COVID-19, Pneumonia
Conditions
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).
Interventions
DRUGHeparin
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.
Sponsors
University Health Network, Toronto
University of Manitoba
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Pragmatic, Bayesian adaptive randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality and days free of organ support | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intubation and mortality | 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 | 28 days and 90 days | — |
| Intubation | 30 days | Invasive mechanical ventilation. |
| Hospital-free days | 28 days | Days alive outside of the hospital through 28 days following randomization. |
| Ventilator-free days | 28 days | Days alive not on a ventilator assessed at 28 days following randomization. |
| Myocardial infarction | 28 days and 90 days | — |
| Ischaemic stroke | 28 days and 90 days | — |
| Venous thromboembolism | 28 days and 90 days | Symptomatic proximal venous thromboembolism (DVT or PE). |
| Vasopressor-free days | 28 days | Days alive not on a vasopressor assessed at 28 days following randomization. |
| Arterial and venous thrombotic conditions | 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). |
| Hospital re-admission | 28 days | Hospital re-admission within 28 days. |
| Acute kidney injury | Duration of study | As defined by KDIGO criteria. |
| Systemic arterial thrombosis or embolism | 28 days and 90 days | — |
| ECMO support | Duration of study | Use of extracorporeal membrane oxygenation (ECMO) support. |
| Mechanical circuit thrombosis | Duration of study | Dialysis or ECMO. |
| WHO ordinal scale | 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 | Intervention period (maximum 14 days) | As defined by the International Society on Thrombosis and Haemostasis (ISTH). |
| Heparin-induced thrombocytopenia (HIT) | Intervention period (maximum 14 days) | Laboratory-confirmed. |
| Renal replacement free days | 28 days | Days alive not on renal replacement assessed at 28 days following randomization. |
Countries
Brazil, Canada, Mexico, United States
Outcome results
None listed