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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04372589
Other study ID # ATTACC
Secondary ID OZM-113
Status Completed
Phase Phase 2/Phase 3
First received
Last updated
Start date May 20, 2020
Est. completion date May 17, 2021

Study information

Verified date January 2021
Source University of Manitoba
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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).


Recruitment information / eligibility

Status Completed
Enrollment 1200
Est. completion date May 17, 2021
Est. primary completion date May 17, 2021
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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


Related Conditions & MeSH terms


Intervention

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.

Locations

Country Name City State
Brazil Hospital Felício Rocho Belo Horizonte MG
Brazil AngioCor Blumenau Blumenau Santa Catarina
Brazil Instituto de Pesquisa Clínica de Campinas Campinas Sao Paulo
Brazil Centro de Pesquisas Clínicas Humap - UFMS Campo Grande Mato Grosso Do Sul
Brazil Clinica de Campo Grande S/A Campo Grande MS
Brazil Unimed Campo Grande Campo Grande MS
Brazil Hospital das Clinicas da UFPR Curitiba PR
Brazil Pontifícia Universidade Católica do Paraná Curitiba PR
Brazil Instituto Goiano de Oncologia e Hematologia - INGOH Goiania Goias
Brazil Santa Casa de Misericordia de Itabuna Itabuna BA
Brazil Hospital Unimed do Cariri Juazeiro do Norte CE
Brazil Parana Medical Research Center Maringa PR
Brazil Hospital Sao Vicente de Paulo Passo Fundo Rio Grande Do Sul
Brazil Hospital de Clinicas de Porto Alegre Porto Alegre RS
Brazil Instituto de Cardiologia do Rio Grande do Sul Porto Alegre RS
Brazil Instituto de Medicina Vascular Porto Alegre RS
Brazil Hospital Agamenon Magalhaes Recife Pernanbuco
Brazil Hospital Universitario Pedro Ernesto Rio de Janeiro RJ
Brazil Praxis Pesquisa Medica Santo Andre Sao Paulo
Brazil Instituto de Cardiologia de Santa Catarina Sao Jose Santa Catarina
Brazil Casa de Saúde Santa Marcelina Sao Paulo SP
Brazil Hospital 9 de Julho São Paulo
Brazil Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo São Paulo
Brazil Instituto de Infectologia Emilio Ribas São Paulo
Brazil Instituto do Coração do Estado de São Paulo São Paulo
Brazil Sociedade Beneficente Israelita Hospital Albert Einstein São Paulo
Brazil Instituto de Molestias Cardio Vasculares de Tatui Tatui SP
Brazil Santa Casa de Votuporanga Votuporanga Sao Paulo
Canada Hamilton Health Sciences Hamilton Ontario
Canada St. Joseph's Healthcare Hamilton Hamilton Ontario
Canada Centre Hospitalier de l'université de Montréal (CHUM) Montréal Quebec
Canada Jewish General Hospital Montréal Quebec
Canada McGill University Health Centre Montréal Quebec
Canada Hôpital Montfort Ottawa Ontario
Canada The Ottawa Hospital Ottawa Ontario
Canada CHU de Quebec-University Laval Québec Quebec
Canada Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ) Québec Quebec
Canada Regina General Hospital Regina Saskatchewan
Canada Centre Hospitalier Universitaire de Sherbrooke Sherbrooke Quebec
Canada University Health Network Toronto Ontario
Canada Victoria General Hospital Victoria British Columbia
Canada Grace General Hospital Winnipeg Manitoba
Canada Health Sciences Center Winnipeg Winnipeg Manitoba
Canada St. Boniface General Hospital Winnipeg Manitoba
Mexico Hospital de Infectolog´ñia Centro Médico Nacional La Raza Azcapotzalco Mexico City
Mexico Hospital General Regional 1 Carlos MacGregor Sánchez Navarro Benito Juárez Mexico City
Mexico Hospital General regional 2 El Marqués Querétaro
United States Emory University Hospital Midtown Atlanta Georgia
United States Cooper University Health Care Camden New Jersey
United States University of Chicago Chicago Illinois
United States Henry Ford University Dearborn Michigan
United States Hackensack University Medical Center Hackensack New Jersey
United States Ochsner Clinic Jefferson Louisiana
United States Saint Barnabas Medical Center Livingston New Jersey
United States Vanderbilt University Medical Center Nashville Tennessee
United States Montefiore-Einstein Center for Heart and Vascular Care New York New York
United States Maine Medical Center Portland Maine
United States Mayo Clinic Rochester Minnesota
United States Beaumont Hospital Royal Oak Michigan
United States Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center Saint Louis Missouri

Sponsors (2)

Lead Sponsor Collaborator
University of Manitoba University Health Network, Toronto

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Mexico, 

Outcome

Type Measure Description Time frame Safety issue
Primary Mortality and days free of organ support 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. 21 days
Secondary Arterial and venous thrombotic conditions 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). 28 days and 90 days
Secondary Intubation and mortality 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. 30 days
Secondary All-cause mortality 28 days and 90 days
Secondary Intubation Invasive mechanical ventilation. 30 days
Secondary Hospital-free days Days alive outside of the hospital through 28 days following randomization. 28 days
Secondary Ventilator-free days Days alive not on a ventilator assessed at 28 days following randomization. 28 days
Secondary Myocardial infarction 28 days and 90 days
Secondary Ischaemic stroke 28 days and 90 days
Secondary Venous thromboembolism Symptomatic proximal venous thromboembolism (DVT or PE). 28 days and 90 days
Secondary Vasopressor-free days Days alive not on a vasopressor assessed at 28 days following randomization. 28 days
Secondary Renal replacement free days Days alive not on renal replacement assessed at 28 days following randomization. 28 days
Secondary Hospital re-admission Hospital re-admission within 28 days. 28 days
Secondary Acute kidney injury As defined by KDIGO criteria. Duration of study
Secondary Systemic arterial thrombosis or embolism 28 days and 90 days
Secondary ECMO support Use of extracorporeal membrane oxygenation (ECMO) support. Duration of study
Secondary Mechanical circuit thrombosis Dialysis or ECMO. Duration of study
Secondary WHO ordinal scale Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days. 28 days
Secondary Major bleeding As defined by the International Society on Thrombosis and Haemostasis (ISTH). Intervention period (maximum 14 days)
Secondary Heparin-induced thrombocytopenia (HIT) Laboratory-confirmed. Intervention period (maximum 14 days)
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