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

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ClinicalTrials.gov Identifier: NCT04372589
Recruitment Status : Active, not recruiting
First Posted : May 4, 2020
Last Update Posted : February 1, 2021
Sponsor:
Collaborator:
University Health Network, Toronto
Information provided by (Responsible Party):
University of Manitoba

Tracking Information
First Submitted Date  ICMJE April 24, 2020
First Posted Date  ICMJE May 4, 2020
Last Update Posted Date February 1, 2021
Actual Study Start Date  ICMJE May 20, 2020
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 18, 2020)
Mortality and days free of organ support [ Time Frame: 21 days ]
The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1.
Original Primary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
  • Intubation [ Time Frame: 30 days ]
    Any need for invasive mechanical ventilation or mechanical ventilation 30 days following randomization
  • Mortality [ Time Frame: 30 days ]
    Any deaths that occur 30 days following randomization
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2020)
  • Arterial and venous thrombotic conditions [ Time Frame: 28 days and 90 days ]
    A composite endpoint of death, deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke collected during hospitalization or at 28 days and 90 days after enrollment (whichever is earlier).
  • Intubation and mortality [ Time Frame: 30 days ]
    Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization: no invasive mechanical ventilation, invasive mechanical ventilation, or death.
  • All-cause mortality [ Time Frame: 28 days and 90 days ]
  • Intubation [ Time Frame: 30 days ]
    Invasive mechanical ventilation.
  • Hospital-free days [ Time Frame: 28 days ]
    Days alive outside of the hospital through 28 days following randomization.
  • Ventilator-free days [ Time Frame: 28 days ]
    Days alive not on a ventilator assessed at 28 days following randomization.
  • Myocardial infarction [ Time Frame: 28 days and 90 days ]
  • Ischaemic stroke [ Time Frame: 28 days and 90 days ]
  • Venous thromboembolism [ Time Frame: 28 days and 90 days ]
    Symptomatic proximal venous thromboembolism (DVT or PE).
  • Vasopressor-free days [ Time Frame: 28 days ]
    Days alive not on a vasopressor assessed at 28 days following randomization.
  • Renal replacement free days [ Time Frame: 28 days ]
    Days alive not on renal replacement assessed at 28 days following randomization.
  • Hospital re-admission [ Time Frame: 28 days ]
    Hospital re-admission within 28 days.
  • Acute kidney injury [ Time Frame: Duration of study ]
    As defined by KDIGO criteria.
  • Systemic arterial thrombosis or embolism [ Time Frame: 28 days and 90 days ]
  • ECMO support [ Time Frame: Duration of study ]
    Use of extracorporeal membrane oxygenation (ECMO) support.
  • Mechanical circuit thrombosis [ Time Frame: Duration of study ]
    Dialysis or ECMO.
  • WHO ordinal scale [ Time Frame: 28 days ]
    Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days.
  • Major bleeding [ Time Frame: Intervention period (maximum 14 days) ]
    As defined by the International Society on Thrombosis and Haemostasis (ISTH).
  • Heparin-induced thrombocytopenia (HIT) [ Time Frame: Intervention period (maximum 14 days) ]
    Laboratory-confirmed.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
  • Hospital admission [ Time Frame: 30 days ]
    Days alive without staying overnight at a hospital 30 days post randomization
  • Thrombocytopenia [ Time Frame: 30 days ]
    Any thrombocytopenia attributed to Heparin within 30 days following randomization
  • Bleeding [ Time Frame: 30 days ]
    If patient experiences bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome 30 days after randomization
  • Falls [ Time Frame: 30 days ]
    Number of falls due to hemoglobin level of ≥20 g/L within 30 days after randomization
  • Transfusion [ Time Frame: 30 days ]
    Transfusion of 2 or more more units of whole blood or red cells due to hemoglobin level of ≥20 g/L within 30 days following randomization
  • ICU admission [ Time Frame: 30 days ]
    Whether patient was admitted to the ICU within 30 days following randomization
  • Use of a ventilator [ Time Frame: 30 days ]
    Number of days alive without the use of a ventilator 30 days following randomization.
  • Type of ventilator used [ Time Frame: 30 days ]
    Whether or not patient needed non-invasive mechanical ventilation or high flow nasal cannula 30 days following randomization
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)
Official Title  ICMJE Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)
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. 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.
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Pragmatic, Bayesian adaptive randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • COVID-19
  • Pneumonia
Intervention  ICMJE 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.

Study Arms  ICMJE
  • 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.
    Intervention: Drug: Heparin
  • No Intervention: Control arm
    Participants will receive usual care of thromboprophylactic dose anticoagulation according to local practice.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 28, 2021)
1203
Original Estimated Enrollment  ICMJE
 (submitted: April 30, 2020)
3000
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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, for microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation

• If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening oxygen requirements or acute kidney injury) which is further anticipated to extend the hospital admission by an additional 72 hours from randomization.

Exclusion Criteria:

  1. Patients admitted to an ICU AND receiving organ support (i.e. high flow nasal oxygen, receiving non-invasive or invasive mechanical ventilation, or are requiring vasopressor/inotrope)
  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 (if available per SOC testing)
  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. Anticipated transfer to another hospital that is not a study site within 72 hours
  13. Enrollment in other trials related to anticoagulation or antiplatelet therapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Canada,   Mexico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04372589
Other Study ID Numbers  ICMJE ATTACC
OZM-113 ( Other Identifier: Ozmosis Research Inc )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Manitoba
Study Sponsor  ICMJE University of Manitoba
Collaborators  ICMJE University Health Network, Toronto
Investigators  ICMJE
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
PRS Account University of Manitoba
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP