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A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to (SARS-CoV-2) COVID-19 Pandemic (RAPID-BRAZIL)

Primary Purpose

COVID, Coronavirus Infection, Severe Acute Respiratory Syndrome

Status
Completed
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Therapeutic anticoagulation
Sponsored by
University of Sao Paulo General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID

Eligibility Criteria

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

The inclusion criteria are:

  1. laboratory confirmed diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification.Positive test prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission;
  2. admitted to hospital for COVID-19;
  3. one D-dimer value above ULN (5 days (i.e. 120 hours) of hospital admission) and either: a) D-Dimer ≥2 times ULN; or b) D-dimer above ULN and oxygen saturation ≤ 93% on room air;
  4. ≥18 years of age;
  5. informed consent from the patient (or legally authorized substitute decision maker).

The exclusion criteria are:

  1. pregnancy;
  2. hemoglobin <80 g/L in the last 72 hours;
  3. platelet count <50 x 10^9/L in the last 72 hours;
  4. known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  5. known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
  6. patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration);
  7. patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban);
  8. patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely;
  9. known bleeding within the last 30 days requiring emergency room presentation or hospitalization;
  10. known history of a bleeding disorder of an inherited or active acquired bleeding disorder;
  11. known history of heparin-induced thrombocytopenia;
  12. known allergy to UFH or LMWH;
  13. admitted to the intensive care unit at the time of screening;
  14. treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion).
  15. imminent death according to the judgement of the most responsible physician
  16. enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients

Sites / Locations

  • Hospital das Clínicas da FMUSP

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Therapeutic anticoagulation

Standard care

Arm Description

Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement.

Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.

Outcomes

Primary Outcome Measures

Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.
Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.

Secondary Outcome Measures

All-cause death
All-cause death
Composite outcome of ICU admission or all-cause death
Composite outcome of ICU admission or all-cause death
Composite outcome of mechanical ventilation or all-cause death
Composite outcome of mechanical ventilation or all-cause death
Major bleeding
Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
Red blood cell transfusion
Red Blood Cell transfusion (greater than or equal to 1 unit)
Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Renal replacement therapy
Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis
Hospital-free days alive up to day 28
Hospital-free days alive up to day 28
ICU-free days alive up to day 28
ICU-free days alive up to day 28
Ventilator-free days alive up to day 28
Ventilator-free days alive up to day 28
Organ support-free days alive up to day 28
Organ support-free days alive up to day 28
Venous thromboembolism
Venous thromboembolism
Arterial thromboembolism
Arterial thromboembolism
Heparin induced thrombocytopenia
Heparin induced thrombocytopenia
Changes in D-dimer up to day 3
D-dimer

Full Information

First Posted
June 22, 2020
Last Updated
October 25, 2021
Sponsor
University of Sao Paulo General Hospital
Collaborators
Unity Health Toronto, University of Vermont Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04444700
Brief Title
A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to (SARS-CoV-2) COVID-19 Pandemic
Acronym
RAPID-BRAZIL
Official Title
Utilização da Enoxaparina em Dose Anticoagulante em Pacientes Hospitalizados Com síndrome respiratória Aguda Grave Por COVID-19
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
July 4, 2020 (Actual)
Primary Completion Date
May 10, 2021 (Actual)
Study Completion Date
October 14, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Sao Paulo General Hospital
Collaborators
Unity Health Toronto, University of Vermont Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic multi-centre open-label randomized controlled trial to determine the effect of therapeutic anticoagulation compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer.
Detailed Description
2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation, with low molecular weight heparin or unfractionated heparin (high dose nomogram), compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Eligible participants will be randomized to one of two treatment regimens, receiving either therapeutic anticoagulation or standard care until discharged from hospital, death or day 28. The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days. Key secondary outcomes between study arms up to day 28 include: All-cause death Composite outcome of ICU admission or all-cause death Composite outcome of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation Number of participants who received red blood cell transfusion (≥1 unit) Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate Renal replacement therapy; Number of hospital-free days alive Number of ICU-free days alive Number of ventilator-free days alive Number of organ support-free days alive Number of participants with venous thromboembolism Number of participants with arterial thromboembolism Number of participants with heparin induced thrombocytopenia Changes in D-dimer up to day 3 The treatment arm is therapeutic anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin, or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to the center-specific protocol. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. The standard care arm is the administration of LMWH, UFH or fondaparinux at thromboprophylactic doses in the absence of contraindication. No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through standard of care) up to and including day 3 after randomization for all participants in both study arms. In those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance. All laboratory results will be collected from standard of care from admission to hospital discharge, death or 28 days, where available. An optional biobanking component will collect blood at baseline and 2 follow up time points. This study will immediately impact the clinical care of patients with severe COVID-19 internationally, whether the findings are positive or negative, as COVID-19 coagulopathy is a highly prevalent complication of severe COVID-19 and may precede the respiratory manifestations that characterize it.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID, Coronavirus Infection, Severe Acute Respiratory Syndrome, Thromboembolism, Venous, Anticoagulants and Bleeding Disorders

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This study is a 2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation on the composite outcome of ICU admission, mechanical ventilation and/or death in hospitalized patients with COVID-19.
Masking
None (Open Label)
Masking Description
None (Open Label) Blinding of participants, clinical research staff, and clinicians is not possible due to the nature of the intervention. However, the biostatisticians will be blinded at the data analysis phase.
Allocation
Randomized
Enrollment
465 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Therapeutic anticoagulation
Arm Type
Experimental
Arm Description
Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement.
Arm Title
Standard care
Arm Type
No Intervention
Arm Description
Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.
Intervention Type
Drug
Intervention Name(s)
Therapeutic anticoagulation
Intervention Description
The choice of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.
Primary Outcome Measure Information:
Title
Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.
Description
Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.
Time Frame
up to 28 days
Secondary Outcome Measure Information:
Title
All-cause death
Description
All-cause death
Time Frame
Up to 28 days
Title
Composite outcome of ICU admission or all-cause death
Description
Composite outcome of ICU admission or all-cause death
Time Frame
Up to 28 days
Title
Composite outcome of mechanical ventilation or all-cause death
Description
Composite outcome of mechanical ventilation or all-cause death
Time Frame
Up to 28 days
Title
Major bleeding
Description
Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
Time Frame
Up to 28 days
Title
Red blood cell transfusion
Description
Red Blood Cell transfusion (greater than or equal to 1 unit)
Time Frame
Up to 28 days
Title
Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Description
Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Time Frame
Up to 28 days
Title
Renal replacement therapy
Description
Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis
Time Frame
Up to 28 days
Title
Hospital-free days alive up to day 28
Description
Hospital-free days alive up to day 28
Time Frame
Up to 28 days
Title
ICU-free days alive up to day 28
Description
ICU-free days alive up to day 28
Time Frame
Up to 28 days
Title
Ventilator-free days alive up to day 28
Description
Ventilator-free days alive up to day 28
Time Frame
Up to 28 days
Title
Organ support-free days alive up to day 28
Description
Organ support-free days alive up to day 28
Time Frame
Up to 28 days
Title
Venous thromboembolism
Description
Venous thromboembolism
Time Frame
Up to 28 days
Title
Arterial thromboembolism
Description
Arterial thromboembolism
Time Frame
Up to 28 days
Title
Heparin induced thrombocytopenia
Description
Heparin induced thrombocytopenia
Time Frame
Up to 28 days
Title
Changes in D-dimer up to day 3
Description
D-dimer
Time Frame
Up to day 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
The inclusion criteria are: laboratory confirmed diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification.Positive test prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; admitted to hospital for COVID-19; one D-dimer value above ULN (5 days (i.e. 120 hours) of hospital admission) and either: a) D-Dimer ≥2 times ULN; or b) D-dimer above ULN and oxygen saturation ≤ 93% on room air; ≥18 years of age; informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin <80 g/L in the last 72 hours; platelet count <50 x 10^9/L in the last 72 hours; known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban); patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion). imminent death according to the judgement of the most responsible physician enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Juni, MD, FESC
Organizational Affiliation
St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Elnara M Negri, MD, PhD
Organizational Affiliation
Laboratório de Investigação Médica da FMUSP
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Heraldo P de Souza, MD, PhD
Organizational Affiliation
Disciplina de Emergências Clínicas, Hospital das Clínicas da FMUSP
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hassan Rahhal, MD
Organizational Affiliation
Disciplina de Emergências Clínicas, Hospital das Clínicas da FMUSP
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital das Clínicas da FMUSP
City
São Paulo
State/Province
SP
ZIP/Postal Code
05402-000
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34268513
Citation
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Ni Ainle F, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci L, James PD, Lillicrap D, Carrier M, Beckett A, Colovos C, Jayakar J, Arsenault MP, Wu C, Doyon K, Andreou ER, Dounaevskaia V, Tseng EK, Lim G, Fralick M, Middeldorp S, Lee AYY, Zuo F, da Costa BR, Thorpe KE, Negri EM, Cushman M, Juni P; RAPID Trial investigators. Heparin for Moderately Ill Patients with Covid-19. medRxiv. 2021 Jul 12:2021.07.08.21259351. doi: 10.1101/2021.07.08.21259351. Preprint.
Results Reference
derived

Learn more about this trial

A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to (SARS-CoV-2) COVID-19 Pandemic

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