COVID-19 Antithrombotic Rivaroxaban Evaluation

COVID-19 Clinical Trial

— CARE  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04757857
• Other study ID #: 36066320.5.1001.0070
• Status: Terminated
• Phase: Phase 4
• Start date: September 29, 2020
• Est. completion date: August 30, 2022

Study information

• Verified date: January 2023
• Source: Hospital Alemão Oswaldo Cruz
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 660
• Est. completion date: August 30, 2022
• Est. primary completion date: August 8, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Rivaroxaban 10 mg
Rivaroxaban pharmaceutical form will be tablets of 10 mg

Locations

Country	Name	City	State
Brazil	Irmandade santa Casa de Araras	Araras	São Paulo
Brazil	Hospital Maternidade São Vicente de Paulo	Barbalha	Ceará
Brazil	Alphacor Cardiologia Clínica e Diagnóstica LTDA	Barueri	São Paulo
Brazil	Beneficencia Nipo Brasileira Da Amazonia	Belém	Para
Brazil	Hospital Adventista de Belém	Belém	Para
Brazil	Hospital São Lucas	Belo Horizonte	Minas Gerais
Brazil	Núcleo de Pesquisa Clínica do Hospital Vera Cruz	Belo Horizonte	Minas Gerais
Brazil	Associação Dr. Bartholomeu Tacchini	Bento Gonçalves	Rio Grande Do Sul
Brazil	Clínica Procárdio Ltda	Blumenau	Santa Catarina
Brazil	Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP	Blumenau	São Paulo
Brazil	Hospital de Base do Distrito Federal	Brasília	Distrito Federal
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	Cordeiropolis	São Paulo
Brazil	Clínica Senhor do Bonfim	Feira de Santana	Bahia
Brazil	Hospital de Campanha Covid-19 Goiânia/Sesgo	Goiânia	Goias
Brazil	Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes	Itanhaém	São Paulo
Brazil	H&W Cardiologia LTDA	Joinville	Santa Catarina
Brazil	Hospital Universitário Regional de Maringá	Maringá	Paraná
Brazil	Hospital Carlos Fernando Malzoni	Matão	São Paulo
Brazil	Hospital São Vicente de Paulo	Passo Fundo	Rio Grande Do Sul
Brazil	Santa Casa de Misericórdia de Passos	Passos	Minas Gerais
Brazil	Hospital das Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
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	Hospital Universitario de Santa Maria	Santa Maria	Rio Grande Do Sul
Brazil	Braile Hospital Dia Ltda	São José Do Rio Preto	São Paulo
Brazil	Kaiser Clinica e Hospital Dia	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	Hospital Leforte Liberdade	São Paulo
Brazil	Incor - Instituto do Coração do Hospital das Clínicas da FMUSP	São Paulo
Brazil	International Research Center - Hospital Alemão Oswaldo Cruz	São Paulo
Brazil	Hospital Estadual de Urgências de Trindade/SESGO	Trindade	Goias
Brazil	Santa Casa de Misericórdia de Votuporanga	Votuporanga	São Paulo

Sponsors (8)

Lead Sponsor	Collaborator
Hospital Alemão Oswaldo Cruz	Bayer, Brazilian Clinical Research Institute, Brazilian Research In Intensive Care Network, Hospital do Coracao, Hospital Israelita Albert Einstein, Hospital Moinhos de Vento, Hospital Sirio-Libanes

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Venous thromboembolic events (VTE)	Defined as deep venous thrombosis, acute pulmonary embolism, other major venous thrombotic events.	Within 30 days from randomization
Primary	Mechanical ventilation free-survival	Defined as survival without requirement of mechanical ventilation.	Within 30 days from randomization
Primary	Major Adverse Cardiovascular Events (MACE)	Defined as acute myocardial infarction, stroke or acute limb ischemia	Within 30 days from randomization
Primary	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	Time from randomization to hospitalization	Defined as time elapsed since randomization to hospital admission	30 days from randomization
Secondary	Length of Hospitalization	To assess the duration of hospitalization (length of hospital stay)	30 days from randomization
Secondary	Hospitalization in Intensive Care Unit	Requirement of admission to ICU for intensive care	30 days from randomization
Secondary	Clinical requirement of mechanical ventilation	Requirement of oxygen supplementation through invasive or non invasive mechanical ventilation.	30 days from randomization
Secondary	Clinical duration of mechanical ventilation	Total time on oxygen supplementation through invasive or non invasive mechanical ventilation	30 days from randomization
Secondary	Composite vascular endpoint I	Non-fatal myocardial infarction, non-fatal ischemic stroke or cardiovascular death, VTE	30 days from randomization
Secondary	Composite vascular endpoint II	Cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke or acute limb ischemia, VTE	30 days from randomization
Secondary	Major Bleeding	Defined by International Society of Thrombosis and Hemostasis (ISTH) criteria	30 days from randomization
Secondary	Mortality	Defined by all-cause deaths	30 days from randomization