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

Phase 2

Completed

• Conditions: COVID-19; Pneumonia
• Interventions: Drug: Heparin

• Registration Number: NCT04372589
• Lead Sponsor: 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. 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 Timeline

• Study First Submitted: 2020-04-24
• Study First Submitted QC: 2020-04-30
• Study First Posted: 2020-05-04
• Study Start: 2020-05-20
• Status Verified: 2021-01
• Primary Completion: 2021-05-17
• Study Completion: 2021-05-17
• Last Update Submitted: 2021-07-26
• Last Update Posted: 2021-07-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1200

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Investigational arm	Heparin	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Ischaemic stroke	28 days and 90 days
Myocardial infarction	28 days and 90 days
Ventilator-free days	28 days	Days alive not on a ventilator 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).
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.
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.
Heparin-induced thrombocytopenia (HIT)	Intervention period (maximum 14 days)	Laboratory-confirmed.
Hospital re-admission	28 days	Hospital re-admission within 28 days.
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).
Renal replacement free days	28 days	Days alive not on renal replacement assessed at 28 days following randomization.
Acute kidney injury	Duration of study	As defined by KDIGO criteria.

Trial Locations

Locations (60)

Saint Barnabas Medical Center; 🇺🇸 Livingston, New Jersey, United States

AngioCor Blumenau; 🇧🇷 Blumenau, Santa Catarina, Brazil

Centro de Pesquisas Clínicas Humap - UFMS; 🇧🇷 Campo Grande, Mato Grosso Do Sul, Brazil

Instituto de Cardiologia de Santa Catarina; 🇧🇷 Sao Jose, Santa Catarina, Brazil

Hospital General regional 2 El Marqués; 🇲🇽 Querétaro, Mexico

Hospital de Infectolog´ñia Centro Médico Nacional La Raza; 🇲🇽 Azcapotzalco, Mexico City, Mexico

University of Chicago; 🇺🇸 Chicago, Illinois, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Emory University Hospital Midtown; 🇺🇸 Atlanta, Georgia, United States

Ochsner Clinic; 🇺🇸 Jefferson, Louisiana, United States

Maine Medical Center; 🇺🇸 Portland, Maine, United States

Clinica de Campo Grande S/A; 🇧🇷 Campo Grande, MS, Brazil

Cooper University Health Care; 🇺🇸 Camden, New Jersey, United States

Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center; 🇺🇸 Saint Louis, Missouri, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Montefiore-Einstein Center for Heart and Vascular Care; 🇺🇸 New York, New York, United States

Santa Casa de Misericordia de Itabuna; 🇧🇷 Itabuna, BA, Brazil

Hospital Unimed do Cariri; 🇧🇷 Juazeiro do Norte, CE, Brazil

Instituto Goiano de Oncologia e Hematologia - INGOH; 🇧🇷 Goiania, Goias, Brazil

Unimed Campo Grande; 🇧🇷 Campo Grande, MS, Brazil

Hospital Felício Rocho; 🇧🇷 Belo Horizonte, MG, Brazil

Parana Medical Research Center; 🇧🇷 Maringa, PR, Brazil

Hospital das Clinicas da UFPR; 🇧🇷 Curitiba, PR, Brazil

Hospital Agamenon Magalhaes; 🇧🇷 Recife, Pernanbuco, Brazil

Pontifícia Universidade Católica do Paraná; 🇧🇷 Curitiba, PR, Brazil

Hospital Sao Vicente de Paulo; 🇧🇷 Passo Fundo, Rio Grande Do Sul, Brazil

Hospital Universitario Pedro Ernesto; 🇧🇷 Rio de Janeiro, RJ, Brazil

Instituto de Cardiologia do Rio Grande do Sul; 🇧🇷 Porto Alegre, RS, Brazil

Santa Casa de Votuporanga; 🇧🇷 Votuporanga, Sao Paulo, Brazil

Instituto de Medicina Vascular; 🇧🇷 Porto Alegre, RS, Brazil

Instituto de Pesquisa Clínica de Campinas; 🇧🇷 Campinas, Sao Paulo, Brazil

Instituto de Infectologia Emilio Ribas; 🇧🇷 São Paulo, Brazil

Victoria General Hospital; 🇨🇦 Victoria, British Columbia, Canada

Praxis Pesquisa Medica; 🇧🇷 Santo Andre, Sao Paulo, Brazil

Casa de Saúde Santa Marcelina; 🇧🇷 Sao Paulo, SP, Brazil

Instituto de Molestias Cardio Vasculares de Tatui; 🇧🇷 Tatui, SP, Brazil

Instituto do Coração do Estado de São Paulo; 🇧🇷 São Paulo, Brazil

Hospital 9 de Julho; 🇧🇷 São Paulo, Brazil

Health Sciences Center Winnipeg; 🇨🇦 Winnipeg, Manitoba, Canada

Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo; 🇧🇷 São Paulo, Brazil

Grace General Hospital; 🇨🇦 Winnipeg, Manitoba, Canada

Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

St. Boniface General Hospital; 🇨🇦 Winnipeg, Manitoba, Canada

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Hôpital Montfort; 🇨🇦 Ottawa, Ontario, Canada

University Health Network; 🇨🇦 Toronto, Ontario, Canada

Centre Hospitalier de l'université de Montréal (CHUM); 🇨🇦 Montréal, Quebec, Canada

CHU de Quebec-University Laval; 🇨🇦 Québec, Quebec, Canada

Centre Hospitalier Universitaire de Sherbrooke; 🇨🇦 Sherbrooke, Quebec, Canada

Regina General Hospital; 🇨🇦 Regina, Saskatchewan, Canada

Hospital General Regional 1 Carlos MacGregor Sánchez Navarro; 🇲🇽 Benito Juárez, Mexico City, Mexico

Beaumont Hospital; 🇺🇸 Royal Oak, Michigan, United States

Hospital de Clinicas de Porto Alegre; 🇧🇷 Porto Alegre, RS, Brazil

Sociedade Beneficente Israelita Hospital Albert Einstein; 🇧🇷 São Paulo, Brazil

Henry Ford University; 🇺🇸 Dearborn, Michigan, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

McGill University Health Centre; 🇨🇦 Montréal, Quebec, Canada

Jewish General Hospital; 🇨🇦 Montréal, Quebec, Canada

Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ); 🇨🇦 Québec, Quebec, Canada

St. Joseph's Healthcare Hamilton; 🇨🇦 Hamilton, Ontario, Canada