Vanderbilt Clinical Trials

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

Purpose

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.

Conditions

COVID-19
Pneumonia

Eligibility

Eligible Ages: Over 18 Years
Eligible Genders: All
Accepts Healthy Volunteers: No

Inclusion Criteria

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

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

Study Design

Phase: Phase 2/Phase 3
Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Pragmatic, Bayesian adaptive randomized controlled trial
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
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.

More Details

Status: Completed
Sponsor: University of Manitoba

Study Contact

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).

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.