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.
Brief Title
Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)
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).
Categories
Completion Date
Completion Date Type
Actual
Conditions
COVID-19
Pneumonia
Eligibility 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, 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
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
Inclusion 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, 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.
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.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04372589
Org Class
Other
Org Full Name
University of Manitoba
Org Study Id
ATTACC
Overall Status
Completed
Phases
Phase 2
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)
Primary Outcomes
Outcome Description
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.
Outcome Measure
Mortality and days free of organ support
Outcome Time Frame
21 days
Secondary Ids
Secondary Id
OZM-113
Secondary Outcomes
Outcome Description
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).
Outcome Time Frame
28 days and 90 days
Outcome Measure
Arterial and venous thrombotic conditions
Outcome Description
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.
Outcome Time Frame
30 days
Outcome Measure
Intubation and mortality
Outcome Time Frame
28 days and 90 days
Outcome Measure
All-cause mortality
Outcome Description
Invasive mechanical ventilation.
Outcome Time Frame
30 days
Outcome Measure
Intubation
Outcome Description
Days alive outside of the hospital through 28 days following randomization.
Outcome Time Frame
28 days
Outcome Measure
Hospital-free days
Outcome Description
Days alive not on a ventilator assessed at 28 days following randomization.
Outcome Time Frame
28 days
Outcome Measure
Ventilator-free days
Outcome Time Frame
28 days and 90 days
Outcome Measure
Myocardial infarction
Outcome Time Frame
28 days and 90 days
Outcome Measure
Ischaemic stroke
Outcome Description
Symptomatic proximal venous thromboembolism (DVT or PE).
Outcome Time Frame
28 days and 90 days
Outcome Measure
Venous thromboembolism
Outcome Description
Days alive not on a vasopressor assessed at 28 days following randomization.
Outcome Time Frame
28 days
Outcome Measure
Vasopressor-free days
Outcome Description
Days alive not on renal replacement assessed at 28 days following randomization.
Outcome Time Frame
28 days
Outcome Measure
Renal replacement free days
Outcome Description
Hospital re-admission within 28 days.
Outcome Time Frame
28 days
Outcome Measure
Hospital re-admission
Outcome Description
As defined by KDIGO criteria.
Outcome Time Frame
Duration of study
Outcome Measure
Acute kidney injury
Outcome Time Frame
28 days and 90 days
Outcome Measure
Systemic arterial thrombosis or embolism
Outcome Description
Use of extracorporeal membrane oxygenation (ECMO) support.
Outcome Time Frame
Duration of study
Outcome Measure
ECMO support
Outcome Description
Dialysis or ECMO.
Outcome Time Frame
Duration of study
Outcome Measure
Mechanical circuit thrombosis
Outcome Description
Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days.
Outcome Time Frame
28 days
Outcome Measure
WHO ordinal scale
Outcome Description
As defined by the International Society on Thrombosis and Haemostasis (ISTH).
Outcome Time Frame
Intervention period (maximum 14 days)
Outcome Measure
Major bleeding
Outcome Description
Laboratory-confirmed.
Outcome Time Frame
Intervention period (maximum 14 days)
Outcome Measure
Heparin-induced thrombocytopenia (HIT)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Henny Billett
Investigator Email
hbillett@montefiore.org
Investigator Phone
718-920-6310