Clinical trial NCT04757857: COVID-19 Antithrombotic Rivaroxaban Evaluation
Official title: Randomized, Pragmatic, Open Controlled Multicentre Study, Evaluating the Use of Rivaroxaban in Mild or Moderate COVID-19 Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: COVID-19
Keywords: SARS-Cov-2
COVID-19
Rivaroxaban
Antithrombotic
Lead sponsor: Hospital Alemão Oswaldo Cruz
Sponsor class: OTHER
Collaborators: name: Bayer
name: Hospital Israelita Albert Einstein
name: Hospital do Coracao
name: Hospital Sirio-Libanes
name: Hospital Moinhos de Vento
name: Brazilian Research In Intensive Care Network
name: Brazilian Clinical Research Institute
First posted: 2021-02-17
Enrollment: 660
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pragmatic, open-label, controlled randomized trial
Primary purpose: TREATMENT

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.

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;

Primary outcomes:
measure: Venous thromboembolic events (VTE)
timeFrame: Within 30 days from randomization
measure: Mechanical ventilation free-survival
timeFrame: Within 30 days from randomization
measure: Major Adverse Cardiovascular Events (MACE)
timeFrame: Within 30 days from randomization
measure: Out-of-hospital death not attributed to major injury
timeFrame: Within 30 days from randomization
Secondary outcomes:
measure: Time from randomization to hospitalization
timeFrame: 30 days from randomization
measure: Length of Hospitalization
timeFrame: 30 days from randomization
measure: Hospitalization in Intensive Care Unit
timeFrame: 30 days from randomization
measure: Clinical requirement of mechanical ventilation
timeFrame: 30 days from randomization
measure: Clinical duration of mechanical ventilation
timeFrame: 30 days from randomization
measure: Composite vascular endpoint I
timeFrame: 30 days from randomization
measure: Composite vascular endpoint II
timeFrame: 30 days from randomization
measure: Major Bleeding
timeFrame: 30 days from randomization
measure: Mortality
timeFrame: 30 days from randomization
Other outcomes:
Locations:
city: Feira de Santana
country: Brazil
facility: Clínica Senhor do Bonfim
state: Bahia
city: Barbalha
country: Brazil
facility: Hospital Maternidade São Vicente de Paulo
state: Ceará
city: Brasília
country: Brazil
facility: Hospital de Base do Distrito Federal
state: Distrito Federal
city: Goiânia
country: Brazil
facility: Hospital de Campanha Covid-19 Goiânia/Sesgo
state: Goias
city: Trindade
country: Brazil
facility: Hospital Estadual de Urgências de Trindade/SESGO
state: Goias
city: Belo Horizonte
country: Brazil
facility: Núcleo de Pesquisa Clínica do Hospital Vera Cruz
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Hospital São Lucas
state: Minas Gerais
city: Passos
country: Brazil
facility: Santa Casa de Misericórdia de Passos
state: Minas Gerais
city: Maringá
country: Brazil
facility: Hospital Universitário Regional de Maringá
state: Paraná
city: Belém
country: Brazil
facility: Beneficencia Nipo Brasileira Da Amazonia
state: Para
city: Belém
country: Brazil
facility: Hospital Adventista de Belém
state: Para
city: Bento Gonçalves
country: Brazil
facility: Associação Dr. Bartholomeu Tacchini
state: Rio Grande Do Sul
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital das Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Santa Maria
country: Brazil
facility: Hospital Universitario de Santa Maria
state: Rio Grande Do Sul
city: Blumenau
country: Brazil
facility: Clínica Procárdio Ltda
state: Santa Catarina
city: Joinville
country: Brazil
facility: H&W Cardiologia LTDA
state: Santa Catarina
city: Araras
country: Brazil
facility: Irmandade santa Casa de Araras
state: São Paulo
city: Barueri
country: Brazil
facility: Alphacor Cardiologia Clínica e Diagnóstica LTDA
state: São Paulo
city: Blumenau
country: Brazil
facility: Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP
state: São Paulo
city: Caraguatatuba
country: Brazil
facility: Hospital Regional do Litoral Norte - Instituto Sócrates Guanaes
state: São Paulo
city: Caraguatatuba
country: Brazil
facility: Hospital Santos Dumont Litoral Norte
state: São Paulo
city: Cordeiropolis
country: Brazil
facility: Hospital de Corderiopolis
state: São Paulo
city: Itanhaém
country: Brazil
facility: Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes
state: São Paulo
city: Matão
country: Brazil
facility: Hospital Carlos Fernando Malzoni
state: São Paulo
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: São Paulo
city: Registro
country: Brazil
facility: Hospital Regional de Registro - Instituto Sócrates Guanaes
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Hospital Unimed Ribeirão Preto
state: São Paulo
city: São José do Rio Preto
country: Brazil
facility: Kaiser Clinica e Hospital Dia
state: São Paulo
city: São José Do Rio Preto
country: Brazil
facility: Braile Hospital Dia Ltda
state: São Paulo
city: São José Dos Campos
country: Brazil
facility: Hospital Policlin
state: São Paulo
city: São José Dos Campos
country: Brazil
facility: Hospital Regional de São José dos Campos - Instituto Sócrates Guanaes
state: São Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Misericórdia de Votuporanga
state: São Paulo
city: São Paulo
country: Brazil
facility: International Research Center - Hospital Alemão Oswaldo Cruz
city: São Paulo
country: Brazil
facility: Hospital Leforte Liberdade
city: São Paulo
country: Brazil
facility: Incor - Instituto do Coração do Hospital das Clínicas da FMUSP
Study officials:
affiliation: International Research Center - Hospital Alemão Oswaldo Cruz
name: Álvaro Avezum, Ph.D
role: PRINCIPAL_INVESTIGATOR
References: