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

NCT04372589 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: ATTACCOZM-113
• Study Type: interventional
• Target: 1,200
• Locations: 4 countries
• Sites: 60

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.

Conditions

COVID-19; Pneumonia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• Arterial and venous thrombotic conditions

  28 days and 90 days

• Intubation and mortality

  30 days

• All-cause mortality

  28 days and 90 days

• Intubation

  30 days

• Hospital-free days

  28 days

Study Arms (2)

Investigational arm

EXPERIMENTAL

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

Control arm

NO INTERVENTION

Participants will receive usual care of thromboprophylactic dose anticoagulation according to local practice.

Interventions

Heparin DRUG

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.

Investigational arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.

You may not qualify if:

• 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)
• Patients for whom the intent is to not use pharmacologic thromboprophylaxis
• Active bleeding
• Risk factors for bleeding, including:
• intracranial surgery or stroke within 3 months;
• history of intracerebral arteriovenous malformation;
• cerebral aneurysm or mass lesions of the central nervous system;
• intracranial malignancy
• history of intracranial bleeding
• history of bleeding diatheses (e.g., hemophilia)
• history of gastrointestinal bleeding within previous 3 months
• thrombolysis within the previous 7 days
• presence of an epidural or spinal catheter
• recent major surgery \<14 days
• uncontrolled hypertension (sBP \>200 mmHg, dBP \>120 mmHg)

Sponsors & Collaborators

• University of Manitoba: lead
• University Health Network, Toronto: collaborator

Study Sites (60)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Ochsner Clinic

Jefferson, Louisiana, 70121, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

Henry Ford University

Dearborn, Michigan, 48128, United States

Location

Beaumont Hospital

Royal Oak, Michigan, 48336, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center

St Louis, Missouri, 63104, United States

Location

Cooper University Health Care

Camden, New Jersey, 08103, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Saint Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Montefiore-Einstein Center for Heart and Vascular Care

New York, New York, 10467, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Hospital Unimed do Cariri

