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

COVID-19 Clinical Trial

— ATTACC  

Official title:

Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)

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
• 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
• 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

Related Conditions & MeSH terms

• COVID-19
• Pneumonia

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)