Coagulopathy of COVID-19: A Pragmatic Randomized Controll... | NCT04362085

NCT04362085

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
University of Vermont Medical Center	OTHER
University of Sao Paulo	OTHER
Hopital Charles Lemoyne	OTHER
William Osler Health System

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days.	Composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.	Up to 28 days

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

Eligibility Module

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

Name	Affiliation	Role
Michelle Sholzberg, MD, FRCPC	Unity Health Toronto	Principal Investigator
Peter Jüni, MD, FESC	Unity Health Toronto	Principal Investigator
Mary Cushman, MD	University of Vermont Medical Center, Vermont	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
St. Michael's Hospital		Toronto	Ontario		Canada

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
35244208	Derived	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: a rapid review. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
34649864	Derived	Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Ainle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci LA, 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. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021 Oct 14;375:n2400. doi: 10.1136/bmj.n2400.

Arm/Group Information

ID	Title	Description
FG000	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. 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.
FG001	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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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. 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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days.

Composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.

Posted

Count of Participants

Participants

Up to 28 days

ID	Title	Description
OG000	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. 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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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. 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.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Hospitalization	General disorders		Systematic Assessment	Hospitalization

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Laboratory confirmed SARS-CoV-2 infection	Respiratory, thoracic and mediastinal disorders		Systematic Assessment

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 30, 2020	Aug 20, 2024	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	May 6, 2021	Aug 20, 2024	SAP_001.pdf

ID	Term
D011024	Pneumonia, Viral
D011014	Pneumonia
D012141	Respiratory Tract Infections
D007239	Infections

ID	Term
D000086382	COVID-19
D020141	Hemostatic Disorders