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COVID-19Phase 4CARENCT04757857

COVID-19 Antithrombotic Rivaroxaban Evaluation

A Phase 4 study testing Rivaroxaban 10 mg in people with COVID-19, run by Hospital Alemão Oswaldo Cruz at 36 sites in Brazil.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
COVID-19
What is being tested?
Rivaroxaban 10 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
660 participants
Where
36 sitesBrazil
Study dates
29 Sep 2020to 30 Aug 2022
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adults ≥ 18 years old;
  • Evaluated in the emergency unit with probable or confirmed infection by COVID-19;
  • Time between symptoms and inclusion ≤ 07 days *;
  • Present mild or moderate signs and symptoms, with no clear indication for hospitalization;
  • Present at least 2 risk factors for complication:
  • 65 years
Show all 17Show fewer
  • 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

Who cannot join

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

Trial locations and contacts

36 sites in 1 country.

36 sites in 1 country

Brazil36 sites

  • Irmandade santa Casa de Araras

    Araras, São Paulo, 13600-655

  • Hospital Maternidade São Vicente de Paulo

    Barbalha, Ceará

  • Alphacor Cardiologia Clínica e Diagnóstica LTDA

    Barueri, São Paulo

  • Beneficencia Nipo Brasileira Da Amazonia

    Belém, Pará, 66060-575

  • Hospital Adventista de Belém

    Belém, Pará, 66093-904

  • Núcleo de Pesquisa Clínica do Hospital Vera Cruz

    Belo Horizonte, Minas Gerais, 30190-130

  • Hospital São Lucas

    Belo Horizonte, Minas Gerais

  • Associação Dr. Bartholomeu Tacchini

    Bento Gonçalves, Rio Grande do Sul

  • Clínica Procárdio Ltda

    Blumenau, Santa Catarina

  • Maestri e Kormann Consultoria Medico-Cientifica LTDA - EPP

    Blumenau, São Paulo

  • Hospital de Base do Distrito Federal

    Brasília, Federal District

  • Hospital Regional do Litoral Norte - Instituto Sócrates Guanaes

    Caraguatatuba, São Paulo

  • Hospital Santos Dumont Litoral Norte

    Caraguatatuba, São Paulo

  • Hospital de Corderiopolis

    Cordeirópolis, São Paulo

  • Clínica Senhor do Bonfim

    Feira de Santana, Estado de Bahia

  • Hospital de Campanha Covid-19 Goiânia/Sesgo

    Goiânia, Goiás

  • Hospital Regional Jorge Rossman - Instituto Sócrates Guanaes

    Itanhaém, São Paulo

  • H&W Cardiologia LTDA

    Joinville, Santa Catarina, 89204-250

  • Hospital Universitário Regional de Maringá

    Maringá, Paraná

  • Hospital Carlos Fernando Malzoni

    Matão, São Paulo

  • Hospital São Vicente de Paulo

    Passo Fundo, Rio Grande do Sul, 99010-080

  • Santa Casa de Misericórdia de Passos

    Passos, Minas Gerais

  • Hospital das Clínicas de Porto Alegre

    Porto Alegre, Rio Grande do Sul

  • Hospital Moinhos de Vento

    Porto Alegre, São Paulo, 90035-001

  • Hospital Regional de Registro - Instituto Sócrates Guanaes

    Registro, São Paulo

  • Hospital Unimed Ribeirão Preto

    Ribeirão Preto, São Paulo

  • Hospital Universitario de Santa Maria

    Santa Maria, Rio Grande do Sul, 97900015

  • Kaiser Clinica e Hospital Dia

    São José do Rio Preto, São Paulo, 15015-110

  • Braile Hospital Dia Ltda

    São José do Rio Preto, São Paulo

  • Hospital Policlin

    São José dos Campos, São Paulo, 12 243 000

  • Hospital Regional de São José dos Campos - Instituto Sócrates Guanaes

    São José dos Campos, São Paulo

  • International Research Center - Hospital Alemão Oswaldo Cruz

    São Paulo, 01323-903

  • Hospital Leforte Liberdade

    São Paulo, 01506-000

  • Incor - Instituto do Coração do Hospital das Clínicas da FMUSP

    São Paulo, 05403-010

  • Hospital Estadual de Urgências de Trindade/SESGO

    Trindade, Goiás

  • Santa Casa de Misericórdia de Votuporanga

    Votuporanga, São Paulo

Other trials in Brazil

About this study

Official title: 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.

