Clinical trial NCT04372589: Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)
Official title: Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Pneumonia
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: University Health Network, Toronto
First posted: 2020-05-04
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pragmatic, Bayesian adaptive randomized controlled trial
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Mortality and days free of organ support
timeFrame: 21 days
Secondary outcomes:
measure: Arterial and venous thrombotic conditions
timeFrame: 28 days and 90 days
measure: Intubation and mortality
timeFrame: 30 days
measure: All-cause mortality
timeFrame: 28 days and 90 days
measure: Intubation
timeFrame: 30 days
measure: Hospital-free days
timeFrame: 28 days
measure: Ventilator-free days
timeFrame: 28 days
measure: Myocardial infarction
timeFrame: 28 days and 90 days
measure: Ischaemic stroke
timeFrame: 28 days and 90 days
measure: Venous thromboembolism
timeFrame: 28 days and 90 days
measure: Vasopressor-free days
timeFrame: 28 days
measure: Renal replacement free days
timeFrame: 28 days
measure: Hospital re-admission
timeFrame: 28 days
measure: Acute kidney injury
timeFrame: Duration of study
measure: Systemic arterial thrombosis or embolism
timeFrame: 28 days and 90 days
measure: ECMO support
timeFrame: Duration of study
measure: Mechanical circuit thrombosis
timeFrame: Duration of study
measure: WHO ordinal scale
timeFrame: 28 days
measure: Major bleeding
timeFrame: Intervention period (maximum 14 days)
measure: Heparin-induced thrombocytopenia (HIT)
timeFrame: Intervention period (maximum 14 days)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Jefferson
country: United States
facility: Ochsner Clinic
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Dearborn
country: United States
facility: Henry Ford University
state: Michigan
city: Royal Oak
country: United States
facility: Beaumont Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center
state: Missouri
city: Camden
country: United States
facility: Cooper University Health Care
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: New York
country: United States
facility: Montefiore-Einstein Center for Heart and Vascular Care
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Itabuna
country: Brazil
facility: Santa Casa de Misericordia de Itabuna
state: BA
city: Juazeiro do Norte
country: Brazil
facility: Hospital Unimed do Cariri
state: CE
city: Goiania
country: Brazil
facility: Instituto Goiano de Oncologia e Hematologia - INGOH
state: Goias
city: Campo Grande
country: Brazil
facility: Centro de Pesquisas Clínicas Humap - UFMS
state: Mato Grosso Do Sul
city: Belo Horizonte
country: Brazil
facility: Hospital Felício Rocho
state: MG
city: Campo Grande
country: Brazil
facility: Clinica de Campo Grande S/A
state: MS
city: Campo Grande
country: Brazil
facility: Unimed Campo Grande
state: MS
city: Recife
country: Brazil
facility: Hospital Agamenon Magalhaes
state: Pernanbuco
city: Curitiba
country: Brazil
facility: Hospital das Clinicas da UFPR
state: PR
city: Curitiba
country: Brazil
facility: Pontifícia Universidade Católica do Paraná
state: PR
city: Maringa
country: Brazil
facility: Parana Medical Research Center
state: PR
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Pedro Ernesto
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: RS
city: Porto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
state: RS
city: Porto Alegre
country: Brazil
facility: Instituto de Medicina Vascular
state: RS
city: Blumenau
country: Brazil
facility: AngioCor Blumenau
state: Santa Catarina
city: Sao Jose
country: Brazil
facility: Instituto de Cardiologia de Santa Catarina
state: Santa Catarina
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clínica de Campinas
state: Sao Paulo
city: Santo Andre
country: Brazil
facility: Praxis Pesquisa Medica
state: Sao Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Votuporanga
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Casa de Saúde Santa Marcelina
state: SP
city: Tatui
country: Brazil
facility: Instituto de Molestias Cardio Vasculares de Tatui
state: SP
city: São Paulo
country: Brazil
facility: Hospital 9 de Julho
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo
city: São Paulo
country: Brazil
facility: Instituto de Infectologia Emilio Ribas
city: São Paulo
country: Brazil
facility: Instituto do Coração do Estado de São Paulo
city: São Paulo
country: Brazil
facility: Sociedade Beneficente Israelita Hospital Albert Einstein
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Health Sciences Center Winnipeg
state: Manitoba
city: Winnipeg
country: Canada
facility: Grace General Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Ottawa
country: Canada
facility: Hôpital Montfort
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier de l'université de Montréal (CHUM)
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Québec
country: Canada
facility: CHU de Quebec-University Laval
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ)
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
city: Azcapotzalco
country: Mexico
facility: Hospital de Infectolog´ñia Centro Médico Nacional La Raza
state: Mexico City
city: Benito Juárez
country: Mexico
facility: Hospital General Regional 1 Carlos MacGregor Sánchez Navarro
state: Mexico City
city: Querétaro
country: Mexico
facility: Hospital General regional 2 El Marqués
Study officials:
affiliation: Peter Munk Cardiac Centre/University Health Network
name: Patrick R. Lawler, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Ewan C. Goligher, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Ryan Zarychanski, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Dzavik V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.
citation: ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Dzavik V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, Garcia-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Perez Gonzalez YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4.
citation: Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.
citation: Houston BL, Lawler PR, Goligher EC, Farkouh ME, Bradbury C, Carrier M, Dzavik V, Fergusson DA, Fowler RA, Galanaud JP, Gross PL, McDonald EG, Husain M, Kahn SR, Kumar A, Marshall J, Murthy S, Slutsky AS, Turgeon AF, Berry SM, Rosenson RS, Escobedo J, Nicolau JC, Bond L, Kirwan BA, de Brouwer S, Zarychanski R. Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial. Clin Trials. 2020 Oct;17(5):491-500. doi: 10.1177/1740774520943846. Epub 2020 Aug 20.
citation: Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020 Jun;7(6):e438-e440. doi: 10.1016/S2352-3026(20)30145-9. Epub 2020 May 11. No abstract available.