COVID-19 Antithrombotic Rivaroxaban Evaluation

NCT ID: NCT04757857

Last Updated: 2023-01-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 660 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-29
• Study Completion Date: 2022-08-30

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.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rivaroxaban 10 mg

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

Group Type: ACTIVE_COMPARATOR

Rivaroxaban 10 mg

Intervention Type: DRUG

Rivaroxaban pharmaceutical form will be tablets of 10 mg

Best locally standardized care

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Rivaroxaban 10 mg

Rivaroxaban pharmaceutical form will be tablets of 10 mg

Intervention Type: DRUG

Other Intervention Names

Xarelto

Eligibility Criteria

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;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Hospital Israelita Albert Einstein

OTHER

Sponsor Role: collaborator

Hospital do Coracao

OTHER

Sponsor Role: collaborator

Hospital Sirio-Libanes

OTHER

Sponsor Role: collaborator

Hospital Moinhos de Vento

OTHER

Sponsor Role: collaborator

Brazilian Research In Intensive Care Network

NETWORK

Sponsor Role: collaborator

Brazilian Clinical Research Institute

OTHER

Sponsor Role: collaborator

Hospital Alemão Oswaldo Cruz

OTHER

Sponsor Role: lead

Responsible Party

Álvaro Avezum Junior

Research Manager - International Research Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Álvaro Avezum, Ph.D

Role: PRINCIPAL_INVESTIGATOR

International Research Center - Hospital Alemão Oswaldo Cruz

Locations

Hospital Maternidade São Vicente de Paulo

Barbalha, Ceará, Brazil

Clínica Senhor do Bonfim

Feira de Santana, Estado de Bahia, Brazil

Hospital de Base do Distrito Federal

Brasília, Federal District, Brazil

Hospital de Campanha Covid-19 Goiânia/Sesgo

Goiânia, Goiás, Brazil

Hospital Estadual de Urgências de Trindade/SESGO

Trindade, Goiás, Brazil

Núcleo de Pesquisa Clínica do Hospital Vera Cruz

Belo Horizonte, Minas Gerais, Brazil

Hospital São Lucas

Belo Horizonte, Minas Gerais, Brazil

Santa Casa de Misericórdia de Passos

Passos, Minas Gerais, Brazil

Hospital Universitário Regional de Maringá

Maringá, Paraná, Brazil

Beneficencia Nipo Brasileira Da Amazonia

Belém, Pará, Brazil

Hospital Adventista de Belém

Belém, Pará, Brazil

Associação Dr. Bartholomeu Tacchini

Bento Gonçalves, Rio Grande do Sul, Brazil

Hospital São Vicente de Paulo

Passo Fundo, Rio Grande do Sul, Brazil

Hospital das Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Hospital Universitario de Santa Maria

Santa Maria, Rio Grande do Sul, 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

Alphacor Cardiologia Clínica e Diagnóstica LTDA

Barueri, São Paulo, Brazil

Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP

Blumenau, São Paulo, Brazil

Hospital Regional do Litoral Norte - Instituto Sócrates Guanaes

Caraguatatuba, São Paulo, Brazil

Hospital Santos Dumont Litoral Norte

Caraguatatuba, São Paulo, Brazil

Hospital de Corderiopolis

Cordeirópolis, São Paulo, Brazil

Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes

Itanhaém, São Paulo, Brazil

Hospital Carlos Fernando Malzoni

Matão, São Paulo, Brazil

Hospital Moinhos de Vento

Porto Alegre, São Paulo, Brazil

Hospital Regional de Registro - Instituto Sócrates Guanaes

Registro, São Paulo, Brazil

Hospital Unimed Ribeirão Preto

Ribeirão Preto, São Paulo, Brazil

Kaiser Clinica e Hospital Dia

São José do Rio Preto, São Paulo, Brazil

Braile Hospital Dia Ltda

São José do Rio Preto, São Paulo, Brazil

Hospital Policlin

São José dos Campos, São Paulo, Brazil

Hospital Regional de São José dos Campos - Instituto Sócrates Guanaes

São José dos Campos, São Paulo, Brazil

Santa Casa de Misericórdia de Votuporanga

Votuporanga, São Paulo, Brazil

International Research Center - Hospital Alemão Oswaldo Cruz

São Paulo, , Brazil

Hospital Leforte Liberdade

São Paulo, , Brazil

Incor - Instituto do Coração do Hospital das Clínicas da FMUSP

São Paulo, , Brazil

Countries

Brazil

References

Santos BC, Flumignan RL, Civile VT, Atallah AN, Nakano LC. Prophylactic anticoagulants for non-hospitalised people with COVID-19. Cochrane Database Syst Rev. 2023 Aug 16;8(8):CD015102. doi: 10.1002/14651858.CD015102.pub2.

Reference Type: DERIVED

PMID: 37591523 (View on PubMed)

Avezum A, Oliveira Junior HA, Neves PDMM, Alves LBO, Cavalcanti AB, Rosa RG, Veiga VC, Azevedo LCP, Zimmermann SL, Silvestre OM, Seabra Prudente RC, Morales Kormann AP, Moreira FR, Boszczowski I, de Brito Sobrinho E, da Silva E Souza A, Seligman R, de Souza Paolino B, Razuk A, Diogenes de Magalhaes Feitosa A, Monteiro Belmonte PL, Freitas das Neves Goncalves P, Hernandes ME, Fagundes AL, Sarmet Esteves JM, Tognon AP, Eikelboom J, Berwanger O, Lopes RD, Oliveira GBF; Coalition VIII COVID-19 Brazil Investigators. Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE - COALITION VIII randomised clinical trial. EClinicalMedicine. 2023 Jun;60:102004. doi: 10.1016/j.eclinm.2023.102004. Epub 2023 May 18.

Reference Type: DERIVED

PMID: 37223666 (View on PubMed)

Oliveira GBF, Neves PDMM, Oliveira HA, Catarino DGM, Alves LBO, Cavalcanti AB, Rosa RG, Veiga VC, Azevedo LCP, Berwanger O, Lopes RD, Avezum A. Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII). Arq Bras Cardiol. 2023 Mar;120(3):e20220431. doi: 10.36660/abc.20220431. English, Portuguese.

Reference Type: DERIVED

PMID: 37018790 (View on PubMed)

Other Identifiers

36066320.5.1001.0070

Identifier Type: -

Identifier Source: org_study_id