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Full Anticoagulation Versus Prophylaxis in COVID-19: COALIZAO ACTION Trial (ACTION)

Primary Purpose

Coronavirus Infection

Status
Completed
Phase
Phase 4
Locations
Brazil
Study Type
Interventional
Intervention
Group 1: Rivaroxaban 20mg/d followed by enoxaparin/unfractionated heparin when needed
Group 2: control group with enoxaparin 40mg/d
Sponsored by
Brazilian Clinical Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Coronavirus Infection focused on measuring SARS-CoV2, Anticoagulation, Coronavirus infection, COVID-19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with confirmed diagnosis of COVID-19 admitted to hospital;
  • Duration of symptoms related to hospitalization ≤ 14 days;
  • Patients ≥ 18 year old;
  • D-dimer above the upper limit of normal (collected until 72 hours before the randomization);
  • Agreement to participate by providing the informed consent form (ICF).

Exclusion Criteria:

  • Patients with indication for full anticoagulation during inclusion (for example, diagnosis of venous thromboembolism, atrial fibrillation, mechanical valve prosthesis);
  • Platelets < 50,000 /mm3
  • Need for ASA therapy > 100 mg;
  • Need for P2Y12 inhibitor therapy (clopidogrel, ticagrelor or prasugrel);
  • Chronic use of non-hormonal anti-inflammatory drugs;
  • Sustained uncontrolled systolic blood pressure (BP) of ≥180 mmHg or diastolic BP of ≥100 mmHg;
  • INR > 1,5;
  • Patients contraindicated to full anticoagulation (active bleeding, liver failure, blood dyscrasia or prohibitive hemorrhage risk as evaluated by the investigator);
  • Criteria for disseminated intravascular coagulation (DIC);
  • A history of hemorrhagic stroke or any intracranial bleeding at any time in the past or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm;
  • Active cancer (excluding non-melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy;
  • Hypersensitivity to rivaroxaban;
  • Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) (e.g. protease inhibitors, ketoconazole, Itraconazole) and/or use of P-gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort);
  • Known HIV infection;
  • Creatinine clearance < 30 ml/min according to the Cockcroft-Gault Formula;
  • Pregnancy or breastfeeding.

Sites / Locations

  • Centro de Estudos Clínicos do Hospital Cárdio Pulmonar
  • Instituto de Ensino e Pesquisa do Hospital da Bahia
  • Santa Casa de Misericórdia da Bahia - Hospital Santa Izabel
  • Hospital Maternidade São Vicente de Paulo
  • Centro de Ensino e Aperfeiçoamento em Pesquisa - CEAP
  • Centro de Pesquisas Cardiológicas de Goiânia do Hospital das Clínicas (UFG)
  • Hospital Vera Cruz
  • Núcleo de Ciências de Saúde - Unidade de Pesquisa - Hospital Felício Rocho
  • Centro de Pesquisa Clínica do Hospital de Clínicas da Universidade Federal de Uberlândia
  • Hospital Universitário da Universidade Estadual de Londrina
  • Hospital Agamenon Magalhães
  • Real Hospital Português de Beneficência em Pernambuco
  • Hospital Moinhos de Vento
  • Hospital Nereu Ramos
  • Instituto Baia Sul de Ensino E Pesquisa Dr. Irineu May Brodbeck / Hospital Baía Sul
  • Hospital Regional Hans Dieter Schmidt
  • Hospital de Amor de Barretos - (Pio XII)
  • Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - Unesp
  • Hospital Universitário São Francisco de Assis
  • Hospital Regional do Litoral Norte
  • Hospital Regional de Registro
  • Praxis Pesquisa Médica
  • Centro Integrado de Pesquisa (CIP) - Hospital de Base de Rio Preto
  • Hospital Regional de São José dos Campos
  • Santa Casa de Misericórdia de Votuporanga
  • Hospital Naval Marcílio Dias
  • BP - A Beneficência Portuguesa de São Paulo
  • Hcor - Hospital do Coração
  • Hospital Israelita Albert Einstein
  • Hospital Moriah
  • Hospital Samaritano Paulista
  • Hospital Santa Paula
  • Hospital São Paulo
  • Instituto Dante Pazzanese de Cardiologia
  • Instituto de Assistência Médica ao Servidor Público Estadual de S. Paulo
  • Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Group 1

Group 2

Arm Description

The routine full anticoagulation strategy will be applied for 30 days. In this strategy, full anticoagulation therapy will be maintained for all patients randomized to group 1 and, depending on the patient's clinical condition, there will be 2 possible routes of administration (oral or parenteral): Oral: Rivaroxaban 20 mg 1 x daily (adjust the dose to 15 mg 1x daily if ClCr between 30 and 49ml/min and/or concomitant use of azithromycin); Parenteral: Enoxaparin 1 mg/kg every 12 hours subcutaneously or Unfractionated heparin (preferable option for patients progressing with disseminated intravascular coagulation).