Read the 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
Being tested
Rivaroxaban 10 mg
Keywords
SARS-Cov-2, COVID-19, Rivaroxaban, Antithrombotic
Medical subject headings
COVID-19

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Rivaroxaban 10 mgDrug

    Also called Xarelto

    Rivaroxaban pharmaceutical form will be tablets of 10 mg

Study groups in NCT04757857
Study groupRoleWhat they receive
Rivaroxaban 10 mgActive comparatorParticipants will receive, from the 1st to the 14th day, a dose of 10 mg of rivaroxaban - OA (Oral Administration).
Receives: Drug: Rivaroxaban 10 mg
Best locally standardized careNo interventionAccording 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 being measured

The primary outcome is the main question the study is designed to answer.

  1. Venous thromboembolic events (VTE)

    Defined as deep venous thrombosis, acute pulmonary embolism, other major venous thrombotic events.

    Measured: Within 30 days from randomization

  2. Mechanical ventilation free-survival

    Defined as survival without requirement of mechanical ventilation.

    Measured: Within 30 days from randomization

  3. Major Adverse Cardiovascular Events (MACE)

    Defined as acute myocardial infarction, stroke or acute limb ischemia

    Measured: Within 30 days from randomization

  4. 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

    Measured: Within 30 days from randomization

Secondary outcomes (9)

  1. Time from randomization to hospitalization

    Defined as time elapsed since randomization to hospital admission

    Measured: 30 days from randomization

  2. Length of Hospitalization

    To assess the duration of hospitalization (length of hospital stay)

    Measured: 30 days from randomization

  3. Hospitalization in Intensive Care Unit

    Requirement of admission to ICU for intensive care

    Measured: 30 days from randomization

  4. Clinical requirement of mechanical ventilation

    Requirement of oxygen supplementation through invasive or non invasive mechanical ventilation.

    Measured: 30 days from randomization

  5. Clinical duration of mechanical ventilation

    Total time on oxygen supplementation through invasive or non invasive mechanical ventilation

    Measured: 30 days from randomization

  6. Composite vascular endpoint I

    Non-fatal myocardial infarction, non-fatal ischemic stroke or cardiovascular death, VTE

    Measured: 30 days from randomization

  7. Composite vascular endpoint II

    Cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke or acute limb ischemia, VTE

    Measured: 30 days from randomization

  8. Major Bleeding

    Defined by International Society of Thrombosis and Hemostasis (ISTH) criteria

    Measured: 30 days from randomization

  9. Mortality

    Defined by all-cause deaths

    Measured: 30 days from randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2021
  2. Study start29 Sep 2020
  3. Primary completion8 Aug 2022
  4. Study completion30 Aug 2022

Why it stopped: Sustained reduction in the number of new COVID-19 cases as well as lower than expected event rates

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Pragmatic, open-label, controlled randomized trial
Masking
None (open label)
Enrolment
660 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04757857
Sponsor's protocol ID
36066320.5.1001.0070
Acronym
CARE
Status last verified
Jan 2023
First submitted
8 Feb 2021
Last updated
25 Jan 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 37591523

  • 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.

    PubMed 37223666

  • 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.

    PubMed 37018790

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Rivaroxaban 10 mg in people with COVID-19, run by Hospital Alemão Oswaldo Cruz at 36 sites in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 25 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Sustained reduction in the number of new COVID-19 cases as well as lower than expected event rates). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Venous thromboembolic events (VTE) (time frame: Within 30 days from randomization). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04757857, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2023; AzTrials last refreshed its copy on 1 Nov 2026.

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