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

COVID Clinical Trial

— RAPID-BRAZIL  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04444700
• Other study ID #: CAAE: 33109220.7.0000.0068
• Status: Completed
• Phase: Phase 3
• Start date: July 4, 2020
• Est. completion date: October 14, 2021

Study information

• Verified date: October 2021
• Source: University of Sao Paulo General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 465
• Est. completion date: October 14, 2021
• Est. primary completion date: May 10, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anticoagulants and Bleeding Disorders
• Blood Coagulation Disorders
• Coronavirus Infection
• Coronavirus Infections
• COVID
• Hemostatic Disorders
• Severe Acute Respiratory Syndrome
• Thromboembolism
• Thromboembolism, Venous
• Venous Thromboembolism

Intervention

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.

Locations

Country	Name	City	State
Brazil	Hospital das Clínicas da FMUSP	São Paulo	SP

Sponsors (3)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital	Unity Health Toronto, University of Vermont Medical Center

Country where clinical trial is conducted

Brazil, 

Outcome

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