Patients in this group will receive the usual standard management and currently have no indication of full anticoagulation. Venous thromboembolism (VTE) prophylaxis should be used in group 2 (usual standard of care) as recommended by guidelines.

Outcomes

Primary Outcome Measures

Hierarchical composite endpoint composed of mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days.
The primary objective will be analyzed using the win ratio approach comparing every participant of treatment group to every participant of control group to determine a winner.

Secondary Outcome Measures

Incidence of Venous thromboembolism
Incidence of acute myocardial infarction
Incidence of stroke
Number of days using oxygen therapy
Peak of troponin
Peak of D-dimer
Incidence of Major bleeding and clinically relevant non-major bleeding by the ISTH criteria
It will be considered the main safety endpoint

Full Information

First Posted
May 8, 2020
Last Updated
June 8, 2021
Sponsor
Brazilian Clinical Research Institute
Collaborators
Hospital Israelita Albert Einstein, Hospital do Coracao, Hospital Sirio-Libanes, Hospital Moinhos de Vento, Hospital Alemão Oswaldo Cruz, Beneficência Portuguesa de São Paulo, Brazilian Research In Intensive Care Network
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1. Study Identification

Unique Protocol Identification Number
NCT04394377
Brief Title
Full Anticoagulation Versus Prophylaxis in COVID-19: COALIZAO ACTION Trial
Acronym
ACTION
Official Title
Randomized Clinical Trial to Evaluate a Routine Full Anticoagulation Strategy in Patients With Coronavirus (COVID-19) - COALIZAO ACTION Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Completed
Study Start Date
June 21, 2020 (Actual)
Primary Completion Date
March 26, 2021 (Actual)
Study Completion Date
May 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Brazilian Clinical Research Institute
Collaborators
Hospital Israelita Albert Einstein, Hospital do Coracao, Hospital Sirio-Libanes, Hospital Moinhos de Vento, Hospital Alemão Oswaldo Cruz, Beneficência Portuguesa de São Paulo, Brazilian Research In Intensive Care Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Pragmatic randomized clinical trial of patients admitted to the hospital with confirmed COVID-19 infection and elevated D-Dimer. Randomization 1:1 - Group 1 will undergo a routine full anticoagulation (oral or parenteral when needed) strategy; and group 2 will receive usual standard of care with prophylactic anticoagulation
Detailed Description
Patients admitted to hospital with confirmed COVID-19, and who meet the eligibility criteria will be invited to participate in the proposed study. Following the application of the informed consent form, they will collect the D-dimer (if they have not yet collected it routinely from the hospital) and confirm the value over the normal limit in patients with confirmed COVID-19, will be randomized to 2 groups in the 1:1 ratio. Group 1 will follow the strategy of routine use of full anticoagulation therapy (oral or parenteral when indicated); and group 2 will follow the usual standard care with in-hospital prophylactic anticoagulation (without routine full anticoagulation).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronavirus Infection
Keywords
SARS-CoV2, Anticoagulation, Coronavirus infection, COVID-19

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
615 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Other
Arm Description
The routine full anticoagulation strategy will be applied for 30 days. In this strategy, full anticoagulation therapy will be maintained for all patients randomized to group 1 and, depending on the patient's clinical condition, there will be 2 possible routes of administration (oral or parenteral): Oral: Rivaroxaban 20 mg 1 x daily (adjust the dose to 15 mg 1x daily if ClCr between 30 and 49ml/min and/or concomitant use of azithromycin); Parenteral: Enoxaparin 1 mg/kg every 12 hours subcutaneously or Unfractionated heparin (preferable option for patients progressing with disseminated intravascular coagulation).
Arm Title
Group 2
Arm Type
Other
Arm Description
Patients in this group will receive the usual standard management and currently have no indication of full anticoagulation. Venous thromboembolism (VTE) prophylaxis should be used in group 2 (usual standard of care) as recommended by guidelines.
Intervention Type
Drug
Intervention Name(s)
Group 1: Rivaroxaban 20mg/d followed by enoxaparin/unfractionated heparin when needed
Intervention Description
Routine full anticoagulation strategy
Intervention Type
Drug
Intervention Name(s)
Group 2: control group with enoxaparin 40mg/d
Intervention Description
Usual standard of care and currently have no indication of full anticoagulation.
Primary Outcome Measure Information:
Title
Hierarchical composite endpoint composed of mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days.
Description
The primary objective will be analyzed using the win ratio approach comparing every participant of treatment group to every participant of control group to determine a winner.
Time Frame
In 30 days
Secondary Outcome Measure Information:
Title
Incidence of Venous thromboembolism
Time Frame
In 30 days
Title
Incidence of acute myocardial infarction
Time Frame
In 30 days
Title
Incidence of stroke
Time Frame
In 30 days
Title
Number of days using oxygen therapy
Time Frame
In 30 days
Title
Peak of troponin
Time Frame
In 30 days
Title
Peak of D-dimer
Time Frame
In 30 days
Title
Incidence of Major bleeding and clinically relevant non-major bleeding by the ISTH criteria
Description
It will be considered the main safety endpoint
Time Frame
In 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with confirmed diagnosis of COVID-19 admitted to hospital; Duration of symptoms related to hospitalization ≤ 14 days; Patients ≥ 18 year old; D-dimer above the upper limit of normal (collected until 72 hours before the randomization); Agreement to participate by providing the informed consent form (ICF). Exclusion Criteria: Patients with indication for full anticoagulation during inclusion (for example, diagnosis of venous thromboembolism, atrial fibrillation, mechanical valve prosthesis); Platelets < 50,000 /mm3 Need for ASA therapy > 100 mg; Need for P2Y12 inhibitor therapy (clopidogrel, ticagrelor or prasugrel); Chronic use of non-hormonal anti-inflammatory drugs; Sustained uncontrolled systolic blood pressure (BP) of ≥180 mmHg or diastolic BP of ≥100 mmHg; INR > 1,5; Patients contraindicated to full anticoagulation (active bleeding, liver failure, blood dyscrasia or prohibitive hemorrhage risk as evaluated by the investigator); Criteria for disseminated intravascular coagulation (DIC); A history of hemorrhagic stroke or any intracranial bleeding at any time in the past or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm; Active cancer (excluding non-melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy; Hypersensitivity to rivaroxaban; Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) (e.g. protease inhibitors, ketoconazole, Itraconazole) and/or use of P-gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort); Known HIV infection; Creatinine clearance < 30 ml/min according to the Cockcroft-Gault Formula; Pregnancy or breastfeeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renato D. Lopes, MD, PhD
Organizational Affiliation
BCRI
Official's Role
Study Chair
Facility Information:
Facility Name
Centro de Estudos Clínicos do Hospital Cárdio Pulmonar
City
Salvador
State/Province
Bahia
Country
Brazil
Facility Name
Instituto de Ensino e Pesquisa do Hospital da Bahia
City
Salvador
State/Province
Bahia
Country
Brazil
Facility Name
Santa Casa de Misericórdia da Bahia - Hospital Santa Izabel
City
Salvador
State/Province
Bahia
Country
Brazil
Facility Name
Hospital Maternidade São Vicente de Paulo
City
Barbalha
State/Province
Ceará
Country
Brazil
Facility Name
Centro de Ensino e Aperfeiçoamento em Pesquisa - CEAP
City
Serra
State/Province
Espirito Santo
Country
Brazil
Facility Name
Centro de Pesquisas Cardiológicas de Goiânia do Hospital das Clínicas (UFG)
City
Goiânia
State/Province
Goiás
Country
Brazil
Facility Name
Hospital Vera Cruz
City
Belo Horizonte
State/Province
Minas Gerais
Country
Brazil
Facility Name
Núcleo de Ciências de Saúde - Unidade de Pesquisa - Hospital Felício Rocho
