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

NCT04444700 | Completed Phase 3 DMC

• 1 other identifier: CAAE: 33109220.7.0000.0068
• Study Type: interventional
• Target: 465
• Locations: 1 country
• Sites: 1

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.

Conditions

COVID; Coronavirus Infection; Severe Acute Respiratory Syndrome; Thromboembolism, Venous; Anticoagulants and Bleeding Disorders

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• All-cause death

  Up to 28 days

• Composite outcome of ICU admission or all-cause death

  Up to 28 days

• Composite outcome of mechanical ventilation or all-cause death

  Up to 28 days

• Major bleeding

  Up to 28 days

• Red blood cell transfusion

  Up to 28 days

Study Arms (2)

Therapeutic anticoagulation

EXPERIMENTAL

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

Standard care

NO INTERVENTION

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

Interventions

Therapeutic anticoagulation DRUG

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.

Therapeutic anticoagulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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;
• 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

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• Unity Health Toronto: collaborator
• University of Vermont Medical Center: collaborator

Study Sites (1)

Hospital das Clínicas da FMUSP

São Paulo, São Paulo, 05402-000, Brazil

Location

Related Publications (1)

• 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 [Preprint]. 2021 Jul 12:2021.07.08.21259351. doi: 10.1101/2021.07.08.21259351.

  PMID: 34268513 DERIVED

MeSH Terms

Conditions

Coronavirus Infections; Severe Acute Respiratory Syndrome; Venous Thromboembolism; Hemostatic Disorders

Condition Hierarchy (Ancestors)

Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 22, 2020
• First Posted: June 23, 2020
• Study Start: July 4, 2020
• Primary Completion: May 10, 2021
• Study Completion: October 14, 2021
• Last Updated: October 26, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)