COVID-19 Antithrombotic Rivaroxaban Evaluation (CARE)

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

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.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Rivaroxaban 10 mg

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 Type: Interventional
• Enrollment (Actual): 660
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 01323-903
    • International Research Center - Hospital Alemão Oswaldo Cruz
  • São Paulo, Brazil, 01506-000
    • Hospital Leforte Liberdade
  • São Paulo, Brazil, 05403-010
    • INCOR - Instituto do Coração do Hospital das Clínicas da FMUSP
  • Bahia
    • Feira de Santana, Bahia, Brazil
      • Clinica Senhor do Bonfim
  • Ceará
    • Barbalha, Ceará, Brazil
      • Hospital Maternidade São Vicente de Paulo
  • Distrito Federal
    • Brasília, Distrito Federal, Brazil
      • Hospital de Base do Distrito Federal
  • Goias
    • Goiânia, Goias, Brazil
      • Hospital de Campanha Covid-19 Goiânia/Sesgo
    • Trindade, Goias, Brazil
      • Hospital Estadual de Urgências de Trindade/SESGO
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30190-130
      • Nucleo de Pesquisa Clinica do Hospital Vera Cruz
    • Belo Horizonte, Minas Gerais, Brazil
      • Hospital sao lucas
    • Passos, Minas Gerais, Brazil
      • Santa Casa de Misericórdia de Passos
  • Para
    • Belém, Para, Brazil, 66060-575
      • Beneficencia Nipo Brasileira Da Amazonia
    • Belém, Para, Brazil, 66093-904
      • Hospital Adventista de Belem
  • Paraná
    • Maringá, Paraná, Brazil
      • Hospital Universitário Regional de Maringá
  • Rio Grande Do Sul
    • Bento Gonçalves, Rio Grande Do Sul, Brazil
      • Associação Dr. Bartholomeu Tacchini
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-080
      • Hospital Sao Vicente de Paulo
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Hospital das Clinicas de Porto Alegre
    • Santa Maria, Rio Grande Do Sul, Brazil, 97900015
      • Hospital Universitário de Santa Maria
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil
      • Clínica Procardio Ltda
    • Joinville, Santa Catarina, Brazil, 89204-250
      • H&W Cardiologia LTDA
  • São Paulo
    • Araras, São Paulo, Brazil, 13600-655
      • Irmandade santa Casa de Araras
    • Barueri, São Paulo, Brazil
      • Alphacor Cardiologia Clínica e Diagnóstica LTDA
    • Blumenau, São Paulo, Brazil
      • Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP
    • Caraguatatuba, São Paulo, Brazil
      • Hospital Regional do Litoral Norte - Instituto Sócrates Guanaes
    • Caraguatatuba, São Paulo, Brazil
      • Hospital Santos Dumont Litoral Norte
    • Cordeiropolis, São Paulo, Brazil
      • Hospital de Corderiopolis
    • Itanhaém, São Paulo, Brazil
      • Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes
    • Matão, São Paulo, Brazil
      • Hospital Carlos Fernando Malzoni
    • Porto Alegre, São Paulo, Brazil, 90035-001
      • Hospital Moinhos de Vento
    • Registro, São Paulo, Brazil
      • Hospital Regional de Registro - Instituto Sócrates Guanaes
    • Ribeirão Preto, São Paulo, Brazil
      • Hospital Unimed Ribeirão Preto
    • São José Do Rio Preto, São Paulo, Brazil
      • Braile Hospital Dia Ltda
    • São José Dos Campos, São Paulo, Brazil, 12 243 000
      • Hospital Policlin
    • São José Dos Campos, São Paulo, Brazil
      • Hospital Regional de São José dos Campos - Instituto Sócrates Guanaes
    • São José do Rio Preto, São Paulo, Brazil, 15015-110
      • Kaiser Clinica e Hospital Dia
    • Votuporanga, São Paulo, Brazil
      • Santa Casa de Misericórdia de Votuporanga

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rivaroxaban 10 mg; Participants will receive, from the 1st to the 14th day, a dose of 10 mg of rivaroxaban - OA (Oral Administration).	Drug: Rivaroxaban 10 mg; Rivaroxaban pharmaceutical form will be tablets of 10 mg; Other Names: Xarelto
No Intervention: 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospital Alemão Oswaldo Cruz
• Collaborators: Bayer; Hospital Israelita Albert Einstein; Hospital Moinhos de Vento; Brazilian Clinical Research Institute; Hospital do Coracao; Hospital Sirio-Libanes; Brazilian Research In Intensive Care Network
• Investigators: Principal Investigator: Álvaro Avezum, Ph.D, International Research Center - Hospital Alemão Oswaldo Cruz

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2020
• Primary Completion (Actual): August 8, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: February 8, 2021
• First Submitted That Met QC Criteria: February 16, 2021
• First Posted (Actual): February 17, 2021

Study Record Updates

• Last Update Posted (Actual): January 25, 2023
• Last Update Submitted That Met QC Criteria: January 20, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Rivaroxaban; COVID-19; SARS-Cov-2; Antithrombotic
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: 36066320.5.1001.0070

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No