City
Belo Horizonte
State/Province
Minas Gerais
Country
Brazil
Facility Name
Centro de Pesquisa Clínica do Hospital de Clínicas da Universidade Federal de Uberlândia
City
Uberlândia
State/Province
Minas Gerais
Country
Brazil
Facility Name
Hospital Universitário da Universidade Estadual de Londrina
City
Londrina
State/Province
Paraná
Country
Brazil
Facility Name
Hospital Agamenon Magalhães
City
Recife
State/Province
Pernambuco
Country
Brazil
Facility Name
Real Hospital Português de Beneficência em Pernambuco
City
Recife
State/Province
Pernambuco
Country
Brazil
Facility Name
Hospital Moinhos de Vento
City
Porto Alegre
State/Province
Rio Grande Do Sul
Country
Brazil
Facility Name
Hospital Nereu Ramos
City
Florianópolis
State/Province
Santa Catarina
Country
Brazil
Facility Name
Instituto Baia Sul de Ensino E Pesquisa Dr. Irineu May Brodbeck / Hospital Baía Sul
City
Florianópolis
State/Province
Santa Catarina
Country
Brazil
Facility Name
Hospital Regional Hans Dieter Schmidt
City
Joinville
State/Province
Santa Catarina
Country
Brazil
Facility Name
Hospital de Amor de Barretos - (Pio XII)
City
Barretos
State/Province
São Paulo
Country
Brazil
Facility Name
Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - Unesp
City
Botucatu
State/Province
São Paulo
Country
Brazil
Facility Name
Hospital Universitário São Francisco de Assis
City
Bragança Paulista
State/Province
São Paulo
Country
Brazil
Facility Name
Hospital Regional do Litoral Norte
City
Caraguatatuba
State/Province
São Paulo
Country
Brazil
Facility Name
Hospital Regional de Registro
City
Registro
State/Province
São Paulo
Country
Brazil
Facility Name
Praxis Pesquisa Médica
City
Santo André
State/Province
São Paulo
Country
Brazil
Facility Name
Centro Integrado de Pesquisa (CIP) - Hospital de Base de Rio Preto
City
São José Do Rio Preto
State/Province
São Paulo
Country
Brazil
Facility Name
Hospital Regional de São José dos Campos
City
São José Dos Campos
State/Province
São Paulo
Country
Brazil
Facility Name
Santa Casa de Misericórdia de Votuporanga
City
Votuporanga
State/Province
São Paulo
Country
Brazil
Facility Name
Hospital Naval Marcílio Dias
City
Rio de Janeiro
Country
Brazil
Facility Name
BP - A Beneficência Portuguesa de São Paulo
City
São Paulo
Country
Brazil
Facility Name
Hcor - Hospital do Coração
City
São Paulo
Country
Brazil
Facility Name
Hospital Israelita Albert Einstein
City
São Paulo
Country
Brazil
Facility Name
Hospital Moriah
City
São Paulo
Country
Brazil
Facility Name
Hospital Samaritano Paulista
City
São Paulo
Country
Brazil
Facility Name
Hospital Santa Paula
City
São Paulo
Country
Brazil
Facility Name
Hospital São Paulo
City
São Paulo
Country
Brazil
Facility Name
Instituto Dante Pazzanese de Cardiologia
City
São Paulo
Country
Brazil
Facility Name
Instituto de Assistência Médica ao Servidor Público Estadual de S. Paulo
City
São Paulo
Country
Brazil
Facility Name
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP
City
São Paulo
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
All data provided during study is anonymized to respect the privacy of patients who have participated in the trial in line with applicable regulations.
Citations:
PubMed Identifier
35244208
Citation
Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
Results Reference
derived
PubMed Identifier
34097856
Citation
Lopes RD, de Barros E Silva PGM, Furtado RHM, Macedo AVS, Bronhara B, Damiani LP, Barbosa LM, de Aveiro Morata J, Ramacciotti E, de Aquino Martins P, de Oliveira AL, Nunes VS, Ritt LEF, Rocha AT, Tramujas L, Santos SV, Diaz DRA, Viana LS, Melro LMG, de Alcantara Chaud MS, Figueiredo EL, Neuenschwander FC, Dracoulakis MDA, Lima RGSD, de Souza Dantas VC, Fernandes ACS, Gebara OCE, Hernandes ME, Queiroz DAR, Veiga VC, Canesin MF, de Faria LM, Feitosa-Filho GS, Gazzana MB, Liporace IL, de Oliveira Twardowsky A, Maia LN, Machado FR, de Matos Soeiro A, Conceicao-Souza GE, Armaganijan L, Guimaraes PO, Rosa RG, Azevedo LCP, Alexander JH, Avezum A, Cavalcanti AB, Berwanger O; ACTION Coalition COVID-19 Brazil IV Investigators. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021 Jun 12;397(10291):2253-2263. doi: 10.1016/S0140-6736(21)01203-4. Epub 2021 Jun 4.
Results Reference
derived
PubMed Identifier
33891907
Citation
Lopes RD, de Barros E Silva PGM, Furtado RHM, Macedo AVS, Ramacciotti E, Damini LP, Bronhara B, Cavalcanti AB, Rosa RG, Azevedo LCP, Veiga VC, Machado FR, Ritt LE, Martins PA, Alexander JH, Avezum A, Berwanger O; Coalition COVID-19 Brazil IV Investigators. Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial. Am Heart J. 2021 Aug;238:1-11. doi: 10.1016/j.ahj.2021.04.005. Epub 2021 Apr 20.
Results Reference
derived
PubMed Identifier
33502773
Citation
Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.
Results Reference
derived

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Full Anticoagulation Versus Prophylaxis in COVID-19: COALIZAO ACTION Trial

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