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Antithrombotic Therapy to Ameliorate Complications of COVID-19 ( ATTACC )

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04372589
Recruitment Status : Recruiting
First Posted : May 4, 2020
Last Update Posted : June 4, 2020
Sponsor:
Collaborator:
University Health Network, Toronto
Information provided by (Responsible Party):
University of Manitoba

Brief Summary:
Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19 not initially requiring invasive mechanical ventilation. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.

Condition or disease Intervention/treatment Phase
COVID-19 Pneumonia Drug: Heparin Phase 2 Phase 3

Detailed Description:
This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants will be randomized either to the investigational arm (therapeutic anticoagulation with heparin for 14 days or until "recovery" [defined as hospital discharge or liberation from supplemental oxygen if initially required], whichever comes first), or to the control arm (usual care, including thromboprophylactic dose anticoagulation according to local practice).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Pragmatic, Bayesian adaptive randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Antithrombotic Therapy to Ameliorate Complications of COVID-19
Actual Study Start Date : May 20, 2020
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Experimental: Investigational arm
Participants randomized to the investigational arm will receive therapeutic anticoagulation for 14 days (or until hospital discharge or liberation from supplemental oxygen >24 hours if previously required, whichever comes first) with heparin, with preference for subcutaneous low molecular weight heparin (enoxaparin preferred, although dalteparin or tinzaparin are also acceptable, as available) if no contraindication is present; alternatively, intravenous unfractionated heparin infusion may be used.
Drug: Heparin

Low molecular weight heparin (LMWH) Preferred therapeutic anticoagulant is enoxaparin. Generally regimens: 1.5 mg/kg subcutaneous once daily or 1 mg/kg subcutaneous twice daily. Alternatively, other subcutaneous LMWH used, including tinzaparin (175 anti-Xa IU/kg subcutaneous once daily) or dalteparin (200 IU/kg subcutaneous once daily or 100 IU/kg subcutaneous twice a day).

Unfractionated heparin (UFH) Commenced, administered, and monitored according to local hospital policy, and guidelines that are used for the treatment of venous thromboembolism (i.e. not for acute coronary syndrome). Intravenous infusion of UFH is according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x the reference value. If UFH is used, the availability of a local hospital policy that has specifies an aPTT target in this range or an anti-Xa value is a requirement.


No Intervention: Control arm
Participants will receive usual care of thromboprophylactic dose anticoagulation according to local practice.



Primary Outcome Measures :
  1. Intubation and mortality [ Time Frame: 30 days ]
    The primary endpoint is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation, or death.


Secondary Outcome Measures :
  1. All-cause mortality [ Time Frame: 30 days and 90 days ]
  2. Intubation [ Time Frame: 30 days ]
    Invasive mechanical ventilation

  3. Hospital-free days [ Time Frame: 30 days ]
    Days alive outside of the hospital through 30 days following randomization

  4. ICU-free days [ Time Frame: 30 days ]
    Number of days alive outside of the ICU through 30 days following randomization

  5. Ventilator-free days [ Time Frame: 30 days ]
    Number of days alive without the use of a ventilator through 30 days following randomization.

  6. Non-invasive ventilation [ Time Frame: 30 days ]
    The use of non-invasive mechanical ventilation or high flow nasal cannula

  7. Organ support-free [ Time Frame: 21 days ]
    Number of days alive without the use of vasopressors/inotropes and ventilation (including high flow nasal cannula >30 L/min and FIO2 >40%) through 21 days following randomization, ranked with death at anytime during 21 days as -1

  8. Myocardial infarction [ Time Frame: 30 days and 90 days ]
  9. Ischaemic stroke [ Time Frame: 30 days and 90 days ]
  10. Venous thromboembolism [ Time Frame: 30 days and 90 days ]
  11. Major bleeding [ Time Frame: Intervention period (maximum 14 days) ]
    As defined by the International Society on Thrombosis and Haemostasis (ISTH)

  12. Heparin-induced thrombocytopenia (HIT) [ Time Frame: Intervention period (maximum 14 days) ]
    Laboratory-confirmed



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Patients ≥18 years of age providing (possibly through a substitute decision maker) informed consent who require hospitalization anticipated to last ≥72 hours, with microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation

Exclusion Criteria:

  1. Receiving invasive mechanical ventilation
  2. Patients for whom the intent is to not use pharmacologic thromboprophylaxis
  3. Active bleeding
  4. Risk factors for bleeding, including:

    1. intracranial surgery or stroke within 3 months;
    2. history of intracerebral arteriovenous malformation;
    3. cerebral aneurysm or mass lesions of the central nervous system;
    4. intracranial malignancy
    5. history of intracranial bleeding
    6. history of bleeding diatheses (e.g., hemophilia)
    7. history of gastrointestinal bleeding within previous 3 months
    8. thrombolysis within the previous 7 days
    9. presence of an epidural or spinal catheter
    10. recent major surgery <14 days
    11. uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)
    12. other physician-perceived contraindications to anticoagulation
  5. Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50
  6. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)
  7. Acute or subacute bacterial endocarditis
  8. History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
  9. Current use of dual antiplatelet therapy
  10. Patients with an independent indication for therapeutic anticoagulation
  11. Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention
  12. Pregnancy
  13. Anticipated transfer to another hospital that is not a study site within 72 hours
  14. Enrollment in other trials related to anticoagulation or antiplatelet therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04372589


Contacts
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Contact: Ryan Zarychanski, MD, MSc 204-787-2993 rzarychanski@cancercare.mb.ca
Contact: Patrick R. Lawler, MD, MPH 416-340-3155 patrick.lawler@uhn.ca

Locations
Show Show 26 study locations
Sponsors and Collaborators
University of Manitoba
University Health Network, Toronto
Investigators
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Principal Investigator: Patrick R. Lawler, MD, MPH Peter Munk Cardiac Centre/University Health Network
Principal Investigator: Ewan C. Goligher, MD, PhD University Health Network, Toronto
Principal Investigator: Ryan Zarychanski, MD, MSc University of Manitoba
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Manitoba
ClinicalTrials.gov Identifier: NCT04372589    
Other Study ID Numbers: ATTACC
OZM-113 ( Other Identifier: Ozmosis Research Inc )
First Posted: May 4, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action