COVID-19 Antithrombotic Rivaroxaban Evaluation

Phase 4

Terminated

• Conditions: COVID-19
• Interventions: Drug: Rivaroxaban 10 mg

• Registration Number: NCT04757857
• Lead Sponsor: Hospital Alemão Oswaldo Cruz

Brief Summary

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

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.

Study Timeline

• Study Start: 2020-09-29
• Study First Submitted: 2021-02-08
• Study First Submitted QC: 2021-02-16
• Study First Posted: 2021-02-17
• Primary Completion: 2022-08-08
• Study Completion: 2022-08-30
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-20
• Last Update Posted: 2023-01-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 660

Inclusion Criteria

1. Adults ≥ 18 years old;

2. Evaluated in the emergency unit with probable or confirmed infection by COVID-19;

3. Time between symptoms and inclusion ≤ 07 days *;

4. Present mild or moderate signs and symptoms, with no clear indication for hospitalization;

5. 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

1. Patients <18 years old;
2. Hospitalization indication upon first medical care;
3. Positive test for influenza in the first visit;
4. Any known liver disease associated with coagulopathy; INR (International Normalized Ratio) > 1.5;
5. Pregnant, lactating or with the possibility of becoming pregnant and without using an adequate contraceptive method;
6. 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;
7. 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;
8. 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);
9. Estimated glomerular filtration rate (eGFR) <30 mL / min;
10. Clinical indication for dual antiplatelet therapy or anticoagulation therapy (VTE, atrial fibrillation / flutter, mechanical valve prosthesis);
11. Marked thrombocytopenia (platelets <50,000 / mm3);
12. 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;
13. History of hypersensitivity or known contraindication to rivaroxaban;
14. 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;
15. Current treatment being tested;
16. Concomitant participation in another study with experimental drugs in the context of COVID;
17. Use of chloroquine or hydroxychloroquine associated with azithromycin;
18. Active cancer;
19. Other contraindications to rivaroxaban;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rivaroxaban 10 mg	Rivaroxaban 10 mg	Participants will receive, from the 1st to the 14th day, a dose of 10 mg of rivaroxaban - OA (Oral Administration).

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (36)

Hospital Estadual de Urgências de Trindade/SESGO; 🇧🇷 Trindade, Goias, Brazil

Santa Casa de Misericórdia de Passos; 🇧🇷 Passos, Minas Gerais, Brazil

Hospital de Base do Distrito Federal; 🇧🇷 Brasília, Distrito Federal, Brazil

Núcleo de Pesquisa Clínica do Hospital Vera Cruz; 🇧🇷 Belo Horizonte, Minas Gerais, Brazil

Clínica Senhor do Bonfim; 🇧🇷 Feira de Santana, Bahia, Brazil

Hospital São Lucas; 🇧🇷 Belo Horizonte, Minas Gerais, Brazil

Hospital São Vicente de Paulo; 🇧🇷 Passo Fundo, Rio Grande Do Sul, Brazil

Hospital Universitario de Santa Maria; 🇧🇷 Santa Maria, Rio Grande Do Sul, Brazil

Associação Dr. Bartholomeu Tacchini; 🇧🇷 Bento Gonçalves, Rio Grande Do Sul, Brazil

Hospital das Clínicas de Porto Alegre; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Braile Hospital Dia Ltda; 🇧🇷 São José Do Rio Preto, São Paulo, Brazil

Hospital de Corderiopolis; 🇧🇷 Cordeiropolis, São Paulo, Brazil

Hospital Unimed Ribeirão Preto; 🇧🇷 Ribeirão Preto, São Paulo, Brazil

Hospital Maternidade São Vicente de Paulo; 🇧🇷 Barbalha, Ceará, Brazil

Hospital Moinhos de Vento; 🇧🇷 Porto Alegre, São Paulo, Brazil

Hospital Regional do Litoral Norte - Instituto Sócrates Guanaes; 🇧🇷 Caraguatatuba, São Paulo, Brazil

Hospital Regional de Registro - Instituto Sócrates Guanaes; 🇧🇷 Registro, São Paulo, Brazil

Santa Casa de Misericórdia de Votuporanga; 🇧🇷 Votuporanga, São Paulo, Brazil

Kaiser Clinica e Hospital Dia; 🇧🇷 São José do Rio Preto, São Paulo, Brazil

Beneficencia Nipo Brasileira Da Amazonia; 🇧🇷 Belém, Para, Brazil

Hospital de Campanha Covid-19 Goiânia/Sesgo; 🇧🇷 Goiânia, Goias, Brazil

Hospital Universitário Regional de Maringá; 🇧🇷 Maringá, Paraná, Brazil

Hospital Adventista de Belém; 🇧🇷 Belém, Para, Brazil

Clínica Procárdio Ltda; 🇧🇷 Blumenau, Santa Catarina, Brazil

H&W Cardiologia LTDA; 🇧🇷 Joinville, Santa Catarina, Brazil

Irmandade santa Casa de Araras; 🇧🇷 Araras, São Paulo, Brazil

Hospital Santos Dumont Litoral Norte; 🇧🇷 Caraguatatuba, São Paulo, Brazil

Alphacor Cardiologia Clínica e Diagnóstica LTDA; 🇧🇷 Barueri, São Paulo, Brazil

Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP; 🇧🇷 Blumenau, São Paulo, Brazil

Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes; 🇧🇷 Itanhaém, São Paulo, Brazil

Hospital Carlos Fernando Malzoni; 🇧🇷 Matão, São Paulo, Brazil

Hospital Regional de São José dos Campos - Instituto Sócrates Guanaes; 🇧🇷 São José Dos Campos, São Paulo, Brazil

International Research Center - Hospital Alemão Oswaldo Cruz; 🇧🇷 São Paulo, Brazil

Hospital Policlin; 🇧🇷 São José Dos Campos, São Paulo, Brazil

Hospital Leforte Liberdade; 🇧🇷 São Paulo, Brazil

Incor - Instituto do Coração do Hospital das Clínicas da FMUSP; 🇧🇷 São Paulo, Brazil