in the treatment of patients with a confirmed or probable diagnosis of COVID-19 infection, with no clear indication for hospitalization (mild and moderate cases) upon initial medical care, by reducing the need of hospitalization due to complications related to COVID-19.

Detailed Description
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Initial studies suggest an inflammatory state and hypercoagulation in individuals with COVID-19. Apparently, the fact that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to Angiotensin Converting Enzyme 2 (ACE2) receptors can lead to ACE2 depletion by SARS-CoV-2 favoring the harmful ACE1 / angiotensin II and promoting tissue damage, including stroke. Recent observational studies indicate a higher rate of thromboembolism in patients with COVID-19, especially those in severe condition. They also report that, in patients treated with anticoagulants, complication rates were lower as compared with those not receiving anticoagulant therapies. More recently, in a post-mortem study of patients with Covid-19 compared to recently published cases of influenza, the histopathological pattern on the periphery of the lungs of patients with Covid-19 revealed a diffuse alveolar lesion with infiltration of perivascular T cells and other vascular aspects, consisting of severe endothelial damage (endothelitis) associated with the presence of intracellular viruses and broken cell membranes. In addition, pulmonary vessels showed generalized thrombosis with microangiopathy, and alveolar capillary microthrombi were much more frequent in patients with COVID-19 than with severe influenza respiratory conditions.

Official Title
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Randomized, Pragmatic, Open Controlled Multicentre Study, Evaluating the Use of Rivaroxaban in Mild or Moderate COVID-19 Patients

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Rivaroxaban 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years old; Evaluated in the emergency unit with probable or confirmed infection by COVID-19; Time between symptoms and inclusion ≤ 07 days *; Present mild or moderate signs and symptoms, with no clear indication for hospitalization; Present at least 2 risk factors for complication: 65 years Hypertension Diabetes mellitus Asthma Chronic Obstructive Pulmonary Disease (COPD) or other chronic lung diseases Smoking Immunosuppression Obesity (BMI> 30) History of non-active cancer Bed restriction or reduced mobility (≥50% of the wake time without walking) Previous history of VTE Use of oral hormonal contraceptives Exclusion Criteria: Patients <18 years old; Hospitalization indication upon first medical care; Positive test for influenza in the first visit; Any known liver disease associated with coagulopathy; INR (International Normalized Ratio) > 1.5; Pregnant, lactating or with the possibility of becoming pregnant and without using an adequate contraceptive method; High risk of bleeding; History of bronchiectasis or pulmonary cavitation, Significant bleeding in the last 3 months, Active gastroduodenal ulcer, history of recent bleeding (within 3 months) or a high risk of bleeding; Stroke within 1 month or any history of hemorrhagic or lacunar stroke or any intracranial bleeding or any intracranial neoplasia, brain metastasis, arteriovenous malformation or brain aneurysm; Severe heart failure with left ventricular ejection fraction <30% (echocardiogram or other validated method previously documented) or symptoms of heart failure class III or IV of the New York Heart Association (NYHA); Estimated glomerular filtration rate (eGFR) <30 mL / min; Clinical indication for dual antiplatelet therapy or anticoagulation therapy (VTE, atrial fibrillation / flutter, mechanical valve prosthesis); Marked thrombocytopenia (platelets <50,000 / mm3); Non-cardiovascular disease that is associated with a poor prognosis, for example, active cancer (excluding non-melanoma skin cancer) defined as cancer without remission or requiring active chemotherapy or adjuvant therapies such as immunotherapy or radiation therapy or that increases the risk of an adverse reaction to the evaluated interventions; History of hypersensitivity or known contraindication to rivaroxaban; Systemic treatment with strong inhibitors of Cytochrome P450 3A4 (CYP3A4) and glycoprotein p (Pgp) (for example, systemic azole antimycotics, such as ketoconazole and human immunodeficiency virus [HIV] protein inhibitors, such as ritonavir) or strong inducers of CYP 3A4, that is, rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine; Current treatment being tested; Concomitant participation in another study with experimental drugs in the context of COVID; Use of chloroquine or hydroxychloroquine associated with azithromycin; Active cancer; Other contraindications to rivaroxaban;

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: Parallel Assignment
Interventional Model Description: Pragmatic, open-label, controlled randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rivaroxaban 10 mg<br>Participants will receive, from the 1st to the 14th day, a dose of 10 mg of rivaroxaban - OA (Oral Administration). | Drug: Rivaroxaban 10 mg<br>* Rivaroxaban pharmaceutical form will be tablets of 10 mg<br>* Other names: Xarelto;|
| No Intervention: Best locally standardized care<br>According to the study protocol, participating investigators are advised to follow the best available local practice in each participating site. There is no formal recommendation for any particular COVID-19 treatment, except symptomatic therapies. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous thromboembolic events (VTE) | Defined as deep venous thrombosis, acute pulmonary embolism, other major venous thrombotic events. | Within 30 days from randomization | 
| Mechanical ventilation free-survival | Defined as survival without requirement of mechanical ventilation. | Within 30 days from randomization | 
| Major Adverse Cardiovascular Events (MACE) | Defined as acute myocardial infarction, stroke or acute limb ischemia | Within 30 days from randomization | 
| Out-of-hospital death not attributed to major injury | Death that occurred out of hospital due to any cause not related to trauma or other major injury | Within 30 days from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to hospitalization | Defined as time elapsed since randomization to hospital admission | 30 days from randomization | 
| Length of Hospitalization | To assess the duration of hospitalization (length of hospital stay) | 30 days from randomization | 
| Hospitalization in Intensive Care Unit | Requirement of admission to ICU for intensive care | 30 days from randomization | 
| Clinical requirement of mechanical ventilation | Requirement of oxygen supplementation through invasive or non invasive mechanical ventilation. | 30 days from randomization | 
| Clinical duration of mechanical ventilation | Total time on oxygen supplementation through invasive or non invasive mechanical ventilation | 30 days from randomization | 
| Composite vascular endpoint I | Non-fatal myocardial infarction, non-fatal ischemic stroke or cardiovascular death, VTE | 30 days from randomization | 
| Composite vascular endpoint II | Cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke or acute limb ischemia, VTE | 30 days from randomization | 
| Major Bleeding | Defined by International Society of Thrombosis and Hemostasis (ISTH) criteria | 30 days from randomization | 
| Mortality | Defined by all-cause deaths | 30 days from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-Cov-2, COVID-19, Rivaroxaban, Antithrombotic