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

Utilização da Enoxaparina em Dose Anticoagulante em Pacientes Hospitalizados Com síndrome respiratória Aguda Grave Por COVID-19

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.

Study Overview

• Status: Completed
• Conditions: Severe Acute Respiratory Syndrome; Coronavirus Infection; COVID; Anticoagulants and Bleeding Disorders; Thromboembolism, Venous
• Intervention / Treatment: Drug: Therapeutic anticoagulation

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:

1. All-cause death
2. Composite outcome of ICU admission or all-cause death
3. Composite outcome of mechanical ventilation or all-cause death
4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
5. Number of participants who received red blood cell transfusion (≥1 unit)
6. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
7. Renal replacement therapy;
8. Number of hospital-free days alive
9. Number of ICU-free days alive
10. Number of ventilator-free days alive
11. Number of organ support-free days alive
12. Number of participants with venous thromboembolism
13. Number of participants with arterial thromboembolism
14. Number of participants with heparin induced thrombocytopenia
15. 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.

• Study Type: Interventional
• Enrollment (Actual): 465
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • SP
    • São Paulo, SP, Brazil, 05402-000
      • Hospital das Clinicas da FMUSP

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Therapeutic anticoagulation; 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.	Drug: Therapeutic anticoagulation; 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.
NO_INTERVENTION: Standard care; Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	up to 28 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Collaborators: Unity Health Toronto; University of Vermont Medical Center
• Investigators: Principal Investigator: Peter Juni, MD, FESC, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto; Principal Investigator: Elnara M Negri, MD, PhD, Laboratório de Investigação Médica da FMUSP; Principal Investigator: Heraldo P de Souza, MD, PhD, Disciplina de Emergências Clínicas, Hospital das Clínicas da FMUSP; Principal Investigator: Hassan Rahhal, MD, Disciplina de Emergências Clínicas, Hospital das Clínicas da FMUSP

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 4, 2020
• Primary Completion (ACTUAL): May 10, 2021
• Study Completion (ACTUAL): October 14, 2021

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (ACTUAL): June 23, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 26, 2021
• Last Update Submitted That Met QC Criteria: October 25, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Hematologic Diseases; Hemorrhagic Disorders; Embolism and Thrombosis; Severe Acute Respiratory Syndrome; Coronavirus Infections; Hemostatic Disorders; Blood Coagulation Disorders; Thromboembolism; Venous Thromboembolism
• Other Study ID Numbers: CAAE: 33109220.7.0000.0068

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
• product manufactured in and exported from the U.S.: No