Juazeiro do Norte, Ceará, Brazil

Location

Santa Casa de Misericordia de Itabuna

Itabuna, Estado de Bahia, Brazil

Location

Instituto Goiano de Oncologia e Hematologia - INGOH

Goiânia, Goiás, Brazil

Location

Centro de Pesquisas Clínicas Humap - UFMS

Campo Grande, Mato Grosso do Sul, Brazil

Location

Clinica de Campo Grande S/A

Campo Grande, Mato Grosso do Sul, Brazil

Location

Unimed Campo Grande

Campo Grande, Mato Grosso do Sul, Brazil

Location

Hospital Felício Rocho

Belo Horizonte, Minas Gerais, Brazil

Location

Hospital das Clinicas da UFPR

Curitiba, Paraná, Brazil

Location

Pontifícia Universidade Católica do Paraná

Curitiba, Paraná, Brazil

Location

Parana Medical Research Center

Maringá, Paraná, Brazil

Location

Hospital Agamenon Magalhaes

Recife, Pernanbuco, Brazil

Location

Hospital Universitario Pedro Ernesto

Rio de Janeiro, Rio de Janeiro, Brazil

Location

Hospital Sao Vicente de Paulo

Passo Fundo, Rio Grande do Sul, Brazil

Location

Hospital de Clinicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Location

Instituto de Cardiologia do Rio Grande do Sul

Porto Alegre, Rio Grande do Sul, Brazil

Location

Instituto de Medicina Vascular

Porto Alegre, Rio Grande do Sul, Brazil

Location

AngioCor Blumenau

Blumenau, Santa Catarina, Brazil

Location

Instituto de Cardiologia de Santa Catarina

São José, Santa Catarina, Brazil

Location

Instituto de Pesquisa Clínica de Campinas

Campinas, São Paulo, Brazil

Location

Praxis Pesquisa Medica

Santo André, São Paulo, Brazil

Location

Casa de Saúde Santa Marcelina

São Paulo, São Paulo, Brazil

Location

Instituto de Molestias Cardio Vasculares de Tatui

Tatuí, São Paulo, Brazil

Location

Santa Casa de Votuporanga

Votuporanga, São Paulo, Brazil

Location

Hospital 9 de Julho

São Paulo, Brazil

Location

Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, Brazil

Location

Instituto de Infectologia Emilio Ribas

São Paulo, Brazil

Location

Instituto do Coração do Estado de São Paulo

São Paulo, Brazil

Location

Sociedade Beneficente Israelita Hospital Albert Einstein

São Paulo, Brazil

Location

Victoria General Hospital

Victoria, British Columbia, Canada

Location

Health Sciences Center Winnipeg

Winnipeg, Manitoba, R3A 1R9, Canada

Location

Grace General Hospital

Winnipeg, Manitoba, Canada

Location

St. Boniface General Hospital

Winnipeg, Manitoba, Canada

Location

Hamilton Health Sciences

Hamilton, Ontario, Canada

Location

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Location

Hôpital Montfort

Ottawa, Ontario, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, Canada

Location

University Health Network

Toronto, Ontario, M5G2C4, Canada

Location

McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

Location

Centre Hospitalier de l'université de Montréal (CHUM)

Montreal, Quebec, Canada

Location

Jewish General Hospital

Montreal, Quebec, Canada

Location

CHU de Quebec-University Laval

Québec, Quebec, Canada

Location

Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ)

Québec, Quebec, Canada

Location

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, Canada

Location

Regina General Hospital

Regina, Saskatchewan, Canada

Location

Hospital de Infectolog´ñia Centro Médico Nacional La Raza

Azcapotzalco, Mexico City, Mexico

Location

Hospital General Regional 1 Carlos MacGregor Sánchez Navarro

Benito Juárez, Mexico City, Mexico

Location

Hospital General regional 2 El Marqués

Querétaro, Mexico

Location

Related Publications (7)

• Wahid L, Froess JD, Ortel TL, Zarychanski R, Berger JS, Cushman M, Angus DC, Renard V, Farahani P, Webb S, Heath A, Godoy LC, Farkouh ME, Hochman JS, Neal MD, Lawler PR. On-Treatment Change in d-Dimer Is Associated With Differential Outcomes Among Therapeutic Dose Heparin-Treated Noncritically Ill Patients Hospitalized for COVID-19. Arterioscler Thromb Vasc Biol. 2025 Jan;45(1):162-164. doi: 10.1161/ATVBAHA.124.321108. Epub 2024 Dec 5.

  PMID: 39633573 DERIVED

• Goligher EC, Lawler PR, Jensen TP, Talisa V, Berry LR, Lorenzi E, McVerry BJ, Chang CH, Leifer E, Bradbury C, Berger J, Hunt BJ, Castellucci LA, Kornblith LZ, Gordon AC, McArthur C, Webb S, Hochman J, Neal MD, Zarychanski R, Berry S, Angus DC; REMAP-CAP, ATTACC, and ACTIV-4a Investigators. Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19. JAMA. 2023 Apr 4;329(13):1066-1077. doi: 10.1001/jama.2023.3651.

  PMID: 36942550 DERIVED

• 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.

  PMID: 34351722 DERIVED

• 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.

  PMID: 34351721 DERIVED

• 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.

  PMID: 33502773 DERIVED

• 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.

  PMID: 32815416 DERIVED

• 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.

  PMID: 32407672 DERIVED

MeSH Terms

Conditions

COVID-19; Pneumonia

Interventions

Heparin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Patrick R. Lawler, MD, MPH

  Peter Munk Cardiac Centre/University Health Network

  PRINCIPAL INVESTIGATOR

• Ewan C. Goligher, MD, PhD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

• Ryan Zarychanski, MD, MSc

  University of Manitoba

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Pragmatic, Bayesian adaptive randomized controlled trial

Study Record Dates

• First Submitted: April 24, 2020
• First Posted: May 4, 2020
• Study Start: May 20, 2020
• Primary Completion: May 17, 2021
• Study Completion: May 17, 2021
• Last Updated: July 27, 2021

Record last verified: 2021-01

Locations

CA (16); US (13); BR (28); ME